Limited Type I Interferons and Plasmacytoid Dendritic Cells during Neonatal Respiratory Syncytial Virus Infection Permit Immunopathogenesis upon Reinfection

Cormier, Stephania A.; Shrestha, Bishwas; Saravia, Jordy; Lee, Greg I.; Shen, Li; DeVincenzo, John P.; Kim, Young In; You, Dahui

doi:10.1128/jvi.00818-14

Cited by 82 publications

(108 citation statements)

References 33 publications

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“…In human infants, RSV severity is associated with increased viral loads in nasal aspirates (14), and plasmacytoid dendritic cells (pDCs) from cord blood mononuclear cells (CBMCs) are less able to induce antiviral type I interferons (IFNs) than pDCs from adult human PBMCs are (15). Consistent with human data, neonatal mice are incapable of inducing a robust type I IFN and pDC response in the lung (16).…”

Section: Other Cells That May Play a Role In Rsv Pathogenesis Or Protsupporting

confidence: 69%

Crawling with Virus: Translational Insights from a Neonatal Mouse Model on the Pathogenesis of Respiratory Syncytial Virus in Infants

You

Saravia

Siefker

et al. 2016

J Virol

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The infant immune response to respiratory syncytial virus (RSV) remains incompletely understood. Here we review the use of a neonatal mouse model of RSV infection to mimic severe infection in human infants. We describe numerous age-specific responses, organized by cell type, observed in RSV-infected neonatal mice and draw comparisons (when possible) to human infants. R espiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections in infants, and severe RSV disease during infancy is associated with an increased risk of asthma development. The medical and economic burdens of RSV infection are enormous. In the United States alone, there are 85,000 to 144,000 annual hospitalizations with $2.6 billion in associated estimated medical cost (1). Despite its continued impact on global health, RSV remains without a vaccine or adequate therapeutic.While prematurity, immunodeficiency, and congenital heart or chronic lung diseases are risk factors for severe RSV disease, the majority of the infants requiring hospitalization were previously healthy and less than 6 months of age (2), suggesting that age at the time of initial infection is an important predictive factor for disease severity. Therefore, our grasp of severe RSV disease in infants is inevitably tied to our understanding of developmental immunity during the first year of life.The neonatal mouse model of RSV infection has been an invaluable tool for RSV research (3, 4). Briefly, neonatal mice (Յ7 days of age) are infected with RSV and then reinfected 4 weeks later as adults. Compared to mice initially infected as adults, these mice develop the characteristic Th2-biased immunopathologies, including exaggerated pulmonary Th2 cells/cytokines, eosinophilia, mucus hyperproduction, and airway hyperreactivity. In recent years, this model spurred several significant advances in research on how age-dependent differences in various immune and nonimmune cells initiate the immunopathogenesis of RSV infection in infants. This article will briefly discuss said advances, organized by the cell types involved in responding to RSV. EPITHELIAL CELLSThe major cellular target of RSV is airway epithelial cells. In the lower respiratory tract, RSV infects bronchiolar and alveolar (type I and II) epithelial cells (5) and similar cells in mice (6). During infection, the airway epithelium is a major source of the "alarmin" cytokine interleukin-33 (IL-33). Intriguingly, nasal aspirates from infants with severe RSV disease have elevated levels of 8), and variants of the IL-33 receptor gene IL1RL1 are associated with severe RSV disease in human infants (9). Immediately following RSV infection in neonatal mice, a robust IL-33 response is elicited in CD45 Ϫ EpCam ϩ pneumocytes (7); this type of response to RSV infection does not occur in adult mice, suggesting age-dependent regulation of IL-33 expression in the lung. Furthermore, the severity of RSV infection (i.e., Th2-mediated immunopathology) is dependent on the levels of IL-33 early during infection. ILC2SMor...

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Section: Other Cells That May Play a Role In Rsv Pathogenesis Or Protsupporting

confidence: 69%

Crawling with Virus: Translational Insights from a Neonatal Mouse Model on the Pathogenesis of Respiratory Syncytial Virus in Infants

You

Saravia

Siefker

et al. 2016

J Virol

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“…Such conditions might mimic the settings of neonates 16 , elderly 17 , and immunosuppressed individuals, where innate resistance is suboptimal resulting in overdrive of compensatory immune effector mechanisms. Consistent with previous work 11,15 , our findings indicate an antiviral role for CD8 T cells in the ZIKV infection.…”

mentioning

confidence: 99%

Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice

et al. 2017

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Zika virus (ZIKV) is an emerging, mosquito-borne RNA virus. The rapid spread of ZIKV within the Americas has unveiled microcephaly1 and Guillain-Barré syndrome 2,3 as ZIKV-associated neurological complications. Recent reports have further indicated other neurological manifestations to be associated with ZIKV including myelitis 4, meningoencephalitis 5 and fatal encephalitis6. Here, we investigate the neuropathogenesis of ZIKV infection in IFNAR knockout (Ifnar1−/−) mice, an infection model that exhibits high viral burden within the central nervous system (CNS). We show that systemic spread of ZIKV from the site of infection to the brain requires Ifnar1-deficiency in the hematopoietic compartment. However, spread of ZIKV within the CNS is supported by Ifnar1-deficient non-hematopoietic cells. Within this context, ZIKV infection of astrocytes results in breakdown of the blood-brain barrier and a large influx of CD8+ effector T cells. Further, we find antiviral activity of CD8+ T cells within the brain markedly limits ZIKV infection of neurons, but as a consequence instigates ZIKV-associated paralysis. Taken together, our study uncovers mechanisms underlying ZIKV-neuropathogenesis within a susceptible mouse model and suggests BBB breakdown and T cell mediated neuropathology as potential underpinnings of ZIKV-associated neurological complications in humans.

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“…Also, a deficiency in type I IFN production by cells from infants 47 and from neonatal mice 48, 49 has been shown. In contrast, some studies show a higher level of IFN-α in nasopharyngeal wash in more severely sick infants compared to controls 50 .…”

Section: Innate Immune Responses To Rsvmentioning

confidence: 99%

Respiratory syncytial virus infection: an innate perspective

Johansson

2016

F1000Res

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Respiratory syncytial virus (RSV) is a common cause of upper respiratory tract infection in children and adults. However, infection with this virus sometimes leads to severe lower respiratory disease and is the major cause of infant hospitalisations in the developed world. Several risk factors such as baby prematurity and congenital heart disease are known to predispose towards severe disease but previously healthy, full-term infants can also develop bronchiolitis and viral pneumonia during RSV infection. The causes of severe disease are not fully understood but may include dysregulation of the immune response to the virus, resulting in excessive recruitment and activation of innate and adaptive immune cells that can cause damage. This review highlights recent discoveries on the balancing act of immune-mediated virus clearance versus immunopathology during RSV infection.

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Limited Type I Interferons and Plasmacytoid Dendritic Cells during Neonatal Respiratory Syncytial Virus Infection Permit Immunopathogenesis upon Reinfection

Cited by 82 publications

References 33 publications

Crawling with Virus: Translational Insights from a Neonatal Mouse Model on the Pathogenesis of Respiratory Syncytial Virus in Infants

Crawling with Virus: Translational Insights from a Neonatal Mouse Model on the Pathogenesis of Respiratory Syncytial Virus in Infants

Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice

Respiratory syncytial virus infection: an innate perspective

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