Pattern recognition receptors (PRRs) including Toll-like receptors (TLRs) and RIG like helicase (RLH) receptors are involved in innate immune antiviral responses. Here we show that nucleotide-binding oligomerization domain 2 (NOD2) can also function as a cytoplasmic viral PRR by triggering activation of interferon regulatory factor-3 (IRF3) and production of interferon-β (IFN). Following recognition of viral ssRNA genome, NOD2 utilized the adaptor protein MAVS (mitochondrial antiviral signaling) to activate IRF3. NOD2-deficient mice failed to produce IFN efficiently and exhibited enhanced susceptibility to virus-induced pathogenesis. Thus, the function of NOD2 as a viral PRR highlights the important role of NOD2 in host antiviral defense mechanisms.

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Activation of innate immune antiviral responses by Nod2

Summary: In global terms, respiratory viral infection is a major cause of morbidity and mortality. Infancy, in particular, is a time of increased disease susceptibility and severity. Early-life viral infection causes acute illness and can be associated with the development of wheezing and asthma in later life. The most commonly detected viruses are respiratory syncytial virus (RSV), rhinovirus (RV), and influenza virus. In this review we explore the complete picture from epidemiology and virology to clinical impact and immunology. Three striking aspects emerge. The first is the degree of similarity: although the infecting viruses are all different, the clinical outcome, viral evasion strategies, immune response, and long-term sequelae share many common features. The second is the interplay between the infant immune system and viral infection: the immaturity of the infant immune system alters the outcome of viral infection, but at the same time, viral infection shapes the development of the infant immune system and its future responses. Finally, both the virus and the immune response contribute to damage to the lungs and subsequent disease, and therefore, any prevention or treatment needs to address both of these factors.

Respiratory Viral Infections in Infants: Causes, Clinical Symptoms, Virology, and Immunology

Tetherin Inhibits HIV-1 Release by Directly Tethering Virions to Cells

This review on bronchiolitis in young children considers the viruses involved, the current understanding of pathogenesis, host genetic factors and the environment, and the role of season, race, and sex on attack rates and subsequent episodes of wheezing.

https://www.nejm.org/doi/pdf/10.1056/NEJMra1413456

Viral Bronchiolitis in Children

Human respiratory syncytial virus (RSV) was first isolated in 1956 from a laboratory chimpanzee with upper respiratory tract disease (for general reviews, see references [21][1], [57][2], [102][3], and [145][4]). RSV was quickly determined to be of human origin and was shown to be the leading

Viral and Host Factors in Human Respiratory Syncytial Virus Pathogenesis

Background Respiratory syncytial virus (RSV) and influenza virus are common causes of infantile lower respiratory tract infection (LRTI). It is widely believed that both viral replication and inappropriately enhanced immune responses contribute to disease severity. In infants, RSV LRTI is known to be more severe than influenza virus LRTI. Methods We compared cytokines and chemokines in secretions of infants surviving various forms of respiratory illness caused by RSV or influenza viruses, to determine which mediators were associated with more-severe illness. We analyzed lung tissue from infants with fatal cases of RSV and influenza virus LRTI to determine the types of inflammatory cells present. Autopsy tissues were studied for the lymphotoxin granzyme and the apoptosis marker caspase 3. Results Quantities of lymphocyte-derived cytokines were minimal in secretions from infants with RSV infection. Concentrations of most cytokines were greater in influenza virus, rather than RSV, infection. Lung tissues from infants with fatal RSV and influenza virus LRTI demonstrated an extensive presence of viral antigen and a near absence of CD8-positive lymphocytes and natural killer cells, with marked expression of markers of apoptosis. Conclusions Severe infantile RSV and influenza virus LRTI is characterized by inadequate (rather than excessive) adaptive immune responses, robust viral replication, and apoptotic crisis.

Severe Human Lower Respiratory Tract Illness Caused by Respiratory Syncytial Virus and Influenza Virus Is Characterized by the Absence of Pulmonary Cytotoxic Lymphocyte Responses

Respiratory syncytial virus (RSV) and influenza virus are common causes of infantile lower respiratory tract infection (LRTI). It is widely believed that both viral replication and inappropriately enhanced immune responses contribute to disease severity. In infants, RSV LRTI is known to be more severe than influenza virus LRTI. We compared cytokines and chemokines in secretions of infants surviving various forms of respiratory illness caused by RSV or influenza viruses, to determine which mediators were associated with more severe illness. We analyzed lung tissue from fatal cases of RSV and influenza LRTI to determine the types of inflammatory cells present. Quantities of lymphocyte-derived cytokines were minimal in secretions from infants with RSV infection. Concentrations of most cytokines were greater in influenza, rather than RSV, infection. Lung tissues from fatal RSV and influenza LRTI cases demonstrated extensive presence of viral antigen and a near absence of CD8-positive lymphocytes and natural killer cells, with marked expression of markers of apoptosis. Severe infantile RSV and influenza virus LRTI is characterized by inadequate (rather than excessive) adaptive immune responses, robust viral replication and apoptotic crisis.

Respiratory syncytial virus and influenza virus infections: observations from tissues of fatal infant cases.

Although respiratory syncytial virus (RSV) infection is the most important cause of bronchiolitis in infants, the pathogenesis of RSV disease is poorly described. We studied histopathologic changes in a panel of lung tissue specimens obtained from infants with fatal cases of primary RSV infection. In these tissues, airway occlusion with accumulations of infected, apoptotic cellular debris and serum protein was consistently observed. Similar observations were found after RSV infection in New Zealand black (NZB) mice, which have constitutive deficiencies in macrophage function, but not in BALB/c mice. A deficiency in the number of alveolar macrophages in NZB mice appears to be central to enhanced disease, because depletion of alveolar macrophages in BALB/c mice before RSV exposure resulted in airway occlusion. In mice with insufficient numbers of macrophages, RSV infection yielded an increased viral load and enhanced expression of type I interferon-associated genes at the height of disease. Together, our data suggest that innate, rather than adaptive, immune responses are critical determinants of the severity of RSV bronchiolitis.

https://www.jstor.org/stable/pdfplus/40254352.pdf

Macrophage Impairment Underlies Airway Occlusion in Primary Respiratory Syncytial Virus Bronchiolitis

Antiviralantibodyproductionduringrespiratorysyncytialvirus(RSV)infectionininfantsispoorlyunderstood. TocharacterizelocalBlymphocyteresponses,lungtissueandsecretionsfrominfantswithRSVbronchiolitiswere analyzed for innate B cell–stimulating factors and antiviral antibodies. In lung tissues of infants with fatal RSV bronchiolitis,CD20lymphocytesandIgM-positive,IgG-positive,andIgA-positiveplasmacellswereprominent but CD4 T lymphocytes were not. Type I interferon–induced proteins and B cell tropic factors, including B cell–activating factor (BAFF) and a proliferation-inducing ligand (APRIL), were colocalized in infected epithelium. In nasopharyngeal secretions from infants who survived RSV infection, class-switched antiviral and antinucleosomalantibodiesweredetectedatpresentationandcorrelatedwithBAFFandAPRILlevels.Expressionof APRIL and antiviral antibodies of IgA and IgM but not IgG isotype predicted better oxygen saturation. We conclude that B lymphocyte–stimulating factors derived from infected epithelium are primary determinants of the mucosal antibody response in infant RSV bronchiolitis. Respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract infection (LRI) in infants. Virtually all infants have encountered RSV before the age of 2 years, resulting in100,000 infant hospitalizations and 400 infant deaths in the United States each year and 1 million deaths worldwide annually [1–3]. RSV LRI in infancy has been associated with chronic wheezing and asthma later in childhood [4]. Because there is currently no vaccination strategy to prevent infection in infants, RSV continues to pose a signif

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Timothy P. Welliver

Papers

Severe Human Lower Respiratory Tract Illness Caused by Respiratory Syncytial Virus and Influenza Virus Is Characterized by the Absence of Pulmonary Cytotoxic Lymphocyte Responses

Respiratory syncytial virus and influenza virus infections: observations from tissues of fatal infant cases.

Macrophage Impairment Underlies Airway Occlusion in Primary Respiratory Syncytial Virus Bronchiolitis

Innate Immune Signals Modulate Antiviral and Polyreactive Antibody Responses during Severe Respiratory Syncytial Virus Infection