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Proposed model (Left) In uninterrupted lethal MHV-68 infection of IFNγR −/− mice, the gut microbiome and immune response interact to mount an ultimately insufficient response of cells such as T-cells to affected tissues (e.g., the lungs), leading to severe disease and death. Antibiotics suppresses the immune stimulatory effects of the bacterial microbiome, reducing further the immune response and worsening the disease. (Right) In immune modulator-mediated protection by treatments such as Serp-1 or S-7, the interactions leading to a sufficiently mounted immune response are enhanced, promoting an increased T-cell infiltration to affected tissues, reducing disease pathology and leading to survival.
Source publication
Immunopathogenesis in systemic viral infections can induce a septic state with leaky capillary syndrome, disseminated coagulopathy, and high mortality with limited treatment options. Murine gammaherpesvirus-68 (MHV-68) intraperitoneal infection is a gammaherpesvirus model for producing severe vasculitis, colitis and lethal hemorrhagic pneumonia in...
Context in source publication
Context 1
... propose here that transkingdom interactions with the gut bacterial microbiome are required for host innate immunity to mount a protective response against lethal gammaherpesviral disease (Fig. 6). When www.nature.com/scientificreports www.nature.com/scientificreports/ MHV-68 infection causes viral pulmonary inflammation and sepsis, as induced in the MHV-68 infection model, host innate immune responses mediated by gut bacterial microbiota interactions leads to the recruitment of immune cells (e.g. T-cells) to the lungs. However, ...
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Background:
The inflammatory mechanisms occur with the highest prevalence in pulmonary pathology in addition to oxidative stress and activation of intracellular signaling pathways. The oxidative stress represents the imbalance between pro-oxidants and antioxidants which can lead to the activation of the oxidative mechanisms with noxious potential...
Citations
... The treatment of MHV-68 infections in interferon gamma receptor knockout mice was further tested as a model for lethal vasculitis, DIC, colitis, and lung hemorrhage in a study investigating the gut microbiome. The suppression of gut bacteria by the oral administration of an antibiotic cocktail worsened MHV-68 infection and blocked Serp-1 treatment efficacy, indicating that the Serp-1 therapeutic efficacy in this MHV68 model was dependent upon an intact gut microbiota [27]. While acute transplant rejection is well-controlled with current immunosuppressants, chronic transplant vasculopathy and rejection remain a barrier to long-term transplant function. ...
Serine protease inhibitors, SERPINS, are a highly conserved family of proteins that regulate serine proteases in the central coagulation and immune pathways, representing 2–10% of circulating proteins in the blood. Serine proteases form cascades of sequentially activated enzymes that direct thrombosis (clot formation) and thrombolysis (clot dissolution), complement activation in immune responses and also programmed cell death (apoptosis). Virus-derived serpins have co-evolved with mammalian proteases and serpins, developing into highly effective inhibitors of mammalian proteolytic pathways. Through interacting with extracellular and intracellular serine and cysteine proteases, viral serpins provide a new class of highly active virus-derived coagulation-, immune-, and apoptosis-modulating drug candidates. Viral serpins have unique characteristics: (1) function at micrograms per kilogram doses; (2) selectivity in targeting sites of protease activation; (3) minimal side effects at active concentrations; and (4) the demonstrated capacity to be modified, or fine-tuned, for altered protease targeting. To date, the virus-derived serpin class of biologics has proven effective in a wide range of animal models and in one clinical trial in patients with unstable coronary disease. Here, we outline the known viral serpins and review prior studies with viral serpins, considering their potential for application as new sources for immune-, coagulation-, and apoptosis-modulating therapeutics.
... Activation of latent Epstein-Barr virus (EBV) infection is linked to the development of MS (144,145). EBV is a common virus that is considered part of the commensal microbiome (146). EBV infects B cells and epithelial cells, and because it shares molecular mimicry to some host protein, the viral genome integrates within the host DNA. ...
Trillions of microbes survive and thrive inside the human body. These tiny creatures are crucial to the development and maturation of our immune system and to maintain gut immune homeostasis. Microbial dysbiosis is the main driver of local inflammatory and autoimmune diseases such as colitis and inflammatory bowel diseases. Dysbiosis in the gut can also drive systemic autoimmune diseases such as type 1 diabetes, rheumatic arthritis, and multiple sclerosis. Gut microbes directly interact with the immune system by multiple mechanisms including modulation of the host microRNAs affecting gene expression at the post-transcriptional level or production of microbial metabolites that interact with cellular receptors such as TLRs and GPCRs. This interaction modulates crucial immune functions such as differentiation of lymphocytes, production of interleukins, or controlling the leakage of inflammatory molecules from the gut to the systemic circulation. In this review, we compile and analyze data to gain insights into the underpinning mechanisms mediating systemic autoimmune diseases. Understanding how gut microbes can trigger or protect from systemic autoimmune diseases is crucial to (1) tackle these diseases through diet or lifestyle modification, (2) develop new microbiome-based therapeutics such as prebiotics or probiotics, (3) identify diagnostic biomarkers to predict disease risk, and (4) observe and intervene with microbial population change with the flare-up of autoimmune responses. Considering the microbiome signature as a crucial player in systemic autoimmune diseases might hold a promise to turn these untreatable diseases into manageable or preventable ones.
... This virus, with its surface protein (S) can bind to the host receptor angiotensin converting enzyme 2 (ACE2) to enter the host cell. ACE2 is a peptidase and is attached to the cell membrane in several tissues throughout the body, including the heart, gastrointestinal tract, kidneys, and lungs [5][6][7]. The most common symptoms of COVID-19 infection are respiratory symptoms, fever, cough, dyspnea, malaise, and fatigue. ...
Background: Healthcare providers are high-risk groups for the novel coronavirus disease (COVID-19) infection. Nursing students are an essential part of high-risk healthcare providers. The aim of this study was to evaluate the knowledge, attitude, and practice of nursing and midwifery students at Golestan University of Medical Sciences (GOUMS) toward the prevention of COVID-19. Methods: This cross-sectional study was conducted on 174 nursing and midwifery students of GOUMS (northeast of IRAN) in 2020. Data were gathered using an online questionnaire comprising three parts – Knowledge (8 questions), Attitude (10 questions), and Practice (8 questions) toward the prevention of COVID-19. The range of scores in each subscale (knowledge, attitude, and preventive practices) were 8–24, 10–50, and 8–24, respectively. Data were analyzed using the SPSS v.16 software. The Mann–Whitney and Kruskal–Wallis tests were used for the analysis. Results: Overall, in this study, nursing and midwifery students had a good knowledge (mean score: 23.19 ± 2.56), a positive attitude (mean score: 45.48 ± 4.21), and appropriate practice (mean score: 23.30 ± 3.51) regarding COVID-19 prevention. Also, the results revealed a positive correlation between knowledge and attitude (r = 0.1, P = 0.18) and attitude and practice (r = 0.2, P = 0.01) among the students. Conclusion: The findings demonstrated a good preventive knowledge, attitude, and practice toward COVID-19 among nursing and midwifery students.
... In contrast to the above, the gut microbiome can affect the infection processes of various eukaryotic enteric viruses in the gastrointestinal tract [194] and can induce an immune response that controls the infection process of eukaryotic viruses [195]. The enteric microbiota enhances the production of mucus and the synthesis of potential antiviral compounds, such as lactic acid, acetic acid, reactive oxygen species, and defensins, which inhibit local viral replication [196]. ...
The core microbiome, which refers to a set of consistent microbial features across populations, is of major interest in microbiome research and has been addressed by numerous studies. Understanding the core microbiome can help identify elements that lead to dysbiosis, and lead to treatments for microbiome-related health states. However, defining the core microbiome is a complex task at several levels. In this review, we consider the current state of core human microbiome research. We consider the knowledge that has been gained, the factors limiting our ability to achieve a reliable description of the core human microbiome, and the fields most likely to improve that ability. DNA sequencing technologies and the methods for analyzing metagenomics and amplicon data will most likely facilitate higher accuracy and resolution in describing the microbiome. However, more effort should be invested in characterizing the microbiome’s interactions with its human host, including the immune system and nutrition. Other components of this holobiontic system should also be emphasized, such as fungi, protists, lower eukaryotes, viruses, and phages. Most importantly, a collaborative effort of experts in microbiology, nutrition, immunology, medicine, systems biology, bioinformatics, and machine learning is probably required to identify the traits of the core human microbiome.
... and depleted in Clostridia spp. In an experiment with microbiome-depleted hosts, Yaron et al. (53) inoculated axenic mice with murine gammaherpesvirus 68 (MHV-68). These mice had a lower survival rate than the control group. ...
The microorganisms associated with an organism, the microbiome, have a strong and wide impact in their host biology. In particular, the microbiome modulates both the host defense responses and immunity, thus influencing the fate of infections by pathogens. Indeed, this immune modulation and/or interaction with pathogenic viruses can be essential to define the outcome of viral infections. Understanding the interplay between the microbiome and pathogenic viruses opens future venues to fight viral infections and enhance the efficacy of antiviral therapies. An increasing number of researchers are focusing on microbiome-virus interactions, studying diverse combinations of microbial communities, hosts, and pathogenic viruses. Here, we aim to review these studies, providing an integrative overview of the microbiome impact on viral infection across different pathosystems.
... Furthermore, growing evidence suggests that alterations in the human microbiome may also occur in response to viral infections (12)(13)(14)(15)(16)(17). Bacteria can also play important roles during viral infection processes, ranging from offering protection against viral agents (18)(19)(20)(21)(22) to facilitating viral infections or participating in bacterial-viral coinfections (23)(24)(25)(26)(27). The continuous emergence of novel pathogenic viruses at a global scale, such as the H1N1 influenza A virus (28,29), or the coronaviruses responsible for the severe acute respiratory syndrome (SARS-CoV) (30,31), the Middle East respiratory syndrome (MERS-CoV) (32,33), or the more recent SARS-CoV-2 causative of the current COVID-19 pandemic (34,35), emphasizes the need to understand how microbial communities might be related to these pathogens and whether they modulate infection risk. ...
The global emergence of novel pathogenic viruses presents an important challenge for research, as high biosafety levels are required to process samples. While inactivation of infectious agents facilitates the use of less stringent safety conditions, its effect on other biological entities of interest present in the sample is generally unknown. Here, we analyzed the effect of five inactivation methods (heat, ethanol, formaldehyde, psoralen, and TRIzol) on microbiome composition and diversity in samples collected from four different body sites (gut, nasal, oral, and skin) and compared them against untreated samples from the same tissues. We performed 16S rRNA gene sequencing and estimated abundance and diversity of bacterial taxa present in all samples. Nasal and skin samples were the most affected by inactivation, with ethanol and TRIzol inducing the largest changes in composition, and heat, formaldehyde, TRIzol, and psoralen inducing the largest changes in diversity. Oral and stool microbiomes were more robust to inactivation, with no significant changes in diversity and only moderate changes in composition. Firmicutes was the taxonomic group least affected by inactivation, while Bacteroidetes had a notable enrichment in nasal samples and moderate enrichment in fecal and oral samples. Actinobacteria were more notably depleted in fecal and skin samples, and Proteobacteria exhibited a more variable behavior depending on sample type and inactivation method. Overall, our results demonstrate that inactivation methods can alter the microbiome in a tissue-specific manner and that careful consideration should be given to the choice of method based on the sample type under study.
... Examination of viral mutants and host factors has revealed key virus-host interactions that promote fibrosis, vasculitis, pneumonia, and arthritis (111,130,131). Interestingly, the gut microbiome differentially influences MHV68-driven pathologies (132,133). Such models serve as a foundation to explore therapeutics that impair virus-driven inflammatory processes in the specific tissues that relate to human disease (127, 132). ...
Gammaherpesviruses are an important class of oncogenic pathogens that are exquisitely evolved to their respective hosts. As such, the human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi sarcoma herpesvirus (KSHV) do not naturally infect nonhuman primates or rodents. There is a clear need to fully explore mechanisms of gammaherpesvirus pathogenesis, host control, and immune evasion in the host. A gammaherpesvirus pathogen isolated from murid rodents was first reported in 1980; 40 years later, murine gammaherpesvirus 68 (MHV68, MuHV-4, γHV68) infection of laboratory mice is a well-established pathogenesis system recognized for its utility in applying state-of-the-art approaches to investigate virus-host interactions ranging from the whole host to the individual cell. Here, we highlight recent advancements in our understanding of the processes by which MHV68 colonizes the host and drives disease. Lessons that inform KSHV and EBV pathogenesis and provide future avenues for novel interventions against infection and virus-associated cancers are emphasized.
... Compelling evidence has shown that the gut microbiota can play a role in pathogenesis of various human diseases including those with primary involvement outside of the gut, such as respiratory, renal, or neurologic [20][21][22]. For instance, recent studies reveal that immune protection and severity of infection by gammaherpesvirus, which can cause severe vasculitis and lethal pneumonia or respiratory syncytial virus infection of the lungs, can be dependent on the profile of the human gut microbiota [23,24]. ...
... Recent studies have shown that interaction between host microbiota and viruses may play a crucial role in dictating disease pathogenesis in mammalian hosts [24,48,49]. As in all vertebrates, chicken mucosal surfaces are shared by diverse and dynamic population of microbiota [50][51][52]. ...
Background
A commensal microbiota regulates and is in turn regulated by viruses during host infection which can influence virus infectivity. In this study, analysis of colon microbiota population changes following a low pathogenicity avian influenza virus (AIV) of the H9N2 subtype infection of two different chicken breeds was conducted.
Methods
Colon samples were taken from control and infected groups at various timepoints post infection. 16S rRNA sequencing on an Illumina MiSeq platform was performed on the samples and the data mapped to operational taxonomic units of bacterial using a QIIME based pipeline. Microbial community structure was then analysed in each sample by number of observed species and phylogenetic diversity of the population.
Results
We found reduced microbiota alpha diversity in the acute period of AIV infection (day 2–3) in both Rhode Island Red and VALO chicken lines. From day 4 post infection a gradual increase in diversity of the colon microbiota was observed, but the diversity did not reach the same level as in uninfected chickens by day 10 post infection, suggesting that AIV infection retards the natural accumulation of colon microbiota diversity, which may further influence chicken health following recovery from infection. Beta diversity analysis indicated a bacterial species diversity difference between the chicken lines during and following acute influenza infection but at phylum and bacterial order level the colon microbiota dysbiosis was similar in the two different chicken breeds.
Conclusion
Our data suggest that H9N2 influenza A virus impacts the chicken colon microbiota in a predictable way that could be targeted via intervention to protect or mitigate disease.
... The importance of the microbiota in establishing an appropriate anti-viral immune response has been noted [25,26]. Exacerbated systemic infection by several enteric and non-enteric viruses was observed in Ab-treated mice, including vesicular stomatitis and influenza virus [27], murine gamma herpesvirus [28], respiratory syncytial virus [29], encephalomyocarditis virus [30], and West Nile, Dengue, and Zika viruses [31]. In some cases, microbiota depletion has been linked to a defective innate immune response characterized by low levels of type I IFN expression (IFNβ), which hampered the ability to mount an effective anti-viral macrophage response [27,29]. ...
Intestinal microbiota-virus-host interaction has emerged as a key factor in mediating enteric virus pathogenicity. With the aim of analyzing whether human gut bacteria improve the inefficient replication of human rotavirus in mice, we performed fecal microbiota transplant (FMT) with healthy infants as donors in antibiotic-treated mice. We showed that a simple antibiotic treatment, irrespective of FMT, resulted in viral shedding for 6 days after challenge with the human rotavirus G1P[8] genotype Wa strain (RVwa). Rotavirus titers in feces were also significantly higher in antibiotic-treated animals with or without FMT but they were decreased in animals subject to self-FMT, where a partial re-establishment of specific bacterial taxons was evidenced. Microbial composition analysis revealed profound changes in the intestinal microbiota of antibiotic-treated animals, whereas some bacterial groups, including members of Lactobacillus, Bilophila, Mucispirillum, and Oscillospira, recovered after self-FMT. In antibiotic-treated and FMT animals where the virus replicated more efficiently, differences were observed in gene expression of immune mediators, such as IL1β and CXCL15, as well as in the fucosyltransferase FUT2, responsible for H-type antigen synthesis in the small intestine. Collectively, our results suggest that antibiotic-induced microbiota depletion eradicates the microbial taxa that restrict human rotavirus infectivity in mice.
... Studies have shown that the intestinal microbiota plays an important role in modulating the immune system against viruses (12)(13)(14)(15). The regulatory effects of the intestinal microbiota on viral infection are closely intertwined with local and systemic immune responses and contribute to both congenital and adaptive immune responses (16,17). ...
The intestinal microbiota is thought to be an important biological barrier against enteric pathogens. Its depletion, however, also has curative effects against some viral infections, suggesting that different components of the intestinal microbiota can play both promoting and inhibitory roles depending on the type of viral infection. The two primary mechanisms by which the microbiota facilitates or inhibits viral invasion involve participation in the innate and adaptive immune responses and direct or indirect interaction with the virus, during which the abundance and composition of the intestinal microbiota might be changed by the virus. Oral administration of probiotics, faecal microbiota transplantation (FMT), and antibiotics are major therapeutic strategies for regulating intestinal microbiota balance. However, these three methods have shown limited curative effects in clinical trials. Therefore, the intestinal microbiota might represent a new and promising supplementary antiviral therapeutic target, and more efficient and safer methods for regulating the microbiota require deeper investigation. This review summarizes the latest research on the relationship among the intestinal microbiota, anti-viral immunity and viruses and the most commonly used methods for regulating the intestinal microbiota with the goal of providing new insight into the antiviral effects of the gut microbiota.
