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Respiratory virus-induced heterologous immunity
Abstract
Purpose
To provide current knowledge on respiratory virus-induced heterologous immunity (HI) with a focus on humoral and cellular cross-reactivity. Adaptive heterologous immune responses have broad implications on infection, autoimmunity, allergy and transplant immunology. A better understanding of the mechanisms involved might ultimately open up possibilities for disease prevention, for example by vaccination.
Methods
A structured literature search was performed using Medline and PubMed to provide an overview of the current knowledge on respiratory-virus induced adaptive HI.
Results
In HI the immune response towards one antigen results in an alteration of the immune response towards a second antigen. We provide an overview of respiratory virus-induced HI, including viruses such as respiratory syncytial virus (RSV), rhinovirus (RV), coronavirus (CoV) and influenza virus (IV). We discuss T cell receptor (TCR) and humoral cross-reactivity as mechanisms of HI involving those respiratory viruses. Topics covered include HI between respiratory viruses as well as between respiratory viruses and other pathogens. Newly developed vaccines which have the potential to provide protection against multiple virus strains are also discussed. Furthermore, respiratory viruses have been implicated in the development of autoimmune diseases, such as narcolepsy, Guillain–Barré syndrome, type 1 diabetes or myocarditis. Finally, we discuss the role of respiratory viruses in asthma and the hygiene hypothesis, and review our recent findings on HI between IV and allergens, which leads to protection from experimental asthma.
Conclusion
Respiratory-virus induced HI may have protective but also detrimental effects on the host. Respiratory viral infections contribute to asthma or autoimmune disease development, but on the other hand, a lack of microbial encounter is associated with an increasing number of allergic as well as autoimmune diseases. Future research might help identify the elements which determine a protective or detrimental outcome in HI-based mechanisms.
... Environmental factors are also important in the development of atopic diseases and T1DM [6]. The "Hygiene Hypothesis" is a theory suggesting that reduced or delayed exposure to infections at early ages may increase the risk of the onset of autoimmune disorders (atopic diseases or T1DM) [20]. Several studies have shown an increased incidence of asthma and other atopic diseases in the general population, particularly in patients with T1DM [21][22][23][24][25]. ...
... Protective effects of bacteria (Listeria monocytogenes, Propionibacterium acnes, Chlamydia, Lactococcus species) or bacterial products on asthma development have been well documented [20,36]. Viruses also seemed to have a protective role against asthma in murine models [37]. ...
... Viruses also seemed to have a protective role against asthma in murine models [37]. Bacterial infections protect against asthma development by stimulating innate immune receptors, such as Toll-like receptors (TLR), and inducing Th1 responses [20]. Viral infections exert their action against asthma development by induction of a natural killer (NK) cell subset or monocytes with a regulatory phenotype [20,37]. ...
Asthma and type 1 diabetes mellitus (T1DM) are two of the most frequent chronic diseases in children, representing a model of the atopic and autoimmune diseases respectively. These two groups of disorders are mediated by different immunological pathways, T helper (Th)1 for diabetes and Th2 for asthma. For many years, these two groups were thought to be mutually exclusive according to the Th1/Th2 paradigm. In children, the incidence of both diseases is steadily increasing worldwide. In this narrative review, we report the evidence of the potential link between asthma and T1DM in childhood. We discuss which molecular mechanisms could be involved in the link between asthma and T1DM, such as genetic predisposition, cytokine patterns, and environmental influences. Cytokine profile of children with asthma and T1DM shows an activation of both Th1 and Th2 pathways, suggesting a complex genetic-epigenetic interaction. In conclusion, in children, the potential link between asthma and T1DM needs further investigation to improve the diagnostic and therapeutic approach to these patients. The aim of this review is to invite the pediatricians to consider the potential copresence of these two disorders in clinical practice.
... 5,[8][9][10] GBS is a heterogeneous condition with several variant forms: the most common presentation is the progressively ascending tetraparesis (acute inflammatory demyelinating polyneuropathy), but other localized clinical variants are also recognized. About 60% of the above-mentioned autoimmune syndromes can be infection-related by humoral and cellular cross-reactivity, 11,12 most frequently gastrointestinal (Campylobacter jejuni) or respiratory tract infections, including flu syndrome and pneumonia. 13,14 In COVID-19, a trigger for autoimmune reactions could be the release of a large amount of pro-inflammatory cytokines in an event known as "cytokine storm." ...
This case series describes three patients affected by SARS‐CoV‐2 who developed polyradiculoneuritis as a probable neurological complication of COVID‐19. A diagnosis of Guillain Barré syndrome was made on the basis of clinical symptoms, cerebrospinal fluid analysis and electroneurography (ENG). In all of them therapeutic approach included the administration of intravenous immunoglobulin (0.4 gr/kg for 5 days), which resulted in the improvement of neurological symptoms. Clinical neurophysiology revealed the presence of conduction block, absence of F waves, and in two cases significant decrease in amplitude of compound motor action potential cMAP. Due to the potential role of inflammation on symptoms development and prognosis, interleukin‐6 (IL‐6) and ‐8 (IL‐8) levels were measured in serum and cerebrospinal fluid during the acute phase, while only serum was tested after recovery. Both IL‐6 and IL‐8 were found increased during the acute phase, both in serum and cerebrospinal fluid, whereas four months after admission (at complete recovery), only IL‐8 remained elevated in serum. These results confirm the inflammatory response that might be linked to peripheral nervous system complications, and encourage the use of IL‐6 and IL‐8 as prognostic biomarkers in COVID‐19.
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... No studies have described differences in insulin level or insulin resistance to establish a direct link between the coronavirus infection and hyperglycemia. Viral infections are known to cause type 1 diabetes by triggering the production of cross-reactive antibodies as a result of molecular mimicry or by activating cross-reactive T cells99 . Although this is well-known with enterovirus, influenza virus, cytomegalovirus, rotavirus and coxsackie virus ...
SARS-CoV-2 virus has spread across the globe rapidly causing an unprecedented pandemic. Due to the novelty of the disease, the possible impact on endocrine system is not clear. In order to compile a mini-review describing possible endocrine consequences of SARS-CoV-2 infection we performed a literature survey using the key words Covid-19, Coronavirus, SARS CoV-1, SARS Cov-2, Endocrine and related terms in medical databases including PubMed, Google Scholar, and MedARXiv from year 2000. Additional references were identified through manual screening of bibliographies and via citations in the selected articles. The literature review is current until April 28, 2020. In light of the literature, we discuss SARS-CoV-2 and explore the endocrine consequences based on the experience with structurally-similar SARS-CoV-1. Studies from the SARS -CoV-1 epidemic have reported variable changes in the endocrine organs. SARS-CoV-2 attaches to the ACE2 system in the pancreas causing perturbation of insulin production resulting in hyperglycemic emergencies. In patients with pre-existing endocrine disorders who develop COVID-19, several factors warrant management decisions. Hydrocortisone dose-adjustments are required in patients with adrenal insufficiency. Identification and management of Critical Illness Related Corticosteroid Insufficiency is crucial. Patients with Cushing’s syndrome may have poorer outcomes due to the associated immunodeficiency and coagulopathy. Vitamin D deficiency appears to be associated with increased susceptibility or severity to SARS-CoV-2 infection, and replacement may improve outcomes. Robust strategies required for the optimal management of endocrinopathies in COVID-19 are discussed extensively in this mini-review.
... Miller Fisher syndrome (MFS), a variant of Guillain-Barré syndrome (GBS), is characterized by the clinical triad of ophthalmoplegia, ataxia, and areflexia. About 60% of the above mentioned autoimmune syndromes can be infection-related by humoral and cellular cross-reactivity (Pusch et al. 2018), most frequently gastrointestinal (Campylobacter jejuni) or respiratory tract infections, including influenza (Sellers et al. 2017). ...
This case report describes the clinical characteristics of a 50-year-old woman that developed SARS-CoV-2 pneumonia and was admitted at the COVID-19 dedicated unit where she developed neurological symptoms 10 days after admission. After neurological examination, including a panel of blood cerebrospinal fluid biomarkers, a diagnosis of Miller Fisher syndrome (MFS) was hypothesized and intravenous immunoglobulin therapy (IVIG) was initiated. Fourteen days after the start of IVIG treatment, the patient has been discharged at home with the resolution of respiratory symptoms and only minor hyporeflexia at the lower limbs, without any side effect.
Temperature and humidity are studied in the context of seasonal infections in temperate and tropical zones, but the relationship between viral trends and climate variables in temperate subtropical zones remains underexplored. Our retrospective study analyzes respiratory pathogen incidence and its correlation with climate data in a subtropical zone. Retrospective observational study at Moinhos de Vento Hospital, South Brazil, aiming to assess seasonal trends in respiratory pathogens, correlating them with climate data. The study included patients of all ages from various healthcare settings, with data collected between April 2022 and July 2023. Biological samples were analyzed for 24 pathogens using polymerase chain reaction and hybridization techniques; demographic variables were also collected. The data was analyzed descriptively and graphically. Spearman tests and Poisson regression were used as correlation tests. Tests were clustered according to all pathogens, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), influenza viruses, rhinovirus, and respiratory syncytial virus (RSV). Between April 2022 and July 2023, 3329 tests showed a 71.6% positivity rate. Rhinovirus and RSV predominated, exhibiting seasonal patterns. Temperature was inversely correlated with the viruses, notably rhinovirus, but SARS‐CoV‐2 was positively correlated. Air humidity was positively correlated with all pathogens, RSV, rhinovirus, and atmospheric pressure with all pathogens and rhinovirus. Our results showed statistically significant correlations, with modest effect sizes. Our study did not evaluate causation effects. Despite the correlation between climate and respiratory pathogens, our work suggests additional factors influencing transmission dynamics. Our findings underscore the complex interplay between climate and respiratory infections in subtropical climates.
Zusammenfassung
Hintergrund Die chronische Rhinosinusitis mit Nasenpolypen (CRSwNP) ist eine multifaktorielle entzündliche Erkrankung der paranasalen Schleimhäute, der als häufigstem Endotyp eine eosinophile Inflammation zugrunde liegt. Der Anti-IL-5-Antikörper Mepolizumab wurde im November 2021 für die Therapie der schweren CRSwNP zugelassen.
Methoden In einer Literatursuche wurde die Immunologie der CRSwNP analysiert und die vorhandene Evidenz ermittelt durch Recherchen in Medline, PubMed sowie den nationalen und internationalen Studien- und Leitlinien-Registern und der Cochrane Library. Es wurden Humanstudien berücksichtigt, die bis einschließlich 12/2021 publiziert wurden und in denen die Wirkung von Mepolizumab bei CRSwNP untersucht wurde.
Ergebnis Basierend auf der internationalen Literatur und bisherigen Erfahrungen werden von einem Expertengremium Empfehlungen für die Anwendung von Mepolizumab bei CRSwNP im deutschen Gesundheitssystem auf der Grundlage eines Dokumentationsbogens gegeben.
Schlussfolgerungen Das Verständnis über die immunologischen Grundlagen der CRSwNP eröffnet neue nichtoperative Therapieansätze mit Biologika für Patienten mit schweren Verlaufsformen. Mepolizumab ist seit November 2021 zugelassen zur Zusatztherapie mit intranasalen Kortikosteroiden zur Behandlung von erwachsenen Patienten mit schwerer CRSwNP, die mit systemischen Kortikosteroiden und/oder chirurgischem Eingriff nicht ausreichend kontrolliert werden können.
Background:
The epithelial immune regulation is an essential and protective feature of the barrier function of the mucous membranes of the airways. Damage to the epithelial barrier can result in chronic inflammatory diseases, such as chronic rhinosinusitis (CRS) or bronchial asthma. Thymic stromal lymphopoietin (TSLP) is a central regulator in the epithelial barrier function and is associated with type 2 (T2) and non-T2 inflammation.
Materials and methods:
The immunology of chronic rhinosinusitis with polyposis nasi (CRSwNP) was analyzed in a literature search, and the existing evidence was determined through searches in Medline, Pubmed as well as the national and international study and guideline registers and the Cochrane Library. Human studies or studies on human cells that were published between 2010 and 2020 and in which the immune mechanisms of TSLP in T2 and non-T2 inflammation were examined were considered.
Results:
TSLP is an epithelial cytokine (alarmin) and a central regulator of the immune reaction, especially in the case of chronic airway inflammation. Induction of TSLP is implicated in the pathogenesis of many diseases like CRS and triggers a cascade of subsequent inflammatory reactions.
Conclusion:
Treatment with TSLP-blocking monoclonal antibodies could therefore open up interesting therapeutic options. The long-term safety and effectiveness of TSLP blockade has yet to be investigated.
We report a case series of 5 patients affected by SARS‐CoV‐2 who developed neurological symptoms, mainly expressing as polyradiculoneuritis and cranial polyneuritis in the two months of COVID‐19 pandemic in a city in the north east of Italy. A diagnosis of Guillain Barré syndrome was made on the basis of clinical presentation, cerebrospinal fluid analysis and electroneurography (ENG). In four of them therapeutic approach included the administration of intravenous immunoglobulin (0.4 gr/kg for 5 days), which resulted in the improvement of neurological symptoms. Clinical neurophysiology revealed the presence of conduction block, absence of F waves, and in two cases significant decrease in amplitude of compound motor action potential cMAP. Four patients presented a mild facial nerve involvement limited to the muscles of the lower face, with sparing of the forehead muscles associated to ageusia. In one patient, taste assessment showed right‐sided ageusia of the tongue, ipsilateral to the mild facial palsy. In three patients we observed albuminocytological dissociation in the cerebrospinal fluid, and notably we found an increase of inflammatory mediators such as the interleukin‐8. Peripheral nervous system involvement after infection with COVID‐19 is possible and may include several signs that may be successfully treated with immunoglobulin therapy.
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Einen systematischen Überblick über die heterologe Immunität, die durch respiratorische Viren induziert wird, haben sich Forscher der Universität Marburg verschafft. Ihre Bilanz fällt gemischt aus.
Fifty years after the discovery of Epstein-Barr virus (EBV), it remains unclear how primary infection with this virus leads to massive CD8 T-cell expansion and acute infectious mononucleosis (AIM) in young adults. AIM can vary greatly in severity, from a mild transient influenza-like illness to a prolonged severe syndrome. We questioned whether expansion of a unique HLA-A2.01-restricted, cross-reactive CD8 T-cell response between influenza virus A-M158 (IAV-M1) and EBV BMLF1280 (EBV-BM) could modulate the immune response to EBV and play a role in determining the severity of AIM in 32 college students. Only ex vivo total IAV-M1 and IAV-M1+EBV-BM cross-reactive tetramer⁺ frequencies directly correlated with AIM severity and were predictive of severe disease. Expansion of specific cross-reactive memory IAV-M1 T-cell receptor (TCR) Vβ repertoires correlated with levels of disease severity. There were unique profiles of qualitatively different functional responses in the cross-reactive and EBV-specific CD8 T-cell responses in each of the three groups studied, severe-AIM patients, mild-AIM patients, and seropositive persistently EBV-infected healthy donors, that may result from differences in TCR repertoire use. IAV-M1 tetramer⁺ cells were functionally cross-reactive in short-term cultures, were associated with the highest disease severity in AIM, and displayed enhanced production of gamma interferon, a cytokine that greatly amplifies immune responses, thus frequently contributing to induction of immunopathology. Altogether, these data link heterologous immunity via CD8 T-cell cross-reactivity to CD8 T-cell repertoire selection, function, and resultant disease severity in a common and important human infection. In particular, it highlights for the first time a direct link between the TCR repertoire with pathogenesis and the diversity of outcomes upon pathogen encounter.
The hygiene hypothesis postulates that the recent increase in allergic diseases such as asthma and hay fever observed in Western countries is linked to reduced exposure to childhood infections. Here we investigated how infection with a gammaherpesvirus affected the subsequent development of allergic asthma. We found that murid herpesvirus 4 (MuHV-4) inhibited the development of house dust mite (HDM)-induced experimental asthma by modulating lung innate immune cells. Specifically, infection with MuHV-4 caused the replacement of resident alveolar macrophages (AMs) by monocytes with regulatory functions. Monocyte-derived AMs blocked the ability of dendritic cells to trigger a HDM-specific response by the TH2 subset of helper T cells. Our results indicate that replacement of embryonic AMs by regulatory monocytes is a major mechanism underlying the long-term training of lung immunity after infection.
Primary Sjögren’s syndrome (pSS) is an autoimmune disease characterized by inflammation in exocrine glands, resulting in reduced secretion of tears and saliva, manifesting as xerophthalmia and xerostomia, respectively. It is commonly associated with Sjögren’s syndrome type A (Ro) and Sjögren’s syndrome type B (La) antigens. However, in most patients, the identity of the triggering antigen is not known. Factors such as genetics of histocompatibility, dysregulation of T-cells, B-cells and viral infections have been implicated. Several important studies on autoantigens in pSS have been published since a review in 2012, and the aim of this review is to provide an update on further peer-reviewed original articles in this field. Oxidative damage of Ro60 antigen may explain the epitope spreading during the immune activation in pSS. Immune-mediated destruction of the muscarinic receptor-3-expressing cells has been associated with a reduction in parasympathetic function, which could cause reduced secretory function of exocrine glands. Such a process also activates reactive oxidative species and antioxidants, which are linked to the triggering of inflammatory responses. Elevated levels of kallikrein, yet another antigen present in the lacrimal gland and other tissues, are similarly involved in triggering an autoimmune T-cell response against target glands. Studying additional antigens, the platelet-selectin and vasoactive intestinal peptides, in patients with pSS can help to elucidate the origin and process of autoimmunity, or even lead to potential biomarkers. In conclusion, the understanding of autoantigens has led to exciting major advances in the biology of pSS and may influence diagnosis and management of pSS in future.
Objective:
To assess the prognostic value of MOG antibodies (abs) in the differential diagnosis of acquired demyelinating syndromes (ADS).
Methods:
Clinical course, MRI, MOG-abs, AQP4-abs, and CSF cells and oligoclonal bands (OCB) in children with ADS and 24 months of follow-up were reviewed in this observational prospective multicenter hospital-based study.
Results:
Two hundred ten children with ADS were included and diagnosed with acute disseminated encephalomyelitis (ADEM) (n = 60), neuromyelitis optica spectrum disorder (NMOSD) (n = 12), clinically isolated syndrome (CIS) (n = 101), and multiple sclerosis (MS) (n = 37) after the first episode. MOG-abs were predominantly found in ADEM (57%) and less frequently in NMOSD (25%), CIS (25%), or MS (8%). Increased MOG-ab titers were associated with younger age (p = 0.0001), diagnosis of ADEM (p = 0.005), increased CSF cell counts (p = 0.011), and negative OCB (p = 0.012). At 24-month follow-up, 96 children had no further relapses. Thirty-five children developed recurrent non-MS episodes (63% MOG-, 17% AQP4-abs at onset). Seventy-nine children developed MS (4% MOG-abs at onset). Recurrent non-MS episodes were associated with high MOG-ab titers (p = 0.0003) and older age at onset (p = 0.024). MS was predicted by MS-like MRI (p < 0.0001) and OCB (p = 0.007). An MOG-ab cutoff titer ≥1:1,280 predicted a non-MS course with a sensitivity of 47% and a specificity of 100% and a recurrent non-MS course with a sensitivity of 46% and a specificity of 86%.
Conclusions:
Our results show that the presence of MOG-abs strongly depends on the age at disease onset and that high MOG-ab titers were associated with a recurrent non-MS disease course.
The links between microorganisms/viruses and autoimmunity are complex and multidirectional. A huge number of studies demonstrated the triggering impact of microbes and viruses as the major environmental factors on the autoimmune and inflammatory diseases. However, growing evidences suggest that infectious agents can also play a protective role or even abrogate these processes. This protective crosstalk between microbes/viruses and us might represent a mutual beneficial equilibrium relationship between two cohabiting ecosystems. The protective pathways might involve post-translational modification of proteins, decreased intestinal permeability, Th1 to Th2 immune shift, induction of apoptosis, auto-aggressive cells relocation from the target organ, immunosuppressive extracellular vesicles and down regulation of auto-reactive cells by the microbial derived proteins. Our analysis demonstrates that the interaction of the microorganisms/viruses and celiac disease (CD) is always a set of multidirectional processes. A deeper inquiry into the CD interplay with Herpes viruses and Helicobacter pylori demonstrates that the role of these infections, suggested to be potential CD protectors, is not as controversial as for the other infectious agents. The outcome of these interactions might be due to a balance between these multidirectional processes.
Aims/hypothesis:
Respiratory infections and onset of islet autoimmunity are reported to correlate positively in two small prospective studies. The Environmental Determinants of Diabetes in the Young (TEDDY) study is the largest prospective international cohort study on the environmental determinants of type 1 diabetes that regularly monitors both clinical infections and islet autoantibodies. The aim was to confirm the influence of reported respiratory infections and to further characterise the temporal relationship with autoantibody seroconversion.
Methods:
During the years 2004-2009, 8676 newborn babies with HLA genotypes conferring an increased risk of type 1 diabetes were enrolled at 3 months of age to participate in a 15 year follow-up. In the present study, the association between parent-reported respiratory infections and islet autoantibodies at 3 month intervals up to 4 years of age was evaluated in 7869 children. Time-dependent proportional hazard models were used to assess how the timing of respiratory infections related to persistent confirmed islet autoimmunity, defined as autoantibody positivity against insulin, GAD and/or insulinoma antigen-2, concordant at two reference laboratories on two or more consecutive visits.
Results:
In total, 87,327 parent-reported respiratory infectious episodes were recorded while the children were under study surveillance for islet autoimmunity, and 454 children seroconverted. The number of respiratory infections occurring in a 9 month period was associated with the subsequent risk of autoimmunity (p < 0.001). For each 1/year rate increase in infections, the hazard of islet autoimmunity increased by 5.6% (95% CI 2.5%, 8.8%). The risk association was linked primarily to infections occurring in the winter (HR 1.42 [95% CI 1.16, 1.74]; p < 0.001). The types of respiratory infection independently associated with autoimmunity were common cold, influenza-like illness, sinusitis, and laryngitis/tracheitis, with HRs (95% CI) of 1.38 (1.11, 1.71), 2.37 (1.35, 4.15), 2.63 (1.22, 5.67) and 1.76 (1.04, 2.98), respectively.
Conclusions/interpretation:
Recent respiratory infections in young children correlate with an increased risk of islet autoimmunity in the TEDDY study. Further studies to identify the potential causative viruses with pathogen-specific assays should focus especially on the 9 month time window leading to autoantibody seroconversion.
Severe influenza infection represents a leading cause of global morbidity and mortality. Although influenza is primarily considered a viral infection that results in pathology limited to the respiratory system, clinical reports suggest that influenza infection is frequently associated with a number of clinical syndromes that involve organ systems outside the respiratory tract. A comprehensive Medline literature review of articles pertaining to extra-pulmonary complications of influenza infection, using organ-specific search terms, yielded 234 articles including case reports, epidemiologic investigations, and autopsy studies that were reviewed to determine the clinical involvement of other organs. The most frequently described clinical entities were viral myocarditis and viral encephalitis. Recognition of these extra-pulmonary complications is critical to determining the true burden of influenza infection and initiating organ-specific supportive care. This article is protected by copyright. All rights reserved.
Transplant recipients can be sensitized against allo-HLA antigens by previous transplantation, blood transfusion, or pregnancy. While there is growing awareness that multiple components of the immune system can act as effectors of the alloresponse, the role of infectious pathogen exposure in triggering sensitization and allograft rejection has remained a matter of much debate. Here, we describe that exposure to pathogens may enhance the immune response to allogeneic HLA antigens via different pathways. The potential role of allo-HLA cross-reactivity of virus-specific memory T cells, activation of innate immunity leading to a more efficient induction of the adaptive alloimmune response by antigen-presenting cells, and bystander activation of existing memory B cell activation will be discussed in this review.
Significance
Peripheral infections exacerbate symptoms of many neurological diseases, including the most common autoimmune demyelinating disease of the central nervous system (CNS), multiple sclerosis (MS). We demonstrate that influenza viral infection of autoimmune-prone mice triggers clinical and histological disease. We further show that influenza infection alters the transcriptome of the central nervous system and facilitates immune cell trafficking to the brain. Finally, we identified a specific chemokine that is upregulated in the CNS during infection that is also increased in the cerebrospinal fluid of MS patients during relapse. These observations improve our understanding of how peripheral infection may act to exacerbate neurological diseases such as multiple sclerosis.
Epidemiological studies have documented that the incidence of human type 1 diabetes was significantly increased after H1N1 epidemic. However, a direct link between human type 1 diabetes and virus infection remains elusive. We generated 84 clones of murine monoclonal antibodies against the H1N1, and carried out immunohistochemistry in normal human tissue microarray. The results showed that two clones specifically cross-reacted with human α-cells of pancreatic islets. Reverse transcription polymerase chain reaction and deoxyribonucleic acid sequencing showed that the amino acid sequences of light and heavy chains of these clones were different. Importantly, the expression profiles of two monoclonal antibodies were individual different. For the first time, we provide direct evidence that monoclonal antibodies against H1N1 can cross-react with human pancreas α-cells, another source of β-cells, suggesting α-cells might be a novel target to be investigated in diabetes research.
Heterologous immunity to a previously encountered pathogen can mediate protection against newly encountered viruses in mouse models. In translational studies we determined whether the 5% of middle-aged adults who remain EBV-seronegative (MA-EBV-SN), despite exposure to EBV, have circulating crossreactive memory CD8 T-cells capable of responding to EBV. A high frequency of influenza-A virus (IAV)-M158-66 tetramer+ CD8 T-cells in HLA-A2.01+ MA-EBV-SN donors expanded dramatically to EBV lytic antigens, produced anti-viral IFNγ, and lysed EBV-infected targets unlike those in young EBV-SN (YA-EBV-SN) donors; despite functional crossreactivity they did not bind EBV-specific tetramers. Uncommon nearly identical oligo-clonal TCR repertoires in these unique, functionally IAV-EBV crossreactive CD8 T-cells in rare individuals, who remain EBV-SN into their fourth decade, may help explain their potential to protect from EBV infection. These results, together with an expanding literature on crossreactivity and TCR repertoire in clinical disease, have implications for better understanding correlates of protection to primary infection.
Myelin oligodendrocyte glycoprotein (MOG), a member of the immunoglobulin (Ig) superfamily, is a myelin protein solely expressed at the outermost surface of myelin sheaths and oligodendrocyte membranes. This makes MOG a potential target of cellular and humoral immune responses in inflammatory demyelinating diseases. Due to its late postnatal developmental expression, MOG is an important marker for oligodendrocyte maturation. Discovered about 30 years ago, it is one of the best-studied autoantigens for experimental autoimmune models for multiple sclerosis (MS). Human studies, however, have yielded controversial results on the role of MOG, especially MOG antibodies (Abs), as a biomarker in MS. But with improved detection methods using different expression systems to detect Abs in patients’ samples, this is meanwhile no longer the case. Using cell-based assays with recombinant full-length, conformationally intact MOG, several recent studies have revealed that MOG Abs can be found in a subset of predominantly pediatric patients with acute disseminated encephalomyelitis (ADEM), aquaporin-4 (AQP4) seronegative neuromyelitis optica spectrum disorders (NMOSD), monophasic or recurrent isolated optic neuritis (ON), or transverse myelitis, in atypical MS and in N-methyl-d-aspartate receptor-encephalitis with overlapping demyelinating syndromes. Whereas MOG Abs are only transiently observed in monophasic diseases such as ADEM and their decline is associated with a favorable outcome, they are persistent in multiphasic ADEM, NMOSD, recurrent ON, or myelitis. Due to distinct clinical features within these diseases it is controversially disputed to classify MOG Ab-positive cases as a new disease entity. Neuropathologically, the presence of MOG Abs is characterized by MS-typical demyelination and oligodendrocyte pathology associated with Abs and complement. However, it remains unclear whether MOG Abs are a mere inflammatory bystander effect or truly pathogenetic. This article provides deeper insight into recent developments, the clinical relevance of MOG Abs and their role in the immunpathogenesis of inflammatory demyelinating disorders.
Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract infection in infants, young children, and the elderly. Two subtypes of RSV, A and B, circulate alternately at 1-2-year intervals during epidemics. The attachment glycoprotein (G protein) of RSV is one of the major targets for immune responses. In this study, we generated a recombinant fusion protein, GcfAB, which consists of the central regions (a.a. residues 131–230) of the G proteins of both RSV A (A2 strain) and B (B1 strain) subtypes, and investigated immunogenicity, protective efficacy, and immunopathology. We immunized mice with GcfAB plus cholera toxin as a mucosal adjuvant via intranasal (IN) or sublingual (SL) routes. The IN group showed higher levels of RSV G-specific antibody responses, including serum IgG and mucosal IgA, compared with the SL group. On the contrary, more vigorous RSV G-specific CD4⁺ T-cell responses were elicited in the SL group than in the IN group after RSV-A but not RSV-B viral challenge. Furthermore, the SL group showed more pulmonary eosinophil recruitment and body weight loss than did the IN group after RSV-A challenge. Both IN and SL immunization with GcfAB provided potential protection against both subtypes of infections. Together, these results suggest that vaccination with GcfAB via an IN route could be a universal vaccine regimen preventing both RSV A and B infections.
Background:
Live attenuated influenza vaccines (LAIV) stimulate a multifaceted immune response including cellular immunity, which may provide protection against newly emerging strains. This study shows proof of concept that LAIV boosts pre-existing, cross-reactive T-cells in children to genetically diverse influenza A strains to which the children had not been exposed.
Methods:
We studied the long-term cross-reactive T-cell response in 14 trivalent LAIV vaccinated children using the fluorescent immunospot assay (FluroSpot) with heterologous H1N1 and H3N2 influenza A viruses and CD8 peptides from the internal proteins (M1, NP, PB1). Serum antibody responses were determined by the Hemagglutination Inhibition (HI). Blood samples were collected before vaccination and up to one year post-vaccination.
Results:
Pre-existing cross-reactive T-cells to genetically diverse influenza A strains were found in the majority of the children, which were further boosted in 50% of the children after LAIV. Further analyses of these T-cells showed significant increases in CD8+ T-cells, mainly dominated by NP specific responses. After LAIV, the youngest children showed the highest increase in T-cell responses.
Conclusion:
LAIV boosts durable, cross-reactive T-cell responses in children and may have a clinically protective effect at the population level. LAIV may be a first step towards the desired universal influenza vaccine.
Background:
Persistent childhood asthma is mainly atopy-driven. However, limited data exist on the risk factors for childhood asthma phenotypes.
Objective:
To identify risk factors at the first severe wheezing episode for the current asthma 7 years later, and separately for atopic and non-atopic asthma.
Methods:
One hundred and twenty-seven steroid-naive children with the first severe wheezing episode (90% hospitalized/10% emergency room treated) were followed for 7 years. The primary outcome was current asthma at age 8 years, which was also analyzed separately as atopic and non-atopic asthma. Risk factors including sensitization, viral etiology and other main asthma risk factors were analyzed.
Results:
At study entry, median age was 11 months (interquartile range 6;16 months), 17% were sensitized and 98% were virus-positive. Current asthma (n = 37) at 8 years was divided to atopic (n = 19) and non-atopic (n = 18) asthma. The risk factors for current atopic asthma at study entry were sensitization (adjusted odds ratio 12; P<.001), eczema (4.8; P .014, respectively) and wheezing with rhinovirus (5.0; P .035). The risk factors for non-atopic asthma were the first severe respiratory syncytial virus/rhinovirus-negative wheezing episode (adjusted odds ratio 8.0; P .001), first wheezing episode at age <12 months (7.3; P = .007, respectively), and parental smoking (3.8; P .028).
Conclusions:
The data suggest diverse asthma phenotypes and mechanisms that can be predicted using simple clinical markers at the time of the first severe wheezing episode. Findings are important in designing early intervention strategies for secondary prevention of asthma. (ClinicalTrials.gov number, NCT00494624 and NCT00731575).
Respiratory syncytial virus (RSV) causes severe respiratory disease in young children. Antibodies specific for the RSV prefusion F protein have guided RSV vaccine research, and in human serum, these antibodies contribute to >90% of the neutralization response; however, detailed insight into the composition of the human B cell repertoire against RSV is still largely unknown. In order to study the B cell repertoire of three healthy donors for specificity against RSV, CD27⁺ memory B cells were isolated and immortalized using BCL6 and Bcl-xL. Of the circulating memory B cells, 0.35% recognized RSV-A2-infected cells, of which 59% were IgA-expressing cells and 41% were IgG-expressing cells. When we generated monoclonal B cells selected for high binding to RSV-infected cells, 44.5% of IgG-expressing B cells and 56% of IgA-expressing B cells reacted to the F protein, while, unexpectedly, 41.5% of IgG-expressing B cells and 44% of IgA expressing B cells reacted to the G protein. Analysis of the G-specific antibodies revealed that 4 different domains on the G protein were recognized. These epitopes predicted cross-reactivity between RSV strain A (RSV-A) and RSV-B and matched the potency of antibodies to neutralize RSV in HEp-2 cells and in primary epithelial cell cultures. G-specific antibodies were also able to induce antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis of RSV-A2-infected cells. However, these processes did not seem to depend on a specific epitope. In conclusion, healthy adults harbor a diverse repertoire of RSV glycoprotein-specific antibodies with a broad range of effector functions that likely play an important role in antiviral immunity.
IMPORTANCE
Human RSV remains the most common cause of severe lower respiratory tract disease in premature babies, young infants, the elderly, and immunocompromised patients and plays an important role in asthma exacerbations. In developing countries, RSV lower respiratory tract disease has a high mortality. Without an effective vaccine, only passive immunization with palivizumab is approved for prophylactic treatment. However, highly potent RSV-specific monoclonal antibodies could potentially serve as a therapeutic treatment and contribute to disease control and mortality reduction. In addition, these antibodies could guide further vaccine development. In this study, we isolated and characterized several novel antibodies directed at the RSV G protein. This information can add to our understanding and treatment of RSV disease.
Importance:
MERS-CoV was first identified in June 2012 and has since spread in humans and camels. Mutations in its spike (S) protein receptor-binding domain (RBD), a key vaccine target, have been identified, raising concerns over the efficacy of RBD-based MERS vaccines against circulating human and camel MERS-CoV strains. Here, we constructed five vaccine candidates, designated 2012-RBD, 2013-RBD, 2014-RBD, 2015-RBD, and camel-RBD, respectively, containing single or multiple mutations in the RBD of representative human and camel MERS-CoV strains during the 2012-2015 outbreaks. These RBD-based vaccine candidates maintained good functionality, antigenicity and immunogenicity, and they induced strong cross-neutralizing antibodies against infection by divergent pseudotyped and live MERS-CoV strains, as well as antibody-escape MERS-CoV mutants. This study provides impetus for further development of a safe, highly effective, and broad-spectrum RBD-based subunit vaccine to prevent MERS-CoV infection.
Many infections are caused by pathogens that are similar, but not identical, to previously encountered viruses, bacteria, or vaccines. In such re-infections, pathogens introduce known antigens, which are recognized by memory T cells and new antigens that activate naive T cells. How preexisting memory T cells impact the repertoire of T cells responding to new antigens is still largely unknown. We demonstrate that even a minimum epitope overlap between infections strongly increases the activation threshold and narrows the diversity of T cells recruited in response to new antigens. Thus, minimal cross-reactivity between infections can significantly impact the outcome of a subsequent immune response. Interestingly, we found that non-transferrable memory T cells are most effective in raising the activation threshold. Our findings have implications for designing vaccines and suggest that vaccines meant to target low-affinity T cells are less effective when they contain a strong CD8 T cell epitope that has previously been encountered.
Despite robust secondary T cell expansion primed by vaccination, the impact on primary immune responses to heterotypic antigens remains undefined. Here we show that secondary expansion of epitope-specific memory CD8⁺ T cells primed by prior infection with recombinant pathogens limits the primary expansion of naive CD8⁺ T cells with specificity to new heterologous antigens, dampening protective immunity against subsequent pathogen challenge. The degree of naive T cell repression directly paralleled the magnitude of the recall response. Suppressed primary T cell priming reflects competition for antigen accessibility, since clonal expansion was not inhibited if the primary and secondary epitopes were expressed on different dendritic cells. Interestingly, robust recall responses did not impact antigen-specific NK cells, suggesting that adaptive and innate lymphocyte responses possess different activation requirements or occur in distinct anatomical locations. These findings have important implications in pathogen vaccination strategies that depend on the targeting of multiple T cell epitopes.
Rhinovirus (RV) is a major cause of common cold and an important trigger of acute episodes of chronic lung diseases. Antigenic variation across the numerous RV strains results in frequent infections and a lack of durable cross-protection. Because the nature of human CD4(+) T cells that target RV is largely unknown, T cell epitopes of RV capsid proteins were analyzed, and cognate T cells were characterized in healthy subjects and those infected by intranasal challenge. Peptide epitopes of the RV-A16 capsid proteins VP1 and VP2 were identified by peptide/MHC class II tetramer-guided epitope mapping, validated by direct ex vivo enumeration, and interrogated using a variety of in silico methods. Among noninfected subjects, those circulating RV-A16-specific CD4(+) T cells detected at the highest frequencies targeted 10 unique epitopes that bound to diverse HLA-DR molecules. T cell epitopes localized to conserved molecular regions of biological significance to the virus were enriched for HLA class I and II binding motifs, and constituted both species-specific (RV-A) and pan-species (RV-A, -B, and -C) varieties. Circulating epitope-specific T cells comprised both memory Th1 and T follicular helper cells, and were rapidly expanded and activated after intranasal challenge with RV-A16. Cross-reactivity was evidenced by identification of a common *0401-restricted epitope for RV-A16 and RV-A39 by tetramer-guided epitope mapping and the ability for RV-A16-specific Th1 cells to proliferate in response to their RV-A39 peptide counterpart. The preferential persistence of high-frequency RV-specific memory Th1 cells that recognize a limited set of conserved epitopes likely arises from iterative priming by previous exposures to different RV strains.
Current hemagglutinin (HA)-based seasonal influenza vaccines induce vaccine strain-specific neutralizing antibodies that usually fail to provide protection against mismatched circulating viruses. Inclusion in the vaccine of highly conserved internal proteins such as the nucleoprotein (NP) and the matrix protein 1 (M1) was shown previously to increase vaccine efficacy by eliciting cross-reactive T-cells. However, appropriate delivery systems are required for efficient priming of T-cell responses. In this study, we demonstrated that administration of novel self-amplifying mRNA (SAM®) vectors expressing influenza NP (SAM(NP)), M1 (SAM(M1)), and NP and M1 (SAM(M1-NP)) delivered with lipid nanoparticles (LNP) induced robust polyfunctional CD4 T helper 1 cells, while NP-containing SAM also induced cytotoxic CD8 T cells. Robust expansions of central memory (TCM) and effector memory (TEM) CD4 and CD8 T cells were also measured. An enhanced recruitment of NP-specific cytotoxic CD8 T cells was observed in the lungs of SAM(NP)-immunized mice after influenza infection that paralleled with reduced lung viral titers and pathology, and increased survival after homologous and heterosubtypic influenza challenge. Finally, we demonstrated for the first time that the co-administration of RNA (SAM(M1-NP)) and protein (monovalent inactivated influenza vaccine (MIIV)) was feasible, induced simultaneously NP-, M1- and HA-specific T cells and HA-specific neutralizing antibodies, and enhanced MIIV efficacy against a heterologous challenge. In conclusion, systemic administration of SAM vectors expressing conserved internal influenza antigens induced protective immune responses in mice, supporting the SAM® platform as another promising strategy for the development of broad-spectrum universal influenza vaccines.
In HIV-1-infected patients, increased numbers of circulating CD8+ T cells are linked to increased risk of morbidity and mortality. Here, we identified a bystander mechanism that promotes CD8 T cell activation and expansion in untreated HIV-1-infected patients. Compared with healthy controls, untreated HIV-1-infected patients have an increased population of proliferating, granzyme B+, CD8+ T cells in circulation. Vβ expression and deep sequencing of CDR3 revealed that in untreated HIV-1 infection, cycling memory CD8 T cells possess a broad T cell repertoire that reflects the repertoire of the resting population. This suggests that cycling is driven by bystander activation, rather than specific antigen exposure. Treatment of peripheral blood mononuclear cells with IL-15 induced a cycling, granzyme B+ phenotype in CD8+ T cells. Moreover, elevated IL-15 expression in the lymph nodes of untreated HIV-1-infected patients correlated with circulating CD8+ T cell counts and was normalized in these patients following antiretroviral therapy. Together, these results suggest that IL-15 drives bystander activation of CD8+ T cells, which predicts disease progression in untreated HIV-1-infected patients and suggests that elevated IL-15 may also drive CD8+ T cell expansion that is linked to increased morbidity and mortality in treated patients.
There is mounting evidence that in the absence of neutralizing antibodies cross-reactive T cells provide protection against pandemic influenza viruses. Here, we compared protection and CD8+ T cell responses following challenge with H1N1 2009 pandemic and H3N2 viruses of mice that had been immunized with hemagglutinin (HA), neuraminidase (NA) and the extracellular domain of matrix protein 2 (M2e) fused to a virus-like particle (VLP). Mice were challenged a first time with a sublethal dose of H1N1 2009 pandemic virus and, four weeks later, challenged again with an H3N2 virus. Mice that had been vaccinated with HA, NA, NA + M2e-VLP and HA + NA + M2e-VLP were protected against homologous H1N1 virus challenge. Challenged NA and NA + M2e-VLP vaccinated mice mounted CD8+ T cell responses that correlated with protection against secondary H3N2 challenge. HA-vaccinated mice were fully protected against challenge with homologous H1N1 2009 virus, failed to mount cross-reactive CD8+ T cells and succumbed to the second challenge with heterologous H3N2 virus. In summary, NA- and M2e-based immunity can protect against challenge with (homologous) virus without compromising the induction of robust cross-reactive CD8+ T cell responses upon exposure to virus.
Language disorders and infections may occur together and often concur, to a different extent and via different modalities, in characterizing brain pathologies, such as schizophrenia, autism, epilepsies, bipolar disorders, frontotemporal neurodegeneration, and encephalitis, inter alia. The biological mechanism(s) that might channel language dysfunctions and infections into etiological pathways connected to neuropathologic sequelae are unclear. Searching for molecular link(s) between language disorders and infections, the present study explores the language-associated NMDA 2A subunit for peptide sharing with pathogens that have been described in concomitance with neuropsychiatric diseases. It was found that a vast peptide commonality links the human glutamate ionotropic receptor NMDA 2A subunit to infectious agents. Such a link expands to and interfaces with neuropsychiatric disorders in light of the specific allocation of NMDA 2A gene expression in brain areas related to language functions. The data hint at a possible pathologic scenario based on anti-pathogen immune responses cross-reacting with NMDA 2A in the brain.
Significance
Influenza is a rapidly spreading acute respiratory infection that causes profound morbidity and mortality. Established CD8 ⁺ T-lymphocyte (CTL) immunity directed at conserved viral regions provides protection against distinct influenza A viruses (IAVs). In this study, we show that public T-cell receptors (TCRs) specific for the most prominent human CTL epitope (M1 58–66 restricted by HLA-A*0201) are capable of recognizing sporadically emerging variant IAVs. We also identify the structural mechanisms that enable promiscuous TCR recognition in this context. Our analysis suggests that preexisting cross-reactive TCRs may limit the spread of newly emerging pandemic IAVs.
Type 1 diabetes mellitus (T1DM) is caused by progressive autoimmune-mediated loss of pancreatic β-cell mass via apoptosis. The onset of T1DM depends on environmental factors that interact with predisposing genes to induce an autoimmune assault against β cells. Epidemiological, clinical and pathology studies in humans support viral infection - particularly by enteroviruses (for example, coxsackievirus) - as an environmental trigger for the development of T1DM. Many candidate genes for T1DM, such as MDA5, PTPN2 and TYK2, regulate antiviral responses in both β cells and the immune system. Cellular permissiveness to viral infection is modulated by innate antiviral responses that vary among different tissues or cell types. Some data indicate that pancreatic islet α cells trigger a more efficient antiviral response to infection with diabetogenic viruses than do β cells, and so are able to eradicate viral infections without undergoing apoptosis. This difference could account for the varying ability of islet-cell subtypes to clear viral infections and explain why chronically infected pancreatic β cells, but not α cells, are targeted by an autoimmune response and killed during the development of T1DM. These issues and attempts to target viral infection as a preventive therapy for T1DM are discussed in the present Review.
One of the challenges of developing influenza A vaccines is the diversity of antigenically distinct isolates. Previously, a novel hemagglutinin (HA) for H5N1 influenza was derived from a methodology termed computationally optimized broadly reactive antigen (COBRA). This COBRA HA elicited a broad antibody response against H5N1 isolates from different clades. We now report the development and characterization of a COBRA-based vaccine for both seasonal and pandemic H1N1 influenza virus isolates. Nine prototype H1N1 COBRA HA proteins were developed and tested in mice using a virus-like particle (VLP) format for the elicitation of broadly reactive, functional antibody responses and protection against viral challenge. These candidates were designed to recognize H1N1 viruses isolated within the last 30 years. In addition, several COBRA candidates were designed based on sequences of H1N1 viruses spanning the past 100 years, including modern pandemic H1N1 isolates. Four of the 9 H1N1 COBRA HA proteins (X1, X3, X6, and P1) had the broadest hemagglutination inhibition (HAI) activity against a panel of 17 H1N1 viruses. These vaccines were used in cocktails or prime-boost combinations. The most effective regimens that both elicited the broadest HAI response and protected mice against a pandemic H1N1 challenge were vaccines that contained the P1 COBRA VLP and either the X3 or X6 COBRA VLP vaccine. These mice had little or no detectable viral replication, comparable to that observed with a matched licensed vaccine. This is the first report describing a COBRA-based HA vaccine strategy that elicits a universal, broadly reactive, protective response against seasonal and pandemic H1N1 isolates.
IMPORTANCE
Universal influenza vaccine approaches have the potential to be paradigm shifting for the influenza vaccine field, with the goal of replacing the current standard of care with broadly cross-protective vaccines. We have used COBRA technology to develop an HA head-based strategy that elicits antibodies against many H1 strains that have undergone genetic drift and has potential as a “subtype universal” vaccine. Nine HA COBRA candidates were developed, and these vaccines were used alone, in cocktails or in prime-boost combinations. The most effective regimens elicited the broadest hemagglutination inhibition (HAI) response against a panel of H1N1 viruses isolated over the past 100 years. This is the first report describing a COBRA-based HA vaccine strategy that elicits a broadly reactive response against seasonal and pandemic H1N1 isolates.
BACKGROUND Community-acquired pneumonia is a leading infectious cause of hospitalization and death among U.S. adults. Incidence estimates of pneumonia confirmed radio-graphically and with the use of current laboratory diagnostic tests are needed. METHODS We conducted active population-based surveillance for community-acquired pneumonia requiring hospitalization among adults 18 years of age or older in five hospitals in Chicago and Nashville. Patients with recent hospitalization or severe immunosuppression were excluded. Blood, urine, and respiratory specimens were systematically collected for culture, serologic testing, antigen detection, and molecular diagnostic testing. Study radiologists independently reviewed chest radiographs. We calculated population-based incidence rates of community-acquired pneumonia requiring hospitalization according to age and pathogen. RESULTS From January 2010 through June 2012, we enrolled 2488 of 3634 eligible adults (68%). Among 2320 adults with radiographic evidence of pneumonia (93%), the median age of the patients was 57 years (interquartile range, 46 to 71); 498 patients (21%) required intensive care, and 52 (2%) died. Among 2259 patients who had radiographic evidence of pneumonia and specimens available for both bacterial and viral testing, a pathogen was detected in 853 (38%): one or more viruses in 530 (23%), bacteria in 247 (11%), bacterial and viral pathogens in 59 (3%), and a fungal or mycobacterial pathogen in 17 (1%). The most common pathogens were human rhinovirus (in 9% of patients), influenza virus (in 6%), and Streptococcus pneumoniae (in 5%). The annual incidence of pneumonia was 24.8 cases (95% confidence interval, 23.5 to 26.1) per 10,000 adults, with the highest rates among adults 65 to 79 years of age (63.0 cases per 10,000 adults) and those 80 years of age or older (164.3 cases per 10,000 adults). For each pathogen, the incidence increased with age. CONCLUSIONS The incidence of community-acquired pneumonia requiring hospitalization was highest among the oldest adults. Despite current diagnostic tests, no pathogen was detected in the majority of patients. Respiratory viruses were detected more frequently than bacteria.
Background:
Oral vaccination with live-attenuated S. Typhi (Ty21a) is modestly efficacious, however the mechanisms of protection are currently unknown. While humoral and cellular immune responses are well-described in peripheral blood, the cellular response at the intestinal mucosa has never been directly assessed.
Methods:
We vaccinated healthy adults with Ty21a and assessed humoral and cellular immunity in vaccinated volunteers and controls after 18 days. Immunoglobulin levels were assessed in peripheral blood by enzyme-linked immunosorbent assay. Cellular responses were assessed in peripheral blood and at the duodenal and colonic mucosa by flow cytometry.
Results:
We demonstrate the generation of Ty21a-responsive and heterologous influenza-responsive CD4(+) and CD8(+) T-cells at the duodenal mucosa. All duodenal responses were consistently correlated and no responses were observed at the colonic mucosa. Peripheral anti-lippopolysaccharide IgG and IgA responses were significantly correlated with duodenal responses. The assessment of integrin β7 expression intensity among peripheral and duodenal T-cell subsets revealed varied capacities for mucosal homing and residence.
Conclusions:
The breadth of duodenal cellular responses was not reflected peripherally. The direct evaluation of mucosal immune defence may yield functional correlates of protection, and could provide insight into mechanisms which may be manipulated in order to enhance vaccine immunogenicity.
Adenoviruses (Ad) are commonly used as vectors for gene therapy and/or vaccine delivery. Recombinant Ad vectors are being tested as vaccines for many pathogens. We have made a surprising observation that peptides derived from various hepatitis C virus (HCV) antigens contain extensive regions of homology with multiple adenovirus proteins, and conclusively demonstrate that adenovirus vector can induce robust, heterologous cellular and humoral immune responses against multiple HCV antigens. Intriguingly, the induction of this cross-reactive immunity leads to significant reduction of viral loads in a recombinant vaccinia-HCV virus infected mouse model, supporting their role in antiviral immunity against HCV. Healthy human subjects with Ad-specific pre-existing immunity demonstrated cross-reactive cellular and humoral immune responses against multiple HCV antigens. These findings reveal the potential of a previously uncharacterized property of natural human adenovirus infection to dictate, modulate and/or alter the course of HCV infection upon exposure. This intrinsic property of adenovirus vectors to cross-prime HCV immunity can also be exploited to develop a prophylactic and/or therapeutic vaccine against HCV.
In animal models, resident memory CD8 + T (Trm) cells assist in respiratory virus elimination but their importance in man has not been determined. Here, using experimental human respiratory syncytial virus (RSV) infection, we investigate systemic and local virus-specific CD8 + T-cell responses in adult volunteers. Having defined the immunodominance hierarchy, we analyse phenotype and function longitudinally in blood and by serial bronchoscopy. Despite rapid clinical recovery, we note surprisingly extensive lower airway inflammation with persistent viral antigen and cellular infiltrates. Pulmonary virus-specific CD8 + T cells display a CD69 + CD103 + Trm phenotype and accumulate to strikingly high frequencies into convalescence without continued proliferation. While these have a more highly differentiated phenotype, they express fewer cytotoxicity markers than in blood. Nevertheless, their abundance before infection correlates with reduced symptoms and viral load, implying that CD8 + Trm cells in the human lung can confer protection against severe respiratory viral disease when humoral immunity is overcome.
Background:
The hygiene hypothesis is the leading concept to explain the current asthma epidemic, which is built on the observation that a lack of bacterial contact early in life induces allergic Th2 immune responses.
Objective:
Since little is known about the contribution of respiratory viruses in this context, we evaluated the effect of prior influenza-infection on the development of allergic asthma.
Methods:
Mice were infected with influenza and once recovered, subjected to an ovalbumin or house dust mite-induced experimental asthma protocol. Influenza-polarized T effector memory cells (Tem) were adoptively transferred to allergen sensitized animals prior to allergen challenge. A comprehensive in silico analysis assessed homologies between virus- and allergen- derived proteins. Influenza-polarized Tem cells were stimulated ex vivo with candidate peptides. Mice were immunized with a pool of virus-derived T-cell epitopes.
Results:
We found in two murine models a long-lasting preventive effect against experimental asthma features. Protection could be attributed about equally to CD4+ and CD8+ T-effector memory (Tem) cells from influenza-infected mice. An in silico bioinformatic analysis identified four influenza and three allergen-derived MHC-class I and -class II candidate T-cell epitopes with potential antigen-specific cross-reactivity between influenza and allergens. Lymphocytes from influenza-infected mice produced IFNγ and IL-2 but not IL-5 upon stimulation with the aforementioned peptides. Immunization with a mixture of the influenza-peptides conferred asthma protection, and peptide immunized mice transferred protection via CD4+ and CD8+ Tem cells.
Conclusion:
Our results illustrate for the first time heterologous immunity of virus-infected animals towards allergens. This finding extends the original hygiene hypothesis.
Viral infections are closely linked to wheezing illnesses in children of all ages. Respiratory syncytial virus (RSV) is the main causative agent of bronchiolitis, whereas rhinovirus (RV) is most commonly detected in wheezing children thereafter. Severe respiratory illness induced by either of these viruses is associated with subsequent development of asthma, and the risk is greatest for young children who wheeze with RV infections. Whether viral illnesses actually cause asthma is the subject of intense debate. RSV-induced wheezing illnesses during infancy influence respiratory health for years. There is definitive evidence that RSV-induced bronchiolitis can damage the airways to promote airway obstruction and recurrent wheezing. RV likely causes less structural damage and yet is a significant contributor to wheezing illnesses in young children and in the context of asthma. For both viruses, interactions between viral virulence factors, personal risk factors (eg, genetics), and environmental exposures (eg, airway microbiome) promote more severe wheezing illnesses and the risk for progression to asthma. In addition, allergy and asthma are major risk factors for more frequent and severe RV-related illnesses. Treatments that inhibit inflammation have efficacy for RV-induced wheezing, whereas the anti-RSV mAb palivizumab decreases the risk of severe RSV-induced illness and subsequent recurrent wheeze. Developing a greater understanding of personal and environmental factors that promote more severe viral illnesses might lead to new strategies for the prevention of viral wheezing illnesses and perhaps reduce the subsequent risk for asthma.
Early infections have been suggested to be associated with increased risk for later celiac disease (CD). We analyzed prospective claims data of n = 295,420 infants from Bavaria, Germany, born between 2005 and 2007 containing information on medically attended infectious diseases according to ICD-10 code on a quarterly basis to calculate hazard ratios and 95% confidence intervals of time to CD diagnosis by infection exposure, adjusting for sex, calendar month of birth and number of previous healthcare visits. CD risk was increased in children who had a gastrointestinal infection during the first year of life (hazard ratio = 1.32, 95% confidence interval: 1.12, 1.55) and to a lesser extent also in children with a respiratory infection during the first year (hazard ratio = 1.22, 95% confidence interval: 1.04, 1.43). Repeated gastrointestinal infections during the first year of life were associated with particularly increased CD risk in later life. These findings indicate that early gastrointestinal infections may be relevant for CD development.
Matrix protein 2 ectodomain (M2e) is considered an attractive component of a broadly protective, universal influenza A vaccine. Here we challenge the canonical view that antibodies against M2e are the prime effectors of protection. Intranasal immunizations of Balb/c mice with CTA1-3M2e-DD-generated M2e-specific memory CD4 T cells that were I-A(d) restricted and critically protected against infection, even in the complete absence of antibodies, as observed in JhD mice. Whereas some M2e-tetramer-specific memory CD4 T cells resided in spleen and lymph nodes, the majority were lung-resident Th17 cells, that rapidly expanded upon a viral challenge infection. Indeed, immunized IL-17A(-/-) mice were significantly less well protected compared with wild-type mice despite exhibiting comparable antibody levels. Similarly, poor protection was also observed in congenic Balb/B (H-2(b)) mice, which failed to develop M2e-specific CD4 T cells, but exhibited comparable antibody levels. Lung-resident CD69(+) CD103(low) M2e-specific memory CD4 T cells were αβ TCR(+) and 50% were Th17 cells that were associated with an early influx of neutrophils after virus challenge. Adoptively transferred M2e memory CD4 T cells were strong helper T cells, which accelerated M2e- but more importantly also hemagglutinin-specific IgG production. Thus, for the first time we demonstrate that M2e-specific memory CD4 T cells are broadly protective.Mucosal Immunology advance online publication 15 March 2017. doi:10.1038/mi.2017.14.
Multiple sclerosis starts with increased migration of auto-reactive lymphocytes across the blood-brain barrier, resulting in persistent neurodegeneration. Clinical and epidemiological studies indicated upper respiratory viral infections are associated with clinical exacerbation of multiple sclerosis. However, so far there is no any direct evidence to support it. Using the experimental autoimmune encephalomyelitis mice as the model for multiple sclerosis, we demonstrated that mice experienced with influenza virus infection were unable to recover from experimental autoimmune encephalomyelitis with a long-term exacerbation. The exacerbated disease was due to more type I T cells, such as CD45highCD4⁺CD44high, CD45highCD4⁺CCR5⁺, CD45high IFNγ⁺CD4⁺, MOG35-55-specific IFNγ⁺CD4⁺ and influenza virus-specific IFNγ⁺CD4⁺ T cells, infiltrating central nervous system in mice with prior influenza virus infection. Influenza virus infection created a notable inflammatory environment in lung and mediastinal lymph node after influenza virus inoculation, suggesting the lung may constitute an inflammatory niche in which auto-aggressive T cells gain the capacity to enter CNS. Indeed, the early stage of EAE disease was accompanied by increased CCR5⁺CD4⁺, CXCR3⁺CD4⁺ T cell and MOG35-55 specific CD4⁺ T cells localized in the lung in influenza virus-infected mice. CCL5/CCR5 might mediate the infiltration of type I T cells into CNS during the disease development after influenza infection. Administration of CCR5 antagonist could significantly attenuate the exacerbated disease. Our study provided the evidence that the prior influenza virus infection may promote the type I T cells infiltration into the CNS, and subsequently cause a long-term exacerbation of experimental autoimmune encephalomyelitis.
Tissue-resident memory T cells (TRM) are a recently defined, noncirculating subset with the potential for rapid in situ protective responses, although their generation and role in vaccine-mediated immune responses is unclear. Here, we assessed TRM generation and lung-localized protection following administration of currently licensed influenza vaccines, including injectable inactivated influenza virus (IIV, Fluzone) and i.n. administered live-attenuated influenza virus (LAIV, FluMist) vaccines. We found that, while IIV preferentially induced strain-specific neutralizing antibodies, LAIV generated lung-localized, virus-specific T cell responses. Moreover, LAIV but not IIV generated lung CD4(+) TRM and virus-specific CD8(+) TRM, similar in phenotype to those generated by influenza virus infection. Importantly, these vaccine-generated TRM mediated cross-strain protection, independent of circulating T cells and neutralizing antibodies, which persisted long-term after vaccination. Interestingly, intranasal administration of IIV or injection of LAIV failed to elicit T cell responses or provide protection against viral infection, demonstrating dual requirements for respiratory targeting and a live-attenuated strain to establish TRM. The ability of LAIV to generate lung TRM capable of providing long-term protection against nonvaccine viral strains, as demonstrated here, has important implications for protecting the population against emergent influenza pandemics by direct fortification of lung-specific immunity.
This chapter reviews the performance of viral vectors based on adenoviruses or adeno-associated virus as vaccine carriers for infectious diseases. Replication-defective adenovirus vectors based on multiple human or non-human serotypes have consistently induced potent transgene product-specific B and T cell responses and are increasingly being explored in human clinical trials. The immunogenicity of most vectors based on adeno-associated virus vectors has been poor with the exception of a recently described hybrid vector from rhesus macaques that due to its ability to induce potent responses in mice warrant further investigation.
Two zoonotic coronaviruses (CoVs)—SARS-CoV and MERS-CoV—have crossed species to cause severe human respiratory disease. Here, we showed that induction of airway memory CD4+ T cells specific for a conserved epitope shared by SARS-CoV and MERS-CoV is a potential strategy for developing pan-coronavirus vaccines. Airway memory CD4+ T cells differed phenotypically and functionally from lung-derived cells and were crucial for protection against both CoVs in mice. Protection was dependent on interferon-γ and required early induction of robust innate and virus-specific CD8+ T cell responses. The conserved epitope was also recognized in SARS-CoV- and MERS-CoV-infected human leukocyte antigen DR2 and DR3 transgenic mice, indicating potential relevance in human populations. Additionally, this epitope was cross-protective between human and bat CoVs, the progenitors for many human CoVs. Vaccine strategies that induce airway memory CD4+ T cells targeting conserved epitopes might have broad applicability in the context of new CoVs and other respiratory virus outbreaks.
Respiratory syncytial virus causes a significant public health burden, particularly in very young infants and the frail elderly. The legacy of enhanced RSV disease (ERD) from a whole formalin-inactivated RSV vaccine, and the complex biology of the virus and the neonate have delayed the development of effective vaccines. However, new insights into factors associated with ERD and breakthroughs in understanding the antigenic structure of the fusion (F) glycoprotein have increased optimism that vaccine development is possible. This has led to investment of time and resources by industry, regulatory authorities, governments, and nonprofit organizations to develop the infrastructure needed to make the advanced clinical development of RSV vaccine candidates a reality.
Clinical evidence strongly suggests that certain live vaccines, in particular bacille Calmette-Guérin (BCG) and measles vaccines, can reduce all-cause mortality, most probably through protection against non-targeted pathogens in addition to the targeted pathogen. The underlying mechanisms are currently unknown. We discuss how heterologous lymphocyte activation and innate immune memory could promote protection beyond the intended target pathogen and consider how vaccinologists could leverage heterologous immunity to improve outcomes in vulnerable populations, in particular the very young and the elderly.
Seasonal influenza virus vaccines have to be re-formulated and re-administered on an annual basis due to antigenic drift of the influenza virus surface glycoproteins. In addition, seasonal vaccines show limited efficacy against novel pandemic influenza virus strains, and producing tailored vaccines for these strains in a timely manner is challenging. Several novel broadly protective vaccine candidates targeting the conserved stalk domain of the viral hemagglutinin have been developed. Here we review these novel constructs and discuss several important findings and considerations regarding the protective efficacy of stalk-based vaccines.
Purpose:
A 2012 report and subsequent case series described anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in patients during the acute phase and relapse of herpes simplex virus 1 (HSV1) encephalitis (HSV1E). However, the prevalence of this phenomenon is unknown and systematic studies on other viral infections of the nervous system are missing.
Materials and methods:
We retrospectively analyzed serial cerebrospinal fluid (CSF) and serum samples of consecutive patients treated for neurological HSV1, HSV2 and varicella zoster virus (VZV) infections in our tertiary care university hospital between 2003 and 2013 for the presence of antibodies directed against the NR1a subunit of the NMDAR using indirect immunofluorescence.
Results:
In total, 88 patients with the following infections were identified through an electronic database search: HSV1 (24 with encephalitis), HSV2 (6 with meningitis, 3 with encephalitis and 1 with myelitis), or VZV (3 with meningitis, 33 with encephalitis, 17 with radiculitis and 1 with myelitis). Two patients with HSV1E and HSV2E, respectively, experienced a clinical relapse. Clinical follow-up was for up to 85 months, and repetitive serum and CSF analyses for up to 43 months. However, at no time did any of the 88 patients exhibit anti-NMDAR NR1a antibodies.
Conclusions:
In this study, we did not detect anti-NMDAR NR1a antibodies in serial CSF and serum samples of HSV1E patients or patients with other viral infections (HSV2 and VZV). However, the presence of antibodies directed against other epitopes of the NMDAR and other neuronal cell surface antigens cannot be excluded, necessitating further studies.
The currently used vaccine strategy to combat influenza A virus (IAV) aims to provide highly specific immunity to circulating seasonal IAV strains. However, the outbreak of 2009 influenza pandemic highlights the danger in this strategy. In this study, we tested the hypothesis that universal vaccination that offers broader but weaker protection would result in cross protective T cell responses after primary IAV infection, which would subsequently provide protective immunity against future pandemic strains. Specifically, we used tandem repeat extracellular domain of M2 (M2e) epitopes on virus-like particles (M2e5x VLP) that induced heterosubtypic immunity by eliciting Abs to a conserved M2e epitope. M2e5x VLP was found to be superior to strain-specific current split vaccine in conferring heterosubtypic cross protection and in equipping the host with cross-protective lung-resident nucleoprotein-specific memory CD8(+) T cell responses to a subsequent secondary infection with a new pandemic potential strain. Immune correlates for subsequent heterosubtypic immunity by M2e5x VLP vaccination were found to be virus-specific CD8(+) T cells secreting IFN-γ and expressing lung-resident memory phenotypic markers CD69(+) and CD103(+) as well as M2e Abs. Hence, vaccination with M2e5x VLP may be developable as a new strategy to combat future pandemic outbreaks.