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p53 suppresses the inflammatory response following respiratory syncytial virus infection by inhibiting TLR2
... As TLR2 is expressed on the apical surfaces of both tissues, TLR2 blockades may be useful for reducing hyperinflammation caused by Gram-positive pathogens when combined with appropriate antibiotics to adequately manage infection. TLR2 blockade, mediated by the p53 protein, may also reduce inflammatory responses to respiratory syncytial virus [178]. These therapies must be employed with caution; they may negatively affect immune homeostasis, as commensal organisms within the small intestine are known to maintain tolerance via TLR2 signaling [179]. ...
Mucosal epithelia represent a diverse group of tissues that function as a barrier against the external environment and exert a wide variety of tissue-specific secondary functions. This review focuses on the lower respiratory tract and small intestinal epithelia, which serve as two distinct sites within the body with respect to their physiological functions. This review provides an overview of their physiology, including both physiological and mechanical defense systems, and their immune responses, which allow both tissues to tolerate commensal organisms while mounting a response against potential pathogens. By highlighting the commonalities and differences across the two tissue types, opportunities to learn from these tissues emerge, which can inform the development of novel therapeutic strategies that harness the unique properties of mucosal epithelia.
Introduction:
The human respiratory syncytial virus (hRSV) is one of childhood diseases' most common respiratory pathogens and is associated with lower respiratory tract infections. The peak in disease that this virus can elicit during outbreaks is often a significant burden for healthcare systems worldwide. Despite theapproval of treatments against hRSV, this pathogen remains one the most common causative agent of infant mortality around the world.
Areas covered:
This review focuses on the key prognostic and immunomodulatory biomarkers associated with hRSV infection, as well as prophylactic monoclonal antibodies and vaccines. The goal is to catalyze a paradigm shift within the scientific community toward the discovery of novel targets to predict the clinical outcome of infected patients, as well as the development of novel antiviral agents targeting hRSV. The most pertinent research on this topic was systematically searched and analyzed using PubMed ISI Thomson Scientific databases.
Expert opinion:
Despite advances in approved therapies against hRSV, it is crucial to continue researching to develop new therapies and to find specific biomarkers to predict the severity of infection. Along these lines, the use of multi-omics data, artificial intelligence and natural-derived compounds with antiviral activity could be evaluated to fight hRSV and develop methods for rapid diagnosis of severity.
Introduction:
Lower respiratory tract infections (LRTI) remain a significant global cause of mortality and disability. Viruses constitute a substantial proportion of LRTI cases, with their pandemic potential posing a latent threat. After the SARS-CoV-2 pandemic, the resurgence of other respiratory viruses, including Influenza and Respiratory Syncytial Virus responsible for LRTI has been observed especially in susceptible populations.
Areas covered:
This review details the inflammatory mechanisms associated with three primary respiratory viruses: SARS-CoV-2, Influenza, and Respiratory Syncytial Virus (RSV). The focus will be on elucidating the activation of inflammatory pathways, understanding cellular contributions to inflammation, exploring the role of interferon and induced cell death in the response to these pathogens and detailing viral evasion mechanisms. Furthermore, the distinctive characteristics of each virus will be explained.
Expert opinion:
The study of viral pneumonia, notably concerning SARS-CoV-2, Influenza, and RSV, offers critical insights into infectious and inflammatory mechanisms with wide-ranging implications. Addressing current limitations, such as diagnostic accuracy and understanding host-virus interactions, requires collaborative efforts and investment in technology. Future research holds promise for uncovering novel therapeutic targets, exploring host microbiome roles, and addressing long-term sequelae. Integrating advances in molecular biology and technology will shape the evolving landscape of viral pneumonia research, potentially enhancing global public health outcomes.
Background Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development.
Pattern recognition receptors (PRRs) are a class of receptors that can directly recognize the specific molecular structures on the surface of pathogens, apoptotic host cells, and damaged senescent cells. PRRs bridge nonspecific immunity and specific immunity. Through the recognition and binding of ligands, PRRs can produce nonspecific anti-infection, antitumor, and other immunoprotective effects. Most PRRs in the innate immune system of vertebrates can be classified into the following five types based on protein domain homology: Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), C-type lectin receptors (CLRs), and absent in melanoma-2 (AIM2)-like receptors (ALRs). PRRs are basically composed of ligand recognition domains, intermediate domains, and effector domains. PRRs recognize and bind their respective ligands and recruit adaptor molecules with the same structure through their effector domains, initiating downstream signaling pathways to exert effects. In recent years, the increased researches on the recognition and binding of PRRs and their ligands have greatly promoted the understanding of different PRRs signaling pathways and provided ideas for the treatment of immune-related diseases and even tumors. This review describes in detail the history, the structural characteristics, ligand recognition mechanism, the signaling pathway, the related disease, new drugs in clinical trials and clinical therapy of different types of PRRs, and discusses the significance of the research on pattern recognition mechanism for the treatment of PRR-related diseases.
The innate immune response is critical for recognizing and controlling infections through the release of cytokines and chemokines. However, severe pathology during some infections, including SARS-CoV-2, is driven by hyperactive cytokine release, or a cytokine storm. The innate sensors that activate production of proinflammatory cytokines and chemokines during COVID-19 remain poorly characterized. In the present study, we show that both TLR2 and MYD88 expression were associated with COVID-19 disease severity. Mechanistically, TLR2 and Myd88 were required for β-coronavirus-induced inflammatory responses, and TLR2-dependent signaling induced the production of proinflammatory cytokines during coronavirus infection independent of viral entry. TLR2 sensed the SARS-CoV-2 envelope protein as its ligand. In addition, blocking TLR2 signaling in vivo provided protection against the pathogenesis of SARS-CoV-2 infection. Overall, our study provides a critical understanding of the molecular mechanism of β-coronavirus sensing and inflammatory cytokine production, which opens new avenues for therapeutic strategies to counteract the ongoing COVID-19 pandemic.
The limited antiviral options and lack of an effective vaccine against human respiratory syncytial virus (RSV) highlight the need for a novel antiviral therapy. One alternative is to identify and target the host factors required for viral infection. Here, using RNA interference to knock down Rab proteins, we provide multiple lines of evidence that Rab5a is required for RSV infection: (a) Rab5a is upregulated both in RSV-A2-infected A549 cells and RSV-A2-challenged BALB/c mice’s airway epithelial cells at early infection phase; (b) shRNA-mediated knockdown of Rab5a is associated with reduced lung pathology in RSV A2 challenged mice; (c) Rab5a expression is correlated with disease severity of RSV infection of infants. Knockdown of Rab5a increases IFN-λ (lambda) production by mediating IRF1 nuclear translocation. Our results highlight a new role for Rab5a in RSV infection, such that its depletion inhibits RSV infection by stimulating the endogenous respiratory epithelial antiviral immunity, which suggests that Rab5a is a potential target for novel therapeutics against RSV infection.
Importance This study highlights the important role of Rab5a in RSV infection, such that its depletion inhibits RSV infection by stimulating the endogenous respiratory epithelial antiviral immunity and attenuates inflammation of the airway, which suggests that Rab5a is a powerful potential target for novel therapeutics against RSV infection.
The onco-suppressor p53 is a transcription factor that regulates a wide spectrum of genes involved in various cellular functions including apoptosis, cell cycle arrest, senescence, autophagy, DNA repair and angiogenesis. p53 and NF-κB generally have opposing effects in cancer cells. While p53 activity is associated with apoptosis induction, the stimulation of NF-κB has been demonstrated to promote resistance to programmed cell death. Although the transcription factor NF-κB family is considered as the master regulator of cancer development and maintenance, it has been mainly studied in relation to its ability to regulate p53. This has revealed the importance of the crosstalk between NF-κB, p53 and other crucial cell signaling pathways. This review analyzes the various mechanisms by which NF-κB regulates the activity of p53 and the role of p53 on NF-κB activity.
Tumor suppressor p53 is not only affects immune responses but also contributes to antibacterial activity. However, its bactericidal function during mycobacterial infection remains unclear. In this study, we found that the p53-deficient macrophages failed to control Mycobacterium tuberculosis (Mtb), manifested as a lower apoptotic cell death rate and enhanced intracellular survival. The expression levels of p53 during Mtb infection were stronger in M1 macrophages than in M2 macrophages. The TLR2/JNK signaling pathway plays an essential role in the modulation of M1 macrophage polarization upon Mtb infection. It facilitates p53-mediated apoptosis through the production of reactive oxygen species, nitric oxide and inflammatory cytokines in Mtb-infected M1 macrophages. In addition, nutlin-3 effectively abrogated the intracellular survival of mycobacteria in both TB patients and healthy controls after H37Ra infection for 24 h, indicating that the enhancement of p53 production effectively suppressed the intracellular survival of Mtb in hosts. These results suggest that p53 can be a new therapeutic target for TB therapy.
The Toll-Like Receptor 8 (TLR8) has an important role in innate immune responses to RNA viral infections including respiratory syncytial virus (RSV). We reported previously that TLR8 expression was increased directly by the tumor suppressor and transcription factor p53 via a single nucleotide polymorphism (SNP: rs3761624) in the TLR8 promoter, thereby placing TLR8 in the p53/immune axis. Because this SNP is in linkage disequilibrium with other SNPs associated with several infectious diseases, we addressed the combined influence of p53 and the SNP on downstream inflammatory signaling in response to a TLR8 cognate ssRNA ligand. Using human primary lymphocytes, p53 induction by chemotherapeutic agents such as ionizing radiation caused SNP-dependent synergistic increases in IL-6 following incubation with an ssRNA ligand, as well as TLR8 RNA and protein expression along with p53 binding at the TLR-p53 SNP site. Because TLR8 is X-linked, the increases were generally reduced in heterozygous females. We found a corresponding association of the p53-responsive allele with RSV disease severity in infants hospitalized with RSV infection. We conclude that p53 can strongly influence TLR8 mediated immune responses and that knowledge of the p53 responsive SNP can inform diagnosis and prognosis of RSV disease and other diseases that might have a TLR8 component, including cancer.
Infants are exposed to a wide range of potential pathogens in the first months of life. Although maternal antibodies acquired transplacentally protect full-term neonates from many systemic pathogens, infections at mucosal surfaces still occur with great frequency, causing significant morbidity and mortality. At least part of this elevated risk is attributable to the neonatal immune system that tends to favor T regulatory and Th2 type responses when microbes are first encountered. Early-life infection with respiratory viruses is of particular interest because such exposures can disrupt normal lung development and increase the risk of chronic respiratory conditions, such as asthma. The immunologic mechanisms that underlie neonatal host–virus interactions that contribute to the subsequent development of asthma have not yet been fully defined. The goals of this review are (1) to outline the differences between the neonatal and adult immune systems and (2) to present murine and human data that support the hypothesis that early-life interactions between the immune system and respiratory viruses can create a lung environment conducive to the development of asthma.
Cancer and infection are predominant causes of human mortality and derive, respectively, from inadequate genomic and host defenses against environmental agents. The transcription factor p53 plays a central role in human tumor suppression. Despite its expression in immune cells and broad responsiveness to stressors, it is virtually unknown whether p53 regulates host defense against infection. We report that the lungs of naive p53(-/-) mice display genome-wide induction of NF-κB response element-enriched proinflammatory genes, suggestive of type 1 immune priming. p53-null and p53 inhibitor-treated mice clear Gram-negative and -positive bacteria more effectively than controls after intrapulmonary infection. This is caused, at least in part, by cytokines produced by an expanded population of apoptosis-resistant, TLR-hyperresponsive alveolar macrophages that enhance airway neutrophilia. p53(-/-) neutrophils, in turn, display heightened phagocytosis, Nox-dependent oxidant generation, degranulation, and bacterial killing. p53 inhibition boosts bacterial killing by mouse neutrophils and oxidant generation by human neutrophils. Despite enhanced bacterial clearance, infected p53(-/-) mice suffer increased mortality associated with aggravated lung injury. p53 thus modulates host defense through regulating microbicidal function and fate of phagocytes, revealing a fundamental link between defense of genome and host during environmental insult.
The transcription factor p53 regulates genes associated with a wide range of functions, including the Toll-like receptor (TLR) set of innate immunity genes, suggesting that p53 also modulates the human immune response. The TLR family comprises membrane glycoproteins that recognize pathogen-associated molecular patterns (PAMP) and mediate innate immune responses, and TLR agonists are being used as adjuvants in cancer treatments. Here, we show that doxorubicin, 5-fluorouracil, and UV and ionizing radiation elicit changes in TLR expression that are cell line- and damage-specific. Specifically, treatment-induced expression changes led to increased downstream cytokine expression in response to ligand stimulation. The effect of DNA stressors on TLR expression was mainly mediated by p53, and several p53 cancer-associated mutants dramatically altered the pattern of TLR gene expression. In all cell lines tested, TLR3 induction was p53-dependent, whereas induction of TLR9, the most stress-responsive family member, was less dependent on status of p53. In addition, each of the 10 members of the innate immune TLR gene family tested was differentially inducible. Our findings therefore show that the matrix of p53 status, chromosome stress, and responsiveness of individual TLRs should be considered in TLR-based cancer therapies.
Respiratory syncytial virus (RSV) is the major cause of viral respiratory infections in children. Our previous study showed that the RSV infection induced lung epithelial cell cycle arrest, which enhanced virus replication. To address the mechanism of RSV-induced cell cycle arrest, we examined the contribution of RSV-matrix (RSV-M) protein. In this report, we show that in both the A549 cell line and primary human bronchial epithelial (PHBE) cells, transfection with RSV-M protein caused the cells to proliferate at a slower rate than in control cells. The cell cycle analysis showed that RSV-M protein induced G1 phase arrest in A549 cells, and G1 and G2/M phase arrest in PHBE cells. Interestingly, RSV-M expression induced p53 and p21 accumulation and decreased phosphorylation of retinoblastoma protein (Rb). Further, induction of cell cycle arrest by RSV-M was not observed in a p53-deficient epithelial cell line (H1299). However, cell cycle arrest was restored after transfection of p53 cDNA into H1299 cells. Taken together, these results indicate that RSV-M protein regulates lung epithelial cell cycle through a p53-dependent pathway, which enhances RSV replication.
Toll-like receptors (TLRs) are recognition molecules for multiple pathogens, including bacteria, viruses, fungi, and parasites. TLR2 forms heterodimers with TLR1 and TLR6, which is the initial step in a cascade of events leading to significant innate immune responses, development of adaptive immunity to pathogens and protection from immune sequelae related to infection with these pathogens. This review will discuss the current status of TLR2 mediated immune responses by recognition of pathogen-associated molecular patterns (PAMPS) on these organisms. We will emphasize both canonical and non-canonical responses to TLR2 ligands with emphasis on whether the inflammation induced by these responses contributes to the disease state or to protection from diseases.
Ultracentrifugation in sucrose density gradient remains the most commonly used technique for hRSV purification. However, the high viscosity and hyper-osmotic property of sucrose can cause damage to the extremely labile virus leading to loss of infectivity. To overcome these limitations, an alternative purification technique was developed using iodixanol as gradient medium, incorporating MgSO(4) as a stabilizing agent and EDTA to disaggregate the virus prior to infectivity assay. Virus particles were banded at the 20-36% interface after purification of polyethylene glycol-concentrated viruses by rate zonal ultracentrifugation on a 20-52% discontinuous iodixanol gradient. The presence of the virus was confirmed by viral fusion glycoprotein content using ELISA. After further purification by buoyant density ultracentrifugation on a 20-52% continuous gradient, the virus was recovered in the region of density 1.15-1.19 g/ml and this was confirmed by the coincidence of the infectivity titre, viral genome and fusion glycoprotein peaks. Analysis of recovery rates showed that the use of iodixanol increased the virus yield up to 69%. Iodixanol was also found to be non-toxic to HeLa cells used in infectivity assay, eliminating the need of its downstream removal by dialysis.
Several direct target genes of the p53 tumor suppressor have been identified within pathways involved in viral sensing, cytokine production, and inflammation, suggesting a potential role of p53 in antiviral immunity. The increasing need to identify immune factors to devise host-targeted therapies against pandemic influenza A virus (IAV) led us to investigate the role of endogenous wild-type p53 on the immune response to IAV. We observed that the absence of p53 resulted in delayed cytokine and antiviral gene responses in lung and bone marrow, decreased dendritic cell activation, and reduced IAV-specific CD8(+) T cell immunity. Consequently, p53(-/-) mice showed a more severe IAV-induced disease compared with their wild-type counterparts. These findings establish that p53 influences the antiviral response to IAV, affecting both innate and adaptive immunity. Thus, in addition to its established functions as a tumor suppressor gene, p53 serves as an IAV host antiviral factor that might be modulated to improve anti-IAV therapy and vaccines.
Abnormal apoptotic events in chronic obstructive pulmonary disease (COPD) subvert cellular homeostasis and may play a primary role in its pathogenesis. However, studies in human subjects are limited.
p53 and bcl2 protein expression was measured by western blot on lung tissue specimens from 43 subjects (23 COPD smokers and 20 non-COPD smokers), using beta-actin as internal control. Additionally, p53 and bcl2 expression patterns were evaluated by immunohistochemistry in formalin-fixed, paraffin-embedded lung tissue sections from the same individuals.
Western blot analysis showed statistically significant increased p53 protein levels in COPD smokers in comparison with non-COPD smokers (p = 0.038), while bcl2 protein levels were not statistically different between the two groups. Lung immunohistochemistry showed increased ratio of positive p53-stained type II pneumocytes/total type II pneumocytes in COPD smokers compared to non-COPD smokers (p = 0.01), whereas the p53 staining ratio in alveolar macrophages and in lymphocyte-like cells did not differ statistically between the two groups. On the other hand, bcl2 expression did not differ between the two groups in all three cell types.
The increased expression of pro-apoptotic p53 in type II pneumocytes of COPD patients not counterbalanced by the anti-apoptotic bcl2 could reflect increased apoptosis in the alveolar epithelium of COPD patients. Our results confirm previous experiments and support the hypothesis of a disturbance in the balance between the pro- and anti-apoptotic mediators in COPD.
Respiratory syncytial virus (RSV) is a common cause of infection that is associated with a range of respiratory illnesses, from common cold-like symptoms to serious lower respiratory tract illnesses such as pneumonia and bronchiolitis. RSV is the single most important cause of serious lower respiratory tract illness in children <1 year of age. Host innate and acquired immune responses activated following RSV infection have been suspected to contribute to RSV disease. Toll-like receptors (TLRs) activate innate and acquired immunity and are candidates for playing key roles in the host immune response to RSV. Leukocytes express TLRs, including TLR2, TLR6, TLR3, TLR4, and TLR7, that can interact with RSV and promote immune responses following infection. Using knockout mice, we have demonstrated that TLR2 and TLR6 signaling in leukocytes can activate innate immunity against RSV by promoting tumor necrosis factor alpha, interleukin-6, CCL2 (monocyte chemoattractant protein 1), and CCL5 (RANTES). As previously noted, TLR4 also contributes to cytokine activation (L. M. Haynes, D. D. Moore, E. A. Kurt-Jones, R. W. Finberg, L. J. Anderson, and R. A. Tripp, J. Virol. 75:10730-10737, 2001, and E. A. Kurt-Jones, L. Popova, L. Kwinn, L. M. Haynes, L. P. Jones, R. A. Tripp, E. E. Walsh, M. W. Freeman, D. T. Golenbock, L. J. Anderson, and R. W. Finberg, Nat. Immunol. 1:398-401, 2000). Furthermore, we demonstrated that signals generated following TLR2 and TLR6 activation were important for controlling viral replication in vivo. Additionally, TLR2 interactions with RSV promoted neutrophil migration and dendritic cell activation within the lung. Collectively, these studies indicate that TLR2 is involved in RSV recognition and subsequent innate immune activation.
Airway epithelial cells are unresponsive to endotoxin (lipopolysaccharide (LPS)) exposure under normal conditions. This study demonstrates that respiratory syncytial virus (RSV) infection results in increased sensitivity to this environmental exposure. Infection with RSV results in increased expression of Toll-like receptor (TLR) 4 mRNA, protein, and increased TLR4 membrane localization. This permits significantly enhanced LPS binding to the epithelial monolayer that is blocked by disruption of the Golgi. The increased TLR4 results in an LPS-induced inflammatory response as demonstrated by increased mitogen-activated protein (MAP) kinase activity, IL-8 production, and tumor necrosis factor alpha production. RSV infection also allowed for tumor necrosis factor alpha production subsequent to TLR4 cross-linking with an immobilized antibody. These data suggest that RSV infection sensitizes airway epithelium to a subsequent environmental exposure (LPS) by altered expression and membrane localization of TLR4. The increased interaction between airway epithelial cells and LPS has the potential to profoundly alter airway inflammation.
Phosphoinositide 3-kinase (PI3K) is thought to contribute to the pathogenesis of asthma by effecting the recruitment, activation, and apoptosis of inflammatory cells. We examined the role of class IA PI3K in antigen-induced airway inflammation and hyperresponsiveness by i.p. administration into mice of Deltap85 protein, a dominant negative form of the class IA PI3K regulatory subunit, p85alpha, which was fused to HIV-TAT (TAT-Deltap85). Intraperitoneal administration of TAT-Deltap85 caused time-dependent transduction into blood leukocytes, and inhibited activated phosphorylation of protein kinase B (PKB), a downstream target of PI3K, in lung tissues in mice receiving intranasal FMLP. Antigen challenge elicited pulmonary infiltration of lymphocytes, eosinophils and neutrophils, increase in mucus-containing epithelial cells, and airway hyperresponsiveness to methacholine. Except for modest airway neutrophilia, these effects all were blocked by treatment with 3-10 mg/kg of TAT-Deltap85. There was also significant reduction in IL-5 and IL-4 secretion into the BAL. Intranasal administration of IL-5 caused eosinophil migration into the airway lumen, which was attenuated by systemic pretreatment with TAT-Deltap85. We conclude that PI3K has a regulatory role in Th2-cell cytokine secretion, airway inflammation, and airway hyperresponsiveness in mice.
Respiratory syncytial virus (RSV) infection causes bronchiolitis in infants and children, which can be fatal, especially in immunocompromised patients. The BALB/c mouse, currently used as a model for studying RSV immunopathology, is semi-permissive to the virus. A mouse model that more closely mimics human RSV infection is needed. Since immunocompromised conditions increase risk of RSV infection, the possibility of enhancing RSV infection in the BALB/c mouse by pretreatment with cyclophosphamide was examined in this study. BALB/c mice were treated with cyclophosphamide (CYP) and five days later, they were infected with RSV intranasally. Pulmonary RSV titers, inflammation and airway hyperresponsiveness were measured five days after infection.
CYP-treated mice show higher RSV titers in their lungs of than the untreated mice. Also, a decreased percentage of macrophages and an increased number of lymphocytes and neutrophils were present in the BAL of CYP-treated mice compared to controls. The CYP-treated group also exhibited augmented bronchoalveolar and interstitial pulmonary inflammation. The increased RSV infection in CYP-treated mice was accompanied by elevated expression of IL-10, IL-12 and IFN-gamma mRNAs and proteins compared to controls. Examination of CYP-treated mice before RSV infection showed that CYP treatment significantly decreased both IFN-gamma and IL-12 expression.
These results demonstrate that CYP-treated BALB/c mice provide a better model for studying RSV immunopathology and that decreased production of IL-12 and IFN-gamma are important determinants of susceptibility to RSV infection.
Respiratory syncytial virus (RSV) is one of the commonest and most troublesome viruses of infancy. It causes most cases of bronchiolitis, which is associated with wheezing in later childhood. In primary infection, the peak of disease typically coincides with the development of specific T- and B-cell responses, which seem, in large part, to be responsible for disease. Animal models clearly show that a range of immune responses can enhance disease severity, particularly after vaccination with formalin-inactivated RSV. Prior immune sensitization leads to exuberant chemokine production, an excessive cellular influx, and an overabundance of cytokines during RSV challenge. Under different circumstances, specific mediators and T-cell subsets and antibody-antigen immune complex deposition are incriminated as major factors in disease. Animal models of immune enhancement permit a deep understanding of the role of specific immune responses in RSV disease, assist in vaccine design, and indicate which immunomodulatory therapy might be beneficial to children with bronchiolitis.
p53 has been well characterized as a tumor suppressor gene, but its role in antiviral defense remains unclear. A recent report
has demonstrated that p53 can be induced by interferons and is activated after vesicular stomatitis virus (VSV) infection.
We observed that different nononcogenic viruses, including encephalomyocarditis virus (EMCV) and human parainfluenza virus
type 3 (HPIV3), induced down-regulation of p53 in infected cells. Double-stranded RNA (dsRNA) and a mutant vaccinia virus
lacking the dsRNA binding protein E3L can also induce this effect, indicating that dsRNA formed during viral infection is
likely the trigger for down-regulation of p53. The mechanism of down-regulation of p53 by dsRNA relies on translation inhibition
mediated by the PKR and RNase L pathways. In the absence of p53, the replication of both EMCV and HPIV3 was retarded, whereas,
conversely, VSV replication was enhanced. Cell cycle analysis indicated that wild-type (WT) but not p53 knockout (KO) fibroblasts
undergo an early-G1 arrest following dsRNA treatment. Moreover, in WT cells the onset of dsRNA-induced apoptosis begins after p53 levels are
down-regulated, whereas p53 KO cells, which lack the early-G1 arrest, rapidly undergo apoptosis. Hence, our data suggest that the down-regulation of p53 facilitates apoptosis, thereby
limiting viral replication.
The tumor suppressor protein, p53, plays a critical role in viro-oncology. However, the role of p53 in adenoviral replication is still poorly understood. In this paper, we have explored further the effect of p53 on adenoviral replicative lysis. Using well-characterized cells expressing a functional p53 (A549, K1neo, RKO) and isogenic derivatives that do not (K1scx, RKOp53.13), we show that virus replication, late virus protein expression and both wtAd5 and ONYX-015 virus-induced cell death are impaired in cells deficient in functional p53. Conversely, by transfecting p53 into these and other cells (IIICF/c, HeLa), we increase late virus protein expression and virus yield. We also show, using reporter assays in IIICF/c, HeLa and K1scx cells, that p53 can cooperate with E1a to enhance transcription from the major late promoter of the virus. Late viral protein production is enhanced by exogenous p53. Taken together, our data suggest that functional p53 can promote the adenovirus (Ad) lytic cycle. These results have implications for the use of Ad mutants that are defective in p53 degradation, such as ONYX-015, as agents for the treatment of cancers.
Respiratory syncytial virus (RSV) bronchiolitis is the most important cause for admission to the paediatric intensive care unit in infants with lower respiratory tract infection. In recent years the importance of extrapulmonary manifestations of RSV infection has become evident. This systematic review aimed at summarizing the available evidence on manifestations of RSV infection outside the respiratory tract, their causes and the changes in clinical management required.
Databases searched were Medline (1950 to present), EMBASE (1974 to present), PubMed and reference lists of relevant articles. Summarized were the findings of articles reporting on manifestations of RSV infection outside the respiratory tract in patients of all age groups.
Extrapulmonary manifestations reported in previous observational studies included cardiovascular failure with hypotension and inotrope requirements associated with myocardial damage as evident from elevated cardiac troponin levels (35-54% of ventilated infants), cardiac arrhythmias like supraventricular tachycardias and ventricular tachycardias, central apnoeas (16-21% of admissions), focal and generalized seizures, focal neurological abnormalities, hyponatraemia (33%) associated with increased antidiuretic hormone secretion, and hepatitis (46-49% of ventilated infants). RSV or its genetic material have been isolated from cerebrospinal fluid, myocardium, liver and peripheral blood.
The data summarized indicate a systemic dissemination of RSV during severe disease. Cerebral and myocardial involvement may explain the association of RSV with some cases of sudden infant death. In infants with severe RSV infection cardiac rhythm, blood pressure and serum sodium need to be monitored and supportive treatment including fluid management adjusted accordingly.
PML nuclear bodies (NBs) are dynamic intranuclear structures harboring numerous transiently or permanently localized proteins.
PML, the NBs' organizer, is directly induced by interferon, and its expression is critical for antiviral host defense. We
describe herein the molecular events following poliovirus infection that lead to PML-dependent p53 activation and protection
against virus infection. Poliovirus infection induces PML phosphorylation through the extracellular signal-regulated kinase
pathway, increases PML SUMOylation, and induces its transfer from the nucleoplasm to the nuclear matrix. These events result
in the recruitment of p53 to PML NBs, p53 phosphorylation on Ser15, and activation of p53 target genes leading to the induction
of apoptosis. Moreover, the knock-down of p53 by small interfering RNA results in higher poliovirus replication, suggesting
that p53 participates in antiviral defense. This effect, which requires the presence of PML, is transient since poliovirus
targets p53 by inducing its degradation in a proteasome- and MDM2-dependent manner. Our results provide evidence of how poliovirus
counteracts p53 antiviral activity by regulating PML and NBs, thus leading to p53 degradation.
Infection of primary fibroblasts with human cytomegalovirus (HCMV) causes a rapid stabilization of the cellular protein p53. p53 is a major effector of the cellular damage response, and activation of this transcription factor can lead either to cell cycle arrest or to apoptosis. Viruses employ many tactics to avoid p53-mediated effects. One method HCMV uses to counteract p53 is sequestration into its viral replication centers. In order to determine whether or not HCMV benefits from this sequestration, we infected a p53(-/-) fibroblast line. We find that although these cells are permissive for viral infection, several parameters are substantially altered compared to wild-type (wt) fibroblasts. p53(-/-) cells show delayed and decreased accumulation of infectious viral particles compared to control fibroblasts, with the largest difference of 100-fold at 72 h post infection (p.i.) and peak titers decreased by approximately 10- to 20-fold at 144 h p.i. Viral DNA accumulation is also delayed and somewhat decreased in p53(-/-) cells; however, on average, levels of DNA are not more than fivefold lower than wt at any time p.i. and thus cannot account entirely for the observed differences in titers. In addition, there are delays in the expression of several key viral proteins, including the early replication protein UL44 and some of the late structural proteins, pp28 (UL99) and MCP (UL86). UL44 localization also indicates delayed formation and maturation of the replication centers throughout the course of infection. Localization of the major tegument protein pp65 (UL83) is also altered in these p53(-/-) cells. Partial reconstitution of the p53(-/-) cells with a wt copy of p53 returns all parameters toward wt, while reconstitution with mutant p53 does not. Taken together, our data suggest that wt p53 enhances the ability of HCMV to replicate and produce high concentrations of infectious virions in permissive cells.
Respiratory syncytial virus (RSV) is a clinically important pathogen. It preferentially infects airway epithelial cells causing bronchiolitis in infants, exacerbations in patients with obstructive lung disease, and life-threatening pneumonia in the immunosuppressed. The p53 protein is a tumor suppressor protein that promotes apoptosis and is tightly regulated for optimal cell growth and survival. A critical negative regulator of p53 is murine double minute 2 (Mdm2), an E3 ubiquitin ligase that targets p53 for proteasome degradation. Mdm2 is activated by phospho-Akt, and we previously showed that RSV activates Akt and delays apoptosis in primary human airway epithelial cells. In this study, we explore further the mechanism by which RSV regulates p53 to delay apoptosis but paradoxically enhance inflammation. We found that RSV activates Mdm2 1-6 h after infection resulting in a decrease in p53 6-24 h after infection. The p53 down-regulation correlates with increased airway epithelial cell longevity. Importantly, inhibition of the PI3K/Akt pathway blocks the activation of Mdm2 by RSV and preserves the p53 response. The effects of RSV infection are antagonized by Nutlin-3, a specific chemical inhibitor that prevents the Mdm2/p53 association. Nutlin-3 treatment increases endogenous p53 expression in RSV infected cells, causing earlier cell death. This same increase in p53 enhances viral replication and limits the inflammatory response as measured by IL-6 protein. These findings reveal that RSV decreases p53 by enhancing Akt/Mdm2-mediated p53 degradation, thereby delaying apoptosis and prolonging survival of airway epithelial cells.
Infection with respiratory syncytial virus (RSV) frequently causes inflammation and obstruction of the small airways, leading
to severe pulmonary disease in infants. We show here that the RSV fusion (F) protein, an integral membrane protein of the
viral envelope, is a strong elicitor of apoptosis. Inducible expression of F protein in polarized epithelial cells triggered
caspase-dependent cell death, resulting in rigorous extrusion of apoptotic cells from the cell monolayer and transient loss
of epithelial integrity. A monoclonal antibody directed against F protein inhibited apoptosis and was also effective if administered
to A549 lung epithelial cells postinfection. F protein expression in epithelial cells caused phosphorylation of tumor suppressor
p53 at serine 15, activation of p53 transcriptional activity, and conformational activation of proapoptotic Bax. Stable expression
of dominant-negative p53 or p53 knockdown by RNA interference inhibited the apoptosis of RSV-infected A549 cells. HEp-2 tumor
cells with low levels of p53 were not sensitive to RSV-triggered apoptosis. We propose a new model of RSV disease with the
F protein as an initiator of epithelial cell shedding, airway obstruction, secondary necrosis, and consequent inflammation.
This makes the RSV F protein a key target for the development of effective postinfection therapies.
The large global burden of respiratory syncytial virus (RSV) respiratory tract infections in young children and older adults has gained increased recognition in recent years. Recent discoveries regarding the neutralization-specific viral epitopes of the pre-fusion RSV glycoprotein have led to a shift from empirical to structure-based design of RSV therapeutics, and controlled human infection model studies have provided early-stage proof of concept for novel RSV monoclonal antibodies, vaccines and antiviral drugs. The world's first vaccines and first monoclonal antibody to prevent RSV among older adults and all infants, respectively, have recently been approved. Large-scale introduction of RSV prophylactics emphasizes the need for active surveillance to understand the global impact of these interventions over time and to timely identify viral mutants that are able to escape novel prophylactics. In this Review, we provide an overview of RSV interventions in clinical development, highlighting global disease burden, seasonality, pathogenesis, and host and viral factors related to RSV immunity.
Mutations in the TP53 tumour suppressor gene are very frequent in cancer, and attempts to restore the functionality of p53 in tumours as a therapeutic strategy began decades ago. However, very few of these drug development programmes have reached late-stage clinical trials, and no p53-based therapeutics have been approved in the USA or Europe so far. This is probably because, as a nuclear transcription factor, p53 does not possess typical drug target features and has therefore long been considered undruggable. Nevertheless, several promising approaches towards p53-based therapy have emerged in recent years, including improved versions of earlier strategies and novel approaches to make undruggable targets druggable. Small molecules that can either protect p53 from its negative regulators or restore the functionality of mutant p53 proteins are gaining interest, and drugs tailored to specific types of p53 mutants are emerging. In parallel, there is renewed interest in gene therapy strategies and p53-based immunotherapy approaches. However, major concerns still remain to be addressed. This Review re-evaluates the efforts made towards targeting p53-dysfunctional cancers, and discusses the challenges encountered during clinical development.
The lungs are constantly exposed to inhaled debris, allergens, pollutants, commensal or pathogenic microorganisms, and respiratory viruses. As a result, innate and adaptive immune responses in the respiratory tract are tightly regulated and are in continual flux between states of enhanced pathogen clearance, immune-modulation, and tissue repair. New single-cell-sequencing techniques are expanding our knowledge of airway cellular complexity and the nuanced connections between structural and immune cell compartments. Understanding these varied interactions is critical in treatment of human pulmonary disease and infections and in next-generation vaccine design. Here, we review the innate and adaptive immune responses in the lung and airways following infection and vaccination, with particular focus on influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The ongoing SARS-CoV-2 pandemic has put pulmonary research firmly into the global spotlight, challenging previously held notions of respiratory immunity and helping identify new populations at high risk for respiratory distress.
Virus invasion activates the host's innate immune response, inducing the production of numerous cytokines and interferons to eliminate the pathogens. Except for viral DNA/RNA, viral proteins are also target of pattern recognition receptors (PRRs). Membrane-bound receptors TLR1, TLR2, TLR4, TLR6 and TLR10 relate to the recognition of viral proteins. Distinct TLRs perform both protective and detrimental roles to specific virus. Here, we review viral proteins serving as pathogen-associated molecular patterns (PAMPs) and their corresponding Toll-like receptors (TLRs). These viruses are all enveloped, including respiratory syncytial virus, hepatitis C virus, measles virus, herpesvirus human immunodeficiency virus and coronavirus, which can encode proteins to activate innate immunity in a TLR-dependent way. TLR-viral protein relationship plays an important role in innate immunity activation. A detailed understanding of their pathways contributes to novel direction for vaccine development.
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Background:
The human respiratory syncytial virus (RSV) has been linked with various respiratory diseases such as common cold to lower respiratory tract illnesses like pneumonia and bronchiolitis. TLRs play a critical role in generating host immune responses against RSV. TLRs are expressed not only on leukocytes but also on many other cell types and can recognize RSV. Previous studies have established that RSV can interact with TLR4 and initiate an inflammatory cascade of cytokines. The data from a recent study indicated that TLR2/TLR6 is involved in RSV recognition and subsequent innate immune activation. However, the nature of binding and the envelope protein of RSV involved in this interaction with TLRs are not studied yet.
Objective:
We hypothesized that RSV G protein could bind to TLRs and mediate the inflammatory immune response against the virus infection. Therefore, we investigated whether RSV G protein could activate innate immune response through TLR signaling.
Methods:
Different TLR antagonists were used to assessing the effect of RSV and RSV G ectodomain exposure in human primary small airway epithelial cells (HSAECs). Various inflammatory cytokines, chemokines, and type I IFNs were measured by ELISA along with their mRNA expression by qPCR. In silico interaction of RSV G protein with TLR2/TLR6 was also analyzed.
Results:
ELISA and qPCR analysis have shown that TLR2/TLR6 signaling is activated in HSAECs upon RSV and RSV G protein exposure which initiates innate immune response against RSV. Moreover, RSV envelope protein G plays a crucial role in the binding and activating TLR2/TLR6 signaling.
Conclusion:
In summary, our study shows that TLR2/TLR6 plays an essential role in activating an innate immune response upon RSV recognition, which could help promote RSV clearance and preventing RSV-induced disease.
Background
Respiratory syncytial virus (RSV) is the leading cause of acute respiratory infections (ARI) in hospitalized children. Although prematurity and underlying medical conditions are known risk factors, most of these children are healthy, and factors including RSV load and subgroups may contribute to RSV-ARI severity. Therefore, we aimed to evaluate the role of RSV in ARI disease severity and determine factors associated with increased RSV-ARI severity in young children.
Method
Children less than five years with fever and/or ARI symptoms were recruited from the emergency department (ED) or inpatient settings at Vanderbilt Children's Hospital. Nasal and/or throat swabs were tested by qRT-PCR for common respiratory viruses, including RSV. A severity score was calculated for RSV-positive children.
Results
From 11/2015 through 07/2016, 898 participants were enrolled, and 681 (76%) had at least one virus detected, with 191 (28%) testing positive for RSV. RSV-positive children were more likely to be hospitalized, require intensive care unit (ICU) admission, and receive oxygen compared to other-virus-positive children. Higher viral load, White race, younger age, and higher severity score were independently associated with hospitalization in RSV-positive children. No differences in disease severity were noted among children infected with RSV A and B.
Conclusion
RSV was associated with increased ARI severity in young children enrolled from ED and inpatient settings, but no differences in disease severity were noted between RSV A and B. . These findings emphasize the need for effective antiviral therapy and/or preventive measures such as vaccines against RSV in young children.
The evolutionarily conserved p53 protein and its cellular pathways mediate tumour suppression through an informed, regulated and integrated set of responses to environmental perturbations resulting in either cellular death or the maintenance of cellular homeostasis. The p53 and MDM2 proteins form a central hub in this pathway that receives stressful inputs via MDM2 and respond via p53 by informing and altering a great many other pathways and functions in the cell. The MDM2–p53 hub is one of the hubs most highly connected to other signalling pathways in the cell, and this may be why TP53 is the most commonly mutated gene in human cancers. Initial or truncal TP53 gene mutations (the first mutations in a stem cell) are selected for early in cancer development inectodermal and mesodermal-derived tissue-specific stem and progenitor cells and then, following additional mutations, produce tumours from those tissue types. In endodermal-derived tissue-specific stem or progenitor cells, TP53 mutations are functionally selected as late mutations transitioning the mutated cell into a malignant tumour. The order in which oncogenes or tumour suppressor genes are functionally selected for in a stem cell impacts the timing and development of a tumour.
Respiratory syncytial virus (RSV) is one of the leading causes of viral respiratory tract infection in infants, the elderly and the immunocompromised worldwide, causing more deaths each year than influenza. Years of research into RSV since its discovery over 60 years ago have elucidated detailed mechanisms of the host-pathogen interface. RSV infection elicits widespread transcriptomic and proteomic changes, which both mediate the host innate and adaptive immune responses to infection, and reflect RSV's ability to circumvent the host stress responses, including stress granule formation, endoplasmic reticulum stress, oxidative stress, and programmed cell death. The combination of these events can severely impact on human lungs, resulting in airway remodeling and pathophysiology. The RSV membrane envelope glycoproteins (fusion F and attachment G), matrix (M) and nonstructural (NS) 1 and 2 proteins play key roles in modulating host cell functions to promote the infectious cycle. This review presents a comprehensive overview of how RSV impacts the host response to infection, and how detailed knowledge of the mechanisms thereof can inform the development of new approaches to develop RSV vaccines and therapeutics.
Innate lymphoid cells (ILCs) are enriched at barrier surfaces of the mammalian body where they rapidly respond to host, microbial or environmental stimuli to promote immunity or tissue homeostasis. Furthermore, ILCs are dysregulated in multiple human diseases. Over the past decade, substantial advances have been made in identifying the heterogeneity and functional diversity of ILCs, which have revealed striking similarities to T cell subsets. However, emerging evidence indicates that ILCs also have a complex role in directly influencing the adaptive immune response in the context of development, homeostasis, infection or inflammation. In turn, adaptive immunity reciprocally regulates ILCs, which indicates that these interactions are a crucial determinant of immune responses within tissues. Here, we summarize our current understanding of functional interactions between ILCs and the adaptive immune system, discuss limitations and future areas of investigation, and consider the potential for these interactions to be therapeutically harnessed to benefit human health. This Review focuses on evidence implicating innate lymphoid cells (ILCs) as previously unappreciated regulators of the adaptive immune system. Reciprocal interactions between ILCs and adaptive immune cells are a crucial determinant of tissue immune responses during homeostasis and disease.
Introduction:
The association between RSV loads (VL) and clinical outcomes in children remains to be defined. In most studies VL were evaluated in hospitalized children and at a single time-point. We investigated the relationship between VLs and disease severity in both outpatients and inpatients with RSV infection.
Methods:
We enrolled previously healthy children with RSV infection. Disease severity was defined by level of care (outpatients vs ward vs PICU), and a clinical disease severity score (CDSS). Nasopharyngeal VL by PCR and CDSSs were measured at enrollment and daily in inpatients. VL decay according to disease severity was analyzed using linear mixed modeling.
Results:
From 2/2015 to 3/2017 we enrolled 150 infants: 39 outpatients and 111 inpatients. VLs were higher in outpatients vs age-matched inpatients. Among inpatients initial VLs were comparable in ward and PICU patients, and preceded the peak CDSS. However, after excluding infants treated with steroids, those hospitalized in the ward had higher VLs than infants requiring PICU care (p<0.001). Dynamic analyses showed that VL decay was delayed in PICU patients, especially in those treated with steroids.
Conclusions:
Higher VLs at presentation, and a faster and consistent VL decline were both associated with less severe RSV disease in children.
p53 transcriptional networks are well-characterized in many organisms. However, a global understanding of requirements for in vivo p53 interactions with DNA and relationships with transcription across human biological systems in response to various p53 activating situations remains limited. Using a common analysis pipeline, we analyzed 41 data sets from genome-wide ChIP-seq studies of which 16 have associated gene expression data, including our recent primary data with normal human lymphocytes. The resulting extensive analysis, accessible at p53 BAER hub via the UCSC browser, provides a robust platform to characterize p53 binding throughout the human genome including direct influence on gene expression and underlying mechanisms. We establish the impact of spacers and mismatches from consensus on p53 binding in vivo and propose that once bound, neither significantly influences the likelihood of expression. Our rigorous approach revealed a large p53 genome-wide cistrome composed of >900 genes directly targeted by p53. Importantly, we identify a core cistrome signature composed of genes appearing in over half the data sets, and we identify signatures that are treatment- or cell-specific, demonstrating new functions for p53 in cell biology. Our analysis reveals a broad homeostatic role for human p53 that is relevant to both basic and translational studies.
The interplay between respiratory syncytial virus (RSV) and the p53 pathway has only been reported in a limited number of studies, yet the underlying abrogation mechanisms of p53 activity during the time course of infection, possibly involving viral proteins, remained unclear. Here, we demonstrate that RSV infection impairs global p53 transcriptional activity, notably via its proteasome-dependent degradation at late stages of infection. We also demonstrate that NS1 and NS2 contribute to the abrogation of p53 activity, and used different experimental strategies (e.g. siRNA, small molecules) to underline the antiviral contribution of p53 in the context of RSV infection. Notably, our study highlights a strong RSV-induced disequilibrium of the p53/NF-κB functional balance, which appears to contribute to the up-regulation of the expression of several proinflammatory cytokines and chemokines.
Respiratory syncytial virus (RSV) is an exceptional mucosal pathogen. It specializes in infection of the ciliated respiratory epithelium, causing disease of variable severity with little or no direct systemic effects. It infects virtually all children by the age of three years and then repeatedly infects throughout life; this it does despite relatively slight variations in antigenicity, apparently by inducing selective immunological amnesia. Inappropriate or dysregulated responses to RSV can be pathogenic, causing disease-enhancing inflammation that contributes to short- and long-term effects. In addition, RSV's importance as a largely unrecognized pathogen of debilitated older people is increasingly evident. Vaccines that induce nonpathogenic protective immunity may soon be available, and it is possible that different vaccines will be optimal for infants; older children; young to middle-age adults (including pregnant women); and elderly persons. At the dawn of RSV vaccination, it is timely to review what is known (and unknown) about immune responses to this fascinating virus. Expected final online publication date for the Annual Review of Immunology Volume 35 is April 26, 2017 . Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Tumour-suppressor genes are indispensable for the maintenance of genomic integrity. Recently, several of these genes, including those encoding p53, PTEN, RB1 and ARF, have been implicated in immune responses and inflammatory diseases. In particular, the p53 tumour- suppressor pathway is involved in crucial aspects of tumour immunology and in homeostatic regulation of immune responses. Other studies have identified roles for p53 in various cellular processes, including metabolism and stem cell maintenance. Here, we discuss the emerging roles of p53 and other tumour-suppressor genes in tumour immunology, as well as in additional immunological settings, such as virus infection. This relatively unexplored area could yield important insights into the homeostatic control of immune cells in health and disease and facilitate the development of more effective immunotherapies. Consequently, tumour-suppressor genes are emerging as potential guardians of immune integrity.
Clin Microbiol Infect 2010; 16: 1399–1404 Abstract It is reported that bacterial colonization of the airway in neonates affects the likelihood and severity of subsequent wheezing in childhood. This study aimed to explore the impact of bacterial colonization on the severity of virus-induced wheezing, and accompanying airway inflammation. Nasopharyngeal aspirates (NPAs) from 68 hospitalized children with bronchiolitis and 85 children with recurrent wheezing were obtained. Eleven common respiratory viruses were sought by PCR and/or direct fluorescence assay. Bacteria were isolated from NPAs by routine culture methods. Cell numbers and concentrations of cytokines/chemokines in the NPAs were measured, and nucleated cells were characterized. The frequency of bacterial colonization in children with recurrent wheezing was significantly higher than in children with an initial attack of bronchiolitis. Bacterial colonization accompanying virus infection had no effect on clinical manifestations, duration of hospitalization, concentrations of cytokines/chemokines (except interleukin-10 (IL-10)) or cellularity in the children with bronchiolitis; however, among the children with recurrent wheezing, those who had coexistent non-invasive bacterial colonization and virus infection presented more frequent cyanosis, longer duration of hospitalization, a higher concentration of IL-10 and a higher percentage of neutrophils in NPAs than those with virus infection but without bacterial colonization. Bacterial colonization was common in children with virus-induced wheezing, particularly in the situation of recurrent wheezing. To some extent, bacterial colonization accompanying virus infection may contribute to the severity of the wheezing because of its impact on airway inflammation.
Purpose of review:
The p53 tumor suppressor is a master regulator of antitumor defenses through its control of growth arrest, senescence and apoptosis. In recent years, p53 regulation was found to extend to a variety of biological processes including autophagy, fertility, metabolism and immune responses. Here, we focus on the role of p53 in the immune system. We explore the relationship between p53 and the innate immune response with particular emphasis on the Toll-like receptor (TLR) pathway and implications for cancer therapy.
Recent findings:
Numerous studies have shown that the immune system, especially innate immunity, has a critical role in tumor development. It appears that p53 can influence innate immune responses as part of its tumor suppressor activities and recent work suggests that the complete set of innate immune TLR genes are responsive to chromosomal stress and the transcriptional network regulated by p53. Activation of p53 by common antitumor agents results in p53 dependent regulation of expression of most TLR genes in human primary and cancer cell lines, resulting in modulation of TLR downstream responses to cognate ligands. In addition several tumor-associated p53 mutants can also affect TLR gene expression. These observations together with the discovery of other immune-related p53 target genes provide new insights into the relationship between p53 and immunity and suggest approaches that might be useful in cancer therapies.
Summary:
The tumor suppressor p53 can modulate innate immune gene responses in response to factors that can activate p53. This is expected to provide new opportunities in cancer diagnosis and in chemotherapeutic strategies that employ specific TLR agonists or antagonists that target the TLR pathway.
The innate immune system contributes to the earliest phase of the host defense against foreign organisms and has both soluble and cellular pattern recognition receptors for microbial products. Two important members of this receptor group, CD14 and the Toll-like receptor (TLR) pattern recognition receptors, are essential for the innate immune response to components of Gram-negative and Gram-positive bacteria, mycobacteria, spirochetes and yeast. We now find that these receptors function in an antiviral response as well. The innate immune response to the fusion protein of an important respiratory pathogen of humans, respiratory syncytial virus (RSV), was mediated by TLR4 and CD14. RSV persisted longer in the lungs of infected TLR4-deficient mice compared to normal mice. Thus, a common receptor activation pathway can initiate innate immune responses to both bacterial and viral pathogens.
The innate immune system is a universal and ancient form of host defense against infection. Innate immune recognition relies on a limited number of germline-encoded receptors. These receptors evolved to recognize conserved products of microbial metabolism produced by microbial pathogens, but not by the host. Recognition of these molecular structures allows the immune system to distinguish infectious nonself from noninfectious self. Toll-like receptors play a major role in pathogen recognition and initiation of inflammatory and immune responses. Stimulation of Toll-like receptors by microbial products leads to the activation of signaling pathways that result in the induction of antimicrobial genes and inflammatory cytokines. In addition, stimulation of Toll-like receptors triggers dendritic cell maturation and results in the induction of costimulatory molecules and increased antigen-presenting capacity. Thus, microbial recognition by Toll-like receptors helps to direct adaptive immune responses to antigens derived from microbial pathogens.