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Respiratory syncytial virus (RSV) is the leading cause of hospitalisation for respiratory infection in young children. RSV disease severity is known to be age-dependent and highest in young infants, but other correlates of severity, particularly the presence of additional respiratory pathogens, are less well understood. In this study, nasopharyngeal swabs were collected from two cohorts of RSV-positive infants <12 months in Spain, the UK, and the Netherlands during 2017-20. We show, using targeted metagenomic sequencing of >100 pathogens, including all common respiratory viruses and bacteria, from samples collected from 433 infants, that burden of additional viruses is common (111/433, 26%) but only modestly correlates with RSV disease severity. In contrast, there is strong evidence in both cohorts and across age groups that presence of Haemophilus bacteria (194/433, 45%) is associated with higher severity, including much higher rates of hospitalisation (odds ratio 4.25, 95% CI 2.03-9.31). There is no evidence for association between higher severity and other detected bacteria, and no difference in severity between RSV genotypes. Our findings reveal the genomic diversity of additional pathogens during RSV infection in infants, and provide an evidence base for future causal investigations of the impact of co-infection on RSV disease severity., (© 2024. The Author(s).)

Background: Respiratory syncytial virus (RSV) is a significant cause of infant morbidity and mortality worldwide. Most children experience at least one 1 RSV infection by the age of two 2 years, but not all develop severe disease. However, the understanding of genetic risk factors for severe RSV is incomplete. Consequently, we conducted a genome-wide association study of RSV severity., Methods: Disease severity was assessed by the ReSVinet scale, in a cohort of 251 infants aged 1 week to 1 year. Genotyping data were collected from multiple European study sites as part of the RESCEU Consortium. Linear regression models were used to assess the impact of genotype on RSV severity and gene expression as measured by microarray., Results: While no SNPs reached the genome-wide statistical significance threshold (P < 5 × 10-8), we identified 816 candidate SNPs with a P-value of <1 × 10-4. Functional annotation of candidate SNPs highlighted genes relevant to neutrophil trafficking and cytoskeletal functions, including LSP1 and RAB27A. Moreover, SNPs within the RAB27A locus significantly altered gene expression (false discovery rate, FDR P < .05)., Conclusions: These findings may provide insights into genetic mechanisms driving severe RSV infection, offering biologically relevant information for future investigations., Competing Interests: Potential conflicts of interest. F. M.-T. and P. J. M. O. have received honoraria from the GSK group of companies, Pfizer, Sanofi Pasteur, MSD, Seqirus, AstraZeneca, Moderna, and Janssen for taking part in advisory boards and expert meetings and for acting as a speaker in congresses outside the scope of the submitted work. F. M.-T. has also acted as principal investigator in randomized controlled trials of the aforementioned companies as well as Ablynx, Gilead, Regeneron, Roche, Abbott, Novavax, and MedImmune, with honoraria paid to his institution. S. B. D. has received honoraria from MSD and Sanofi for taking part in RSV advisory boards and has provided consultancy and/or investigator roles in relation to product development for Janssen, AstraZeneca, Pfizer, Moderna, Valneva, MSD, iLiAD, and Sanofi with fees paid to St George's, University of London. S. B. D. is a member of the UK Department of Health and Social Care's Joint Committee on Vaccination and Immunisation RSV subcommittee and Medicines and Healthcare Products Regulatory Agency's Paediatric Medicine Expert Advisory Group, but the reviews expressed herein do not necessarily represent any of those groups. A. J. P. is chair of the Department of Health and Social Care's Joint Committee on Vaccination and Immunisation. J. W. participated in the advisory board of Janssen and Sanofi with fees paid to University Medical Centre Utrecht and has been an investigator for clinical trials sponsored by pharmaceutical companies including AstraZeneca, Merck, Pfizer, Sanofi, and Janssen. All funds have been paid to University Medical Centre Utrecht. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Whereas most infants infected with respiratory syncytial virus (RSV) show no or only mild symptoms, an estimated 3 million children under five are hospitalized annually due to RSV disease. This study aimed to investigate biological mechanisms and associated biomarkers underlying RSV disease heterogeneity in young infants, enabling the potential to objectively categorize RSV-infected infants according to their medical needs. Immunophenotypic and functional profiling demonstrated the emergence of immature and progenitor-like neutrophils, proliferative monocytes (HLA-DR Low , Ki67+), impaired antigen-presenting function, downregulation of T cell response and low abundance of HLA-DR Low B cells in severe RSV disease. HLA-DR Low monocytes were found as a hallmark of RSV-infected infants requiring hospitalization. Complementary transcriptomics identified genes associated with disease severity and pointed to the emergency myelopoiesis response. These results shed new light on mechanisms underlying the pathogenesis and development of severe RSV disease and identified potential new candidate biomarkers for patient stratification., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Introduction: The immune mechanisms supporting partial protection from reinfection and disease by the respiratory syncytial virus (RSV) have not been fully characterized. In older adults, symptoms are typically mild but can be serious in patients with comorbidities when the infection extends to the lower respiratory tract., Methods: This study formed part of the RESCEU older-adults prospective-cohort study in Northern Europe (2017-2019; NCT03621930) in which a thousand participants were followed over an RSV season. Peripheral-blood samples (taken pre-season, post-season, during illness and convalescence) were analyzed from participants who (i) had a symptomatic acute respiratory tract infection by RSV (RSV-ARTI; N=35) or (ii) asymptomatic RSV infection (RSV-Asymptomatic; N=16). These analyses included evaluations of antibody (Fc-mediated-) functional features and cell-mediated immunity, in which univariate and machine-learning (ML) models were used to explore differences between groups., Results: Pre-RSV-season peripheral-blood biomarkers were predictive of symptomatic RSV infection. T-cell data were more predictive than functional antibody data (area under receiver operating characteristic curve [AUROC] for the models were 99% and 76%, respectively). The pre-RSV season T-cell phenotypes which were selected by the ML modelling and which were more frequent in RSV-Asymptomatic group than in the RSV-ARTI group, coincided with prominent phenotypes identified during convalescence from RSV-ARTI (e.g., IFN-γ+, TNF-α+ and CD40L+ for CD4+, and IFN-γ+ and 4-1BB+ for CD8+)., Conclusion: The evaluation and statistical modelling of numerous immunological parameters over the RSV season suggests a primary role of cellular immunity in preventing symptomatic RSV infections in older adults., Competing Interests: Authors CV and AM were employed by the company Sanofi during the development of the study and own stock options in the company. Authors SB-J, AB, JA and DÖ were employed by the company Janssen Pharmaceutica NV. Authors SB-J, AB and JA own stocks from Johnson & Johnson. Authors MJ, BS, CL, and JD were employed by the company GSK, and BS and CL own stocks from the company. Author CL had submitted a patent application for COMPOSITIONS AND METHODS FOR IMPROVING THE IMMUNE RESPONSE TO SARS-COV2. During this time, he was a GSK representative as a co-leader for a subgroup in the Adventitious Virus Detection Technologies Interest Groups AVDTIG. Author SD has been an investigator for clinical trials of vaccines and antimicrobials for pharmaceutical companies including AstraZeneca, Merck, Pfizer, Valneva, Iliad, Sanofi, and Janssen, and previously sat on RSV advisory boards for Sanofi and Merck. Author JW was a member of Janssen and Sanofi advisory boards. She also worked closely together with author LB on many projects and clinical studies for which LB received grants. Author AP received grants from: Gates, Wellcome, MRC, NIHR and European Commission IMI RESCEU. During this time the laboratory assays were provided by GSK. Author AP is a contributor to intellectual property licensed by Oxford University Innovation to AstraZeneca. He also received consulting fees from Shionogi. He was chair of DHSC’s Joint Committee on Vaccination and Immunisation and also a member of WHOs SAGE until 2022. Author PO received the RESCEU EU IMI award and consulting fees from: GSK, Moderna, Janssen, Seqirus and Pfizer. He also received payments or honoraria from Moderna, Medscape and support for attending meetings for Moderna. During this project he was also a school governor for Sidcot, Somerset. He received grants from UKRI and MRC EMINENT. Author LB has regular interaction with pharmaceutical and other industrial partners. UMCU has received funding for investigator-initiated studies from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD and MeMed Diagnostics. UMCU has received funding for the RSV GOLD study from the Bill and Melinda Gates Foundation. UMCU has received funding as part of the public private partnership IMI funded RESCEU and PROMISE projects with partners GSK, Novavax, Janssen, AstraZeneca, Pfizer and Sanofi. UMCU has received funding by Julius Clinical for participating in clinical studies sponsored by MedImmune and Pfizer. UMCU received funding for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, Astrazeneca, MSD, Sanofi, Genzyme, Janssen. Author LB is the founding chairman of the ReSViNET Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Salaun, De Smedt, Vernhes, Moureau, Öner, Bastian, Janssens, Balla-Jhagjhoorsingh, Aerssens, Lambert, Coenen, Butler, Drysdale, Wildenbeest, Pollard, Openshaw and Bont.)

Despite over half a century of research, respiratory syncytial virus (RSV)-induced bronchiolitis remains a major cause of hospitalisation in infancy, while vaccines and specific therapies still await development. Our understanding of mucosal immune responses to RSV continues to evolve, but recent studies again highlight the role of Type-2 immune responses in RSV disease and hint at the possibility that it dampens Type-1 antiviral immunity. Other immunoregulatory pathways implicated in RSV disease highlight the importance of focussing on localised mucosal responses in the respiratory mucosa, as befits a virus that is essentially confined to the ciliated respiratory epithelium. In this review, we discuss studies of mucosal immune cell infiltration and production of inflammatory mediators in RSV bronchiolitis and relate these studies to observations from peripheral blood. We also discuss the advantages and limitations of studying the nasal mucosa in a disease that is most severe in the lower airway. A fresh focus on studies of RSV pathogenesis in the airway mucosa is set to revolutionise our understanding of this common and important infection.

The variable outcome of viral exposure is only partially explained by known factors. We administered respiratory syncytial virus (RSV) to 58 volunteers, of whom 57% became infected. Mucosal neutrophil activation before exposure was highly predictive of symptomatic RSV disease. This was associated with a rapid, presymptomatic decline in mucosal interleukin-17A (IL-17A) and other mediators. Conversely, those who resisted infection showed presymptomatic activation of IL-17- and tumor necrosis factor-related pathways. Vulnerability to infection was not associated with baseline microbiome but was reproduced in mice by preinfection chemokine-driven airway recruitment of neutrophils, which caused enhanced disease mediated by pulmonary CD8 + T cell infiltration. Thus, mucosal neutrophilic inflammation at the time of RSV exposure enhances susceptibility, revealing dynamic, time-dependent local immune responses before symptom onset and explaining the as-yet unpredictable outcomes of pathogen exposure., (Copyright © 2020, American Association for the Advancement of Science.)

Understanding how immune challenges elicit different responses is critical for diagnosing and deciphering immune regulation. Using a modular strategy to interpret the complex transcriptional host response in mouse models of infection and inflammation, we show a breadth of immune responses in the lung. Lung immune signatures are dominated by either IFN-γ and IFN-inducible, IL-17-induced neutrophil- or allergy-associated gene expression. Type I IFN and IFN-γ-inducible, but not IL-17- or allergy-associated signatures, are preserved in the blood. While IL-17-associated genes identified in lung are detected in blood, the allergy signature is only detectable in blood CD4 + effector cells. Type I IFN-inducible genes are abrogated in the absence of IFN-γ signaling and decrease in the absence of IFNAR signaling, both independently contributing to the regulation of granulocyte responses and pathology during Toxoplasma gondii infection. Our framework provides an ideal tool for comparative analyses of transcriptional signatures contributing to protection or pathogenesis in disease.

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection (LRTI) annually affecting >2 million children in the United States <5 years old. In the elderly (>65 years old), RSV results in ∼175,000 hospitalizations annually in the United States with a worldwide incidence of ∼34 million. There is no approved RSV vaccine, and treatments are limited. Recently, a phase 3 trial in the elderly using a recombinant RSV F protein vaccine failed to meet its efficacy objectives, namely, prevention of moderate-to-severe RSV-associated LRTI and reduced incidence of acute respiratory disease. Moreover, a recent phase 3 trial evaluating suptavumab (REGN2222), an antibody to RSV F protein, did not meet its primary endpoint of preventing medically attended RSV infections in preterm infants. Despite these setbacks, numerous efforts targeting the RSV F protein with vaccines, antibodies, and small molecules continue based on the commercial success of a monoclonal antibody (MAb) against the RSV F protein (palivizumab). As the understanding of RSV biology has improved, the other major coat protein, the RSV G protein, has reemerged as an alternative target reflecting progress in understanding its roles in infecting bronchial epithelial cells and in altering the host immune response. In mouse models, a high-affinity, strain-independent human MAb to the RSV G protein has shown potent direct antiviral activity combined with the alleviation of virus-induced immune system effects that contribute to disease pathology. This MAb, being prepared for clinical trials, provides a qualitatively new approach to managing RSV for populations not eligible for prophylaxis with palivizumab., (Copyright © 2018 American Society for Microbiology.)

Group B streptococcus and respiratory syncytial virus are leading causes of infant morbidity and mortality worldwide. No licensed vaccines are available for either disease, but vaccines for both are under development. Severe respiratory syncytial virus disease can be prevented by passively administered antibody. The presence of maternal IgG antibody specific to respiratory syncytial virus is associated with reduced prevalence and severity of respiratory syncytial virus disease in the first few weeks of life, whereas maternal serotype-specific anticapsular antibody is associated with protection against both early-onset and late-onset group B streptococcus disease. Therefore, vaccination in pregnancy might protect infants against both diseases. This report describes what is known about immune protection against group B streptococcus and respiratory syncytial virus, identifies knowledge gaps regarding the immunobiology of both diseases, and aims to prioritise research directions in maternal immunisation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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.

Pneumonia is of great global public health importance. Viral infections play both direct and indirect parts in its cause across the globe. Influenza is a leading cause of viral pneumonia in both children and adults, and respiratory syncytial virus is increasingly recognized as causing disease at both extremes of age. Vaccination offers the best prospect for prevention but current influenza vaccines do not provide universal and durable protection, and require yearly reformulation. In the future, it is hoped that influenza vaccines will give better and universal protection, and that new vaccines can be found for other causes of viral pneumonia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Respiratory Syncytial Virus (RSV) is a major pathogen causing low respiratory tract disease (bronchiolitis), primarily in infants. Helminthic infections may alter host immune responses to both helminths and to unrelated immune triggers. For example, we have previously shown that filarial cystatin (AvCystatin/Av17) ameliorates allergic airway inflammation. However, helminthic immunomodulators have so far not been tested in virus-induced disease. We now report that AvCystatin prevents Th2-based immunopathology in vaccine-enhanced RSV lung inflammation, a murine model for bronchiolitis. AvCystatin ablated eosinophil influx, reducing both weight loss and neutrophil recruitment without impairing anti-viral immune responses. AvCystatin also protected mice from excessive inflammation following primary RSV infection, significantly reducing neutrophil influx and cytokine production in the airways. Interestingly, we found that AvCystatin induced an influx of CD4+ FoxP3+ interleukin-10-producing T cells in the airway and lungs, correlating with immunoprotection, and the corresponding cells could also be induced by adoptive transfer of AvCystatin-primed F4/80+ macrophages. Thus, AvCystatin ameliorates enhanced RSV pathology without increasing susceptibility to, or persistence of, viral infection and warrants further investigation as a possible therapy for virus-induced airway disease., Competing Interests: The authors of this manuscript have the following competing interests: C.S. and S.H. hold a patent for uses of Cystatin (2 056 867). M.J.S., M.E.S., L.B.R and P.J.M.O declare no relevant conflict of interest. The stated conflicts of interest do not alter our adherence to PLOS ONE policies on sharing data and materials.

Rationale: Despite relative antigenic stability, respiratory syncytial virus (RSV) reinfects throughout life. After more than 40 years of research, no effective human vaccine exists and correlates of protection remain poorly defined. Most current vaccine candidates seek to induce high levels of RSV-specific serum neutralizing antibodies, which are associated with reduced RSV-related hospitalization rates in observational studies but may not actually prevent infection., Objectives: To characterize correlates of protection from infection and the generation of RSV-specific humoral memory to promote effective vaccine development., Methods: We inoculated 61 healthy adults with live RSV and studied protection from infection by serum and mucosal antibody. We analyzed RSV-specific peripheral blood plasmablast and memory B-cell frequencies and antibody longevity., Measurements and Main Results: Despite moderately high levels of preexisting serum antibody, 34 (56%) became infected, of whom 23 (68%) developed symptomatic colds. Prior RSV-specific nasal IgA correlated significantly more strongly with protection from polymerase chain reaction-confirmed infection than serum neutralizing antibody. Increases in virus-specific antibody titers were variable and transient in infected subjects but correlated with plasmablasts that peaked around Day 10. During convalescence, only IgG (and no IgA) RSV-specific memory B cells were detectable in peripheral blood. This contrasted with natural influenza infection, in which virus-specific IgA memory B cells were readily recovered., Conclusions: This observed specific defect in IgA memory may partly explain the ability of RSV to cause recurrent symptomatic infections. If so, vaccines able to induce durable RSV-specific IgA responses may be more protective than those generating systemic antibody alone.

Unlabelled: Type I interferons (IFNs) are produced early upon virus infection and signal through the alpha/beta interferon (IFN-α/β) receptor (IFNAR) to induce genes that encode proteins important for limiting viral replication and directing immune responses. To investigate the extent to which type I IFNs play a role in the local regulation of inflammation in the airways, we examined their importance in early lung responses to infection with respiratory syncytial virus (RSV). IFNAR1-deficient (IFNAR1(-/-)) mice displayed increased lung viral load and weight loss during RSV infection. As expected, expression of IFN-inducible genes was markedly reduced in the lungs of IFNAR1(-/-) mice. Surprisingly, we found that the levels of proinflammatory cytokines and chemokines in the lungs of RSV-infected mice were also greatly reduced in the absence of IFNAR signaling. Furthermore, low levels of proinflammatory cytokines were also detected in the lungs of IFNAR1(-/-) mice challenged with noninfectious innate immune stimuli such as selected Toll-like receptor (TLR) agonists. Finally, recombinant IFN-α was sufficient to potentiate the production of inflammatory mediators in the lungs of wild-type mice challenged with innate immune stimuli. Thus, in addition to its well-known role in antiviral resistance, type I IFN receptor signaling acts as a central driver of early proinflammatory responses in the lung. Inhibiting the effects of type I IFNs may therefore be useful in dampening inflammation in lung diseases characterized by enhanced inflammatory cytokine production., Importance: The initial response to viral infection is characterized by the production of interferons (IFNs). One group of IFNs, the type I IFNs, are produced early upon virus infection and signal through the IFN-α/β receptor (IFNAR) to induce proteins important for limiting viral replication and directing immune responses. Here we examined the importance of type I IFNs in early responses to respiratory syncytial virus (RSV). Our data suggest that type I IFN production and IFNAR receptor signaling not only induce an antiviral state but also serve to amplify proinflammatory responses in the respiratory tract. We also confirm this conclusion in another model of acute inflammation induced by noninfectious stimuli. Our findings are of relevance to human disease, as RSV is a major cause of infant bronchiolitis and polymorphisms in the IFN system are known to impact disease severity.

Infection with respiratory syncytial virus (RSV) in neonatal mice leads to exacerbated disease if mice are reinfected with the same virus as adults. Both T cells and the host major histocompatibility complex genotype contribute to this phenomenon, but the part played by innate immunity has not been defined. Since macrophages and natural killer (NK) cells play key roles in regulating inflammation during RSV infection of adult mice, we studied the role of these cells in exacerbated inflammation following neonatal RSV sensitization/adult reinfection. Compared to mice undergoing primary infection as adults, neonatally sensitized mice showed enhanced airway fluid levels of interleukin-6 (IL-6), alpha interferon (IFN-α), CXCL1 (keratinocyte chemoattractant/KC), and tumor necrosis factor alpha (TNF-α) at 12 to 24 h after reinfection and IL-4, IL-5, IFN-γ, and CCL11 (eotaxin) at day 4 after reinfection. Weight loss during reinfection was accompanied by an initial influx of NK cells and granulocytes into the airways and lungs, followed by T cells. NK cell depletion during reinfection attenuated weight loss but did not alter T cell responses. Depletion of alveolar macrophages with inhaled clodronate liposomes reduced both NK and T cell numbers and attenuated weight loss. These findings indicate a hitherto unappreciated role for the innate immune response in governing the pathogenic recall responses to RSV infection.

Peter Openshaw discusses the challenges in advancing respiratory syncytial virus (RSV) treatments and the implications of a study by Mejias and colleagues using a newly identified gene signature for diagnosis and prediction of RSV severity. Please see later in the article for the Editors' Summary.

During viral infection, inflammation and recovery are tightly controlled by competing proinflammatory and regulatory immune pathways. Respiratory syncytial virus (RSV) is the leading global cause of infantile bronchiolitis, which is associated with recurrent wheeze and asthma diagnosis in later life. Th2-driven disease has been well described under some conditions for RSV-infected mice. In the present studies, we used the Foxp3(DTR) mice (which allow specific conditional depletion of Foxp3(+) T cells) to investigate the functional effects of regulatory T cells (Tregs) during A2-strain RSV infection. Infected Treg-depleted mice lost significantly more weight than wild-type mice, indicating enhanced disease. This enhancement was characterized by increased cellularity in the bronchoalveolar lavage (BAL) fluid and notable lung eosinophilia not seen in control mice. This was accompanied by abundant CD4(+) and CD8(+) T cells exhibiting an activated phenotype and induction of interleukin 13 (IL-13)- and GATA3-expressing Th2-type CD4(+) T cells that remained present in the airways even 14 days after infection. Therefore, Treg cells perform vital anti-inflammatory functions during RSV infection, suppressing pathogenic T cell responses and inhibiting lung eosinophilia. These findings provide additional evidence that dysregulation of normal immune responses to viral infection may contribute to severe RSV disease.

Purpose of Review: Human respiratory syncytial virus (RSV) infection is a major cause of morbidity in children and of morbidity and mortality in elderly or immunocompromised adults. Given prophylactically, antibody can protect against infection, but natural levels are poorly protective. Vaccination may enhance disease, and there is no well tolerated and effective vaccine or antiviral treatment. Despite over 50 years of research, therapy remains nonspecific and supportive., Recent Findings: Experimental human challenge in adult volunteers is beginning to elucidate the dynamics of viral shedding and causes of disease, but investigations of naturally infected children remain logistically challenging. RSV was known to bind several surface ligands, but the recent demonstration that nucleolin acts as a receptor for the RSV fusion protein was unexpected. Recent studies increasingly emphasize the relevance of innate immune responses and the dysregulation of inflammation as key factors in causing the pathological effects of infection. Studies in both human infants and mice indicate that interleukin-17 plays a role in some forms of RSV disease and regulatory T cells may be important in controlling inflammation., Summary: Improved understanding of the human immune response to RSV infection continues to be needed in order to accelerate the development of vaccines and new treatments for bronchiolitis.

Respiratory syncytial virus (RSV) is a major cause of respiratory morbidity, resulting in hospitalization for bronchiolitis in some infected infants that is associated with wheeze in later life. Genetic factors are known to affect the severity of the sequelae after RSV infection, but the complexity of the temporal and genetic effects makes it difficult to analyze this response in studies in man. Therefore, we developed a murine genetic model to analyze the sequelae occurring after RSV infection in early life. Haplotype-based genetic analysis of interstrain differences in severity identified the MHC as an important genetic determinant. This was confirmed by analysis of responses in congenic mice with different MHC haplotypes. We also found that susceptible strains had high CD8 levels during secondary infection. Analysis of first filial generation, second filial generation, and back-cross progeny produced by intercrossing resistant (H-2(k), C3H/HeN) and sensitive (H-2(b), BALB/c) strains indicated that susceptibility to sequelae after RSV infection was dominantly inherited but also segregated in a non-MHC-dependent manner. Thus, MHC haplotype and its effect on CD8 cell response is an important determinant of the outcome of neonatal RSV infection.

Regulatory CD4(+) T cells have been shown to be important in limiting immune responses, but their role in respiratory viral infections has received little attention. Here we observed that following respiratory syncytial virus (RSV) infection, CD4(+) Foxp3(+) CD25(+) natural regulatory T-cell numbers increased in the bronchoalveolar lavage fluid, lung, mediastinal lymph nodes, and spleen. The depletion of CD25(+) natural regulatory T cells prior to RSV infection led to enhanced weight loss with delayed recovery that was surprisingly accompanied by increased numbers of activated natural killer cells in the lung and bronchoalveolar lavage fluid on day 8 postinfection. Increased numbers of neutrophils were also detected within the bronchoalveolar lavage fluid and correlated with elevated levels of myeloperoxidase as well as interleukin-6 (IL-6) and gamma interferon (IFN-gamma). CD25(+) natural regulatory T-cell depletion also led to enhanced numbers of proinflammatory T cells producing IFN-gamma and tumor necrosis factor alpha (TNF-alpha) in the lung. Despite these increases in inflammatory responses and disease severity, the viral load was unaltered. This work highlights a critical role for natural regulatory T cells in regulating the adaptive and innate immune responses during the later stages of lung viral infections.

Respiratory syncytial virus (RSV) is the main cause of bronchiolitis, the major cause of hospitalization of infants. An ideal RSV vaccine would be effective for neonates, but the immune responses of infants differ markedly from those of adults, often showing a bias toward T-helper 2 (Th2) responses and reduced gamma interferon (IFN-gamma) production. We previously developed recombinant RSV vectors expressing IFN-gamma and interleukin-4 (IL-4) that allow us to explore the role of these key Th1 and Th2 cytokines during infection. The aim of the current study was to explore whether an immunomodulation of infant responses could enhance protection. The expression of IFN-gamma by a recombinant RSV vector (RSV/IFN-gamma) attenuated primary viral replication in newborn mice without affecting the development of specific antibody or T-cell responses. Upon challenge, RSV/IFN-gamma mice were protected from the exacerbated disease observed for mice primed with wild-type RSV; however, antiviral immunity was not enhanced. Conversely, the expression of IL-4 by recombinant RSV did not affect virus replication in neonates but greatly enhanced Th2 immune responses upon challenge without affecting weight loss. These studies demonstrate that it is possible to manipulate infant immune responses by using cytokine-expressing recombinant viruses and that neonatal deficiency in IFN-gamma responses may lead to enhanced disease during secondary infection.

Respiratory syncytial virus (RSV) causes bronchiolitis, the main cause of infantile hospitalization. Immunity against reinfection is poor, and there is great interest in boosting vaccine responses using live vectors expressing host cytokines. We therefore constructed a recombinant RSV expressing murine interleukin 18 (RSV/IL-18), a cytokine capable of inducing strong antiviral immune responses. In vitro RSV/IL-18 replicated at wild-type levels and produced soluble IL-18. In naïve BALB/c mice, RSV/IL-18 infection significantly increased both IL-18 mRNA and protein and attenuated the peak viral load 3-fold. Despite a reduced viral load, RSV/IL-18 infection caused a biphasic weight loss at days 2 and 6 postinfection that was not seen in wild-type infection. Day 2 disease was associated with enhanced pulmonary natural killer (NK) cell numbers and activity and was prevented by NK cell depletion during infection; day 6 disease was correlated with CD8 T-cell recruitment and was enhanced by NK cell depletion. IL-18 expression during priming also enhanced RSV-specific antibody responses and T-cell responses on secondary RSV infection. Therefore, while IL-18 boosted antiviral immunity and reduced the viral load, its coexpression worsened disease. This is the first recombinant RSV with this property, and these are the first studies to demonstrate that NK cells can induce pathology during pulmonary viral infections.

Background: CD8 T cells assist in the clearance of respiratory syncytial virus (RSV) infection from the lungs. However, disease after RSV infection is in part caused by excessive T cell activity, and a balance is therefore needed between beneficial and harmful cellular immune responses. The chemokine CCL3 (MIP1alpha) is produced following RSV infection and is broadly chemotactic for both T cells and natural killer (NK) cells. We therefore investigated its role in RSV disease., Methodology/principal Findings: CCL3 was produced biphasically, in both the early (day 1) and late (day 6-7) stages of infection. CCL3 depletion did not alter the recruitment of natural killer (NK) cells to the lungs during the early stage, but depletion did affect the later adaptive phase. While fewer T cells were recruited to the lungs of either CCL3 knockout or anti-CCL3 treated RSV infected mice, more RSV-specific pro-inflammatory T cells were recruited to the lung when CCL3 responses were impaired. This increase in RSV-specific pro-inflammatory T cells was accompanied by increased weight loss and illness after RSV infection., Conclusions/significance: CCL3 regulates the balance of T cell populations in the lung and can alter the outcome of RSV infection. Understanding the role of inflammatory mediators in the recruitment of pathogenic T cells to the lungs may lead to novel methods to control RSV disease.

IL-9 is a cytokine of great current interest associated with allergic/Th2 responses. High levels of IL-9 are present in bronchial secretions from infants with respiratory syncytial virus (RSV) bronchiolitis. To test its effects in RSV disease with a Th2 profile, BALB/c mice were vaccinated with recombinant vaccinia virus expressing the RSV G protein. On RSV challenge, immunized mice developed augmented disease characterized by enhanced pulmonary Th2 and local IL-9 production peaking on days 7-10 of RSV infection. Depletion with anti-IL-9 Ab at vaccination or RSV challenge enhanced viral clearance. Depletion only at challenge had no effect on disease severity, whereas depletion at immunization and challenge enhanced Th1 responses, inhibited virus-specific IgG1 production, and enhanced disease severity. By contrast, depletion of IL-9 at immunization boosted IgG2a and inhibited the Th2 response and disease during subsequent infection without a concomitant increase in type 1 cytokines. Adoptive transfer of secondary memory CD4 T cells from the spleens of IL-9-depleted mice into naive recipients replicated many of the effects of depletion, indicating that IL-9 acts via CD4 T cells. Therefore, IL-9 is a previously unknown but key modulator of antiviral immunity, regulating T and B cell responses and having potent and specific effects on viral lung disease.

Host defenses, while effecting viral clearance, contribute substantially to inflammation and disease. This double action is a substantial obstacle to the development of safe and effective vaccines against many agents, particularly respiratory syncytial virus (RSV). RSV is a common cold virus and the major cause of infantile bronchiolitis worldwide. The role of alphabeta T cells in RSV-driven immunopathology is well studied, but little is known about the role of "unconventional" T cells. During primary RSV challenge of BALB/c mice, some Vgamma7+ gammadelta T cells were present; however, immunization with a live vaccinia vector expressing RSV F protein substantially enhanced Vgamma4+ gammadelta T cell influx after RSV infection. Harvested early, these cells produced IFN-gamma, TNF, and RANTES after ex vivo stimulation. By contrast, those recruited 5 days after challenge made IL-4, IL-5, and IL-10. Depletion of gammadelta T cells in vivo reduced lung inflammation and disease severity and slightly increased peak viral replication but did not prevent viral clearance. These studies demonstrate a novel role for gammadelta T cells in the development of immunopathology and cellular influx into the lungs after immunization and RSV challenge. Though a minor population, gammadelta T cells have a critical influence on disease and are an attractive interventional target in the alleviation of viral lung disease.

Macrophages are abundant in the lower respiratory tract. They play a central role in the innate response to infection but may also modulate excessive inflammation. Both macrophages and ciliated epithelial cells respond to infection by releasing soluble mediators, leading to the recruitment of innate and adaptive effector cells. To study the role of lung macrophages in acute respiratory viral infection, we depleted them by the inhalation of clodronate liposomes in an established mouse model of respiratory syncytial virus (RSV) disease. Infection caused an immediate local release of inflammatory cytokines and chemokines, peaking on day 1, which was virtually abolished by clodronate liposome treatment. Macrophage depletion inhibited the activation (days 1 to 2) and recruitment (day 4) of natural killer (NK) cells and enhanced peak viral load in the lung (day 4). However, macrophage depletion did not affect the recruitment of activated CD4 or CD8 T cells, weight loss, or virus-induced changes in lung function. Therefore, lung macrophages play a central role in the early responses to viral infection but have remarkably little effect on the adaptive response occurring at the time of peak disease severity.

Respiratory syncytial virus (RSV) is the major cause of infantile bronchiolitis and hospitalization. Severe RSV disease is associated with the development of wheezing in later life. In a mouse model of the delayed effects of RSV, the age at primary infection determines responses to reinfection in adulthood. During primary RSV infection, neonatal BALB/c mice developed only mild disease and recruited CD8 cells that were defective in gamma interferon production. Secondary reinfection of neonatally primed mice caused enhanced inflammation and profuse lung T-cell recruitment. CD4 cell depletion during secondary RSV challenge attenuated disease (measured by weight loss); depletion of CD8 cells also markedly attenuated disease severity but enhanced lung eosinophilia, and depletion of both CD4 and CD8 cells together completely abrogated weight loss. Depletion of CD8 (but not CD4) cells during primary neonatal infection was protective against weight loss during adult challenge. Therefore, T cells, in particular CD8 T cells, play a central role in the outcome of neonatal infection by enhancing disease during secondary challenge. These findings demonstrate a crucial role for T cells in the regulation of immune responses after neonatal infection.

Priming with the major surface glycoprotein G of respiratory syncytial virus (RSV) expressed by recombinant vaccinia leads to strong Th2 responses and lung eosinophilia during viral challenge. We now show that DNA vaccination in BALB/c mice with plasmids encoding G attenuated RSV replication but also enhanced disease with lung eosinophilia and increased IL-4/5 production. However, formulating the DNA with PLG microparticles reduced the severity of disease during RSV challenge without significantly lessening protection against viral replication. PLG formulation greatly reduced lung eosinophilia and prevented the induction of IL-4 and IL-5 during challenge, accompanied by a less marked CD4+ T cell response and a restoration of the CD8+ T cell recruitment seen during infection of non-vaccinated animals. After RSV challenge, lung eosinophilia was enhanced and prolonged in mice vaccinated with DNA encoding a secreted form of G; this effect was virtually prevented by PLG formulation. Therefore, PLG microparticulate formulation modifies the pattern of immune responses induced by DNA vaccination boosts CD8+ T cell priming and attenuates Th2 responses. We speculate that PLG microparticles affect antigen uptake and processing, thereby influencing the outcome of DNA vaccination.

Respiratory syncytial virus (RSV) is an important cause of infant morbidity and mortality worldwide and is increasingly recognized to have a role in the development and exacerbation of chronic lung diseases. There is no effective vaccine, and we reasoned that it might be possible to skew the immune system towards beneficial nonpathogenic responses by selectively priming protective T-cell subsets. We therefore tested recombinant RSV (rRSV) candidates expressing prototypic murine Th1 (gamma interferon [IFN-gamma]) or Th2 (interleukin-4 [IL-4]) cytokines, with detailed monitoring of responses to subsequent infections with RSV or (as a control) influenza A virus. Although priming with either recombinant vector reduced viral load during RSV challenge, enhanced weight loss and enhanced pulmonary influx of RSV-specific CD8+ T cells were observed after challenge in mice primed with rRSV/IFN-gamma. By contrast, rRSV/IL-4-primed mice were protected against weight loss during secondary challenge but showed airway eosinophilia. When rRSV/IL-4-primed mice were challenged with influenza virus, weight loss was attenuated but was again accompanied by marked airway eosinophilia. Thus, immunization directed toward enhancement of Th1 responses reduces viral load but is not necessarily protective against disease. Counter to expectation, Th2-biased responses were more beneficial but also influenced the pathological effects of heterologous viral challenge.

CCL5/RANTES is a key proinflammatory chemokine produced by virus-infected epithelial cells and present in respiratory secretions of asthmatics. To examine the role of CCL5 in viral lung disease, we measured its production during primary respiratory syncytial virus (RSV) infection and during secondary infection after sensitizing vaccination that induces Th2-mediated eosinophilia. A first peak of CCL5 mRNA and protein production was seen at 18 to 24 h of RSV infection, before significant lymphocyte recruitment occurred. Treatment in vivo with Met-RANTES (a competitive chemokine receptor blocker) throughout primary infection decreased CD4+ and CD8+ cell recruitment and increased viral replication. In RSV-infected, sensitized mice with eosinophilic disease, CCL5 production was further augmented; Met-RANTES treatment again reduced inflammatory cell recruitment and local cytokine production. A second wave of CCL5 production occurred on day 7, attributable to newly recruited T cells. Paradoxically, mice treated with Met-RANTES during primary infection demonstrated increased cellular infiltration during reinfection. We therefore show that RSV induces CCL5 production in the lung and this causes the recruitment of RSV-specific cells, including those making additional CCL5. If this action is blocked with Met-RANTES, inflammation decreases and viral clearance is delayed. However, the exact effects of chemokine modulation depend critically on time of administration, a factor that may potentially complicate the use of chemokine blockers in inflammatory diseases.

Bronchiolitis is a distressing, potentially life-threatening respiratory condition that affects young babies. Around 2-3% of all infants younger than 1 year are admitted to hospital with bronchiolitis, usually during the seasonal epidemic. The majority of these infants are infected with respiratory syncytial virus and all have an intense inflammatory response in their airways. Although most infants recover, they have an increased risk of recurrent wheezing. Although bronchiolitis is common, little is known about what causes infants to be susceptible. Diagnostic interventions have little effect on clinical outcome, and apart from supportive measures, there is no specific treatment. Bronchiolitis therefore presents an intriguing clinical conundrum and a major challenge to researchers. High quality clinical studies are needed to clarify assessment of disease severity and criteria for hospital admission, particularly the use of pulse oximetry and chest radiography. Careful mapping of the inflammatory pathways in the pathogenesis of bronchiolitis should lead to development of new therapies to alleviate symptoms.

Respiratory syncytial virus (RSV) is a major viral pathogen of infants that also reinfects adults. During RSV infection, inflammatory host cell recruitment to the lung plays a central role in determining disease outcome. Chemokines mediate cell recruitment to sites of inflammation and are influenced by, and influence, the production of cytokines. We therefore compared chemokine production in a mouse model of immunopathogenic RSV infection in which either Th1 or Th2 immunopathology is induced by prior sensitization to individual RSV proteins. Chemokine expression profiles were profoundly affected by the nature of the pulmonary immunopathology: "Th2" immunopathology in BALB/c mice was associated with increased and prolonged expression of CCL2 (MCP-1), CXCL10 (IP-10), and CCL11 (eotaxin) starting within 24 h of challenge. C57BL/6 mice with "Th2" pathology (enabled by a deficiency of CD8+ cells) also showed increased CCL2 production. No differences in chemokine receptor expression were detected. Chemokine blockers may therefore be of use for children with bronchiolitis.

Background: The integrin CD11c is known as a marker for dendritic cells and has recently been described on T cells following lymphotropic choriomeningitis virus infection, a systemic infection affecting a multitude of organs. Here, we characterise CD11c bearing T cells in a murine model of localised pulmonary infection with respiratory syncytial virus (RSV)., Methods: Mice were infected intranasally with RSV and expression of beta2 integrins and T lymphocyte activation markers were monitored by flow cytometry. On day 8 post RSV infection CD11c+ CD8+ and CD11c- CD8+ T cells were assessed for cytokine production, cytotoxic activity and migration. Expression of CD11c mRNA in CD8+ T cells was assessed by quantitative PCR., Results: Following RSV infection CD11c+ CD8+ T cells were detectable in the lung from day 4 onwards and accounted for 45.9 +/- 4.8% of CD8+ T cells on day 8 post infection, while only few such cells were present in mediastinal lymph nodes, spleen and blood. While CD11c was virtually absent from CD8+ T cells in the absence of RSV infection, its mRNA was expressed in CD8+ T cells of both naïve and RSV infected mice. CD11c+, but not CD11c-, CD8+ T cells showed signs of recent activation, including up-regulation of CD11a and expression of CD11b and CD69 and were recruited preferentially to the lung. In addition, CD11c+ CD8+ T cells were the major subset responsible for IFNgamma production, induction of target cell apoptosis in vitro and reduction of viral titres in vivo., Conclusion: CD11c is a useful marker for detection and isolation of pulmonary antiviral cytotoxic T cells following RSV infection. It identifies a subset of activated, virus-specific, cytotoxic T cells that exhibit potent antiviral effects in vivo.

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.

Respiratory syncytial virus (RSV) is a major viral pathogen of infants and the elderly. Significant morbidity is caused by an overexuberant mixed lung cell infiltrate, which is thought to be driven by chemokines. One of the main chemotactic mediators responsible for the movement of eosinophils is CCL11 (eotaxin). Using a mouse model of eosinophilic bronchiolitis induced by RSV, we show here that treatment in vivo with a blocking antibody to CCL11 greatly reduces lung eosinophilia and disease severity. In addition, anti-CCL11 caused a striking inhibition of CD4-T-cell influx and shifted cytokine production away from interleukin-5 without reducing the resistance to viral replication. These results suggest that in addition to influencing eosinophil diapedesis and survival, anti-CCL11 has an action on T cells. These studies strengthen the case for anti-CCL11 treatment of Th2-driven diseases.

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 coincides not with the peak of viral replication but with the development of specific T and B cell responses. This immune response is apparently responsible for much of the 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. The inflammatory host response to viral infection may be relevant not only to childhood bronchiolitis, but also to obstructive lung diseases in adults.

Asthma is an immune-mediated inflammatory condition characterized by increased responsiveness to bronchoconstrictive stimuli. Viruses have been shown to play an important role in asthma, with viral infection being present during about 85% of exacerbations. However, the role they play in the onset of asthma is more controversial. Some respiratory viral infections might be protective, but there is a strong association between respiratory syncytial virus-induced bronchiolitis in infancy and recurrent wheeze up to 12 years of age. Both the respiratory tract and the immune system undergo rapid maturation during the first year of life, and it seems that postnatal development is affected by and affects responses to viral infections. Understanding postnatal developmental changes in the immune system might help to explain the origins and pathogenesis of asthma and thus the effectiveness or ineffectiveness of specific asthma therapies.

Respiratory syncytial virus (RSV) causes intense pulmonary inflammatory responses in some infected infants. The surface attachment protein 'G' of RSV has membrane-bound and secreted forms and shows homology to the CX3C chemokine fractalkine. Using recombinant techniques, we generated replication-competent recombinant clonal RSV expressing normal G proteins ('rRSV') or only the membrane-bound form of G ('Gmem rRSV'). Both recombinants grew well in HEp-2 cells, but after primary intranasal infection in mice, pulmonary Gmem rRSV replication was reduced tenfold compared to parental or rRSV; moreover, CCL2 and CCL5 production was greatly reduced and no apparent disease or pulmonary cellular infiltration was observed. However, Gmem rRSV-infected mice developed good antibody responses and were fully protected against subsequent intranasal challenge with parental virus. Even in mice sensitized to G by cutaneous infection with recombinant vaccinia expressing G, intranasal challenge with Gmem rRSV caused insignificant disease. We conclude that secreted G is a key viral product assisting virus replication in vivo, enhancing CCL2 and CCL5 production and promoting illness. Engineered RSV mutants lacking the ability to secrete G are thus promising vaccine candidates.

A CD8+ T-cell memory response to respiratory syncytial virus (RSV) was generated by using a DNA vaccine construct encoding the dominant Kd-restricted epitope from the viral transcription anti-terminator protein M2 (M2(82-90)), linked covalently to human beta2-microglobulin (beta2m). Cutaneous gene-gun immunization of BALB/c mice with this construct induced an antigen-specific CD8+ T-cell memory. After intranasal RSV challenge, accelerated CD8+ T-cell responses were observed in pulmonary lymph nodes and virus clearance from the lungs was enhanced. The construct induced weaker CD8+ T-cell responses than those elicited with recombinant vaccinia virus expressing the complete RSV M2 protein, but stronger than those induced by a similar DNA construct without the beta2m gene. DNA vaccination led to enhanced pulmonary disease after RSV challenge, with increased weight loss and cell recruitment to the lung. Depletion of CD8+ T cells reduced, but did not abolish, enhancement of disease. Mice vaccinated with a construct encoding a class I-restricted lymphocytic choriomeningitis virus epitope and beta2m suffered more severe weight loss after RSV infection than unvaccinated RSV-infected mice, although RSV-specific CD8+ T-cell responses were not induced. Thus, in addition to specific CD8+ T cell-mediated immunopathology, gene-gun DNA vaccination causes non-specific enhancement of RSV disease without affecting virus clearance.

Respiratory syncytial virus (RSV) causes bronchiolitis in infants, which is associated with recurrent wheezing in later childhood. There is mounting evidence that the virus becomes latent or persists in vivo, but little is known about the mechanisms of its latency, persistence, and immune evasion. We therefore infected BALB/c mice intranasally with human RSV, analyzed sequential tissue samples by direct culture and polymerase chain reaction for viral and messenger RNA, and monitored antiviral immune responses. Virus could not be detected in bronchoalveolar lavage samples beyond Day 14, but viral genomic and messenger RNA was present in lung homogenates for 100 days or more; combined depletion of CD4 and CD8 T cells allowed infective virus to be recovered. Neutralizing antibody and memory cytotoxic T cell responses were intact in mice with latent infections, and latent viral genome contained an authentic nonmutated M2 82-91 K(d) cytotoxic T lymphocyte epitope. A mutation of this epitope, detected in one clone, did not assist evasion. We suggest that RSV latency depends on persistence in privileged sites rather than on viral mutation.

Infants experiencing severe respiratory syncytial virus (RSV) bronchiolitis have an increased frequency of wheeze and asthma in later childhood. Since most severe RSV infections occur between the 8th and 24th postnatal week, we examined whether age at first infection determines the balance of cytokine production and lung pathology during subsequent rechallenge. Primary RSV infection in newborn mice followed the same viral kinetics as in adults but was associated with reduced and delayed IFN-gamma responses. To study rechallenge, mice were infected at 1 day or 1, 4, or 8 weeks of age and reinfected at 12 weeks. Neonatal priming produced more severe weight loss and increased inflammatory cell recruitment (including T helper 2 cells and eosinophils) during reinfection, whereas delayed priming led to enhanced interferon gamma production and less severe disease during reinfection. These results show the crucial importance of age at first infection in determining the outcome of reinfection and suggest that the environment of the neonatal lung is a major determinant of cytokine production and disease patterns in later life. Thus, simply delaying RSV infection beyond infancy might reduce subsequent respiratory morbidity in later childhood.

Viral bronchiolitis is the most common cause of hospitalization in infants under 6 months of age, and 70% of all cases of bronchiolitis are caused by respiratory syncytial virus (RSV). Early RSV infection is associated with respiratory problems such as asthma and wheezing later in life. RSV infection is usually spread by contaminated secretions and infects the upper then lower respiratory tracts. Infected cells release proinflammatory cytokines and chemokines, including IL-1, tumor necrosis factor-alpha, IL-6, and IL-8. These activate other cells and recruit inflammatory cells, including macrophages, neutrophils, eosinophils, and T lymphocytes, into the airway wall and surrounding tissues. The pattern of cytokine production by T lymphocytes can be biased toward 'T-helper-1' or 'T-helper-2' cytokines, depending on the local immunologic environment, infection history, and host genetics. T-helper-1 responses are generally efficient in antiviral defense, but young infants have an inherent bias toward T-helper-2 responses. The ideal intervention for RSV infection would be preventive, but the options are currently limited. Vaccines based on protein subunits, live attenuated strains of RSV, DNA vaccines, and synthetic peptides are being developed; passive antibody therapy is at present impractical in otherwise healthy children. Effective vaccines for use in neonates continue to be elusive but simply delaying infection beyond the first 6 months of life might reduce the delayed morbidity associated with infantile disease.