Type I Interferon Potentiates IgA Immunity to Respiratory Syncytial Virus Infection During Infancy

Hijano, Diego R.; Siefker, David; Shrestha, Bishwas; Jaligama, Sridhar; Vu, Luan; Tillman, Heather; Finkelstein, David; Saravia, Jordy; You, Dahui; Cormier, Stephania A.

doi:10.1038/s41598-018-29456-w

Cited by 34 publications

(33 citation statements)

References 56 publications

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“…MAMPs and PAMPS are able to activate Toll Like Receptors (TLR) on dendritic cells, T cells, epithelial cells, macrophages, and B cells. This activation of TLRs can change cytokine, chemokine, and antibody production in the lung, all of which have been shown to be important in viral clearance for RSV [25,26]. Studies have shown associations between bronchiolitis and the gut microbiome in infants, along with associations between RSV and the gut microbiome of mice.…”

Section: Discussionmentioning

confidence: 99%

Altered gut microbiota in infants is associated with respiratory syncytial virus disease severity

Harding

Siefker

et al. 2020

BMC Microbiol

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Background: Respiratory syncytial virus (RSV) is the number one cause of lower respiratory tract infections in infants. There are still no vaccines or specific antiviral therapies against RSV, mainly due to the inadequate understanding of RSV pathogenesis. Recent data suggest a role for gut microbiota community structure in determining RSV disease severity. Our objective was to determine the gut microbial profile associated with severe RSV patients, which could be used to help identify at-risk patients and develop therapeutically protective microbial assemblages that may stimulate immuno-protection. Results: We enrolled 95 infants from Le Bonheur during the 2014 to 2016 RSV season. Of these, 37 were wellbabies and 58 were hospitalized with RSV. Of the RSV infected babies, 53 remained in the pediatric ward (moderate) and 5 were moved to the pediatric intensive care unit at a later date (severe). Stool samples were collected within 72 h of admission; and the composition of gut microbiota was evaluated via 16S sequencing of fecal DNA. There was a significant enrichment in S24_7, Clostridiales, Odoribacteraceae, Lactobacillaceae, and Actinomyces in RSV (moderate and severe) vs. controls. Patients with severe RSV disease had slightly lower alpha diversity (richness and evenness of the bacterial community) of the gut microbiota compared to patients with moderate RSV and healthy controls. Beta diversity (overall microbial composition) was significantly different between all RSV patients (moderate and severe) compared to controls and had significant microbial composition separating all three groups (control, moderate RSV, and severe RSV). Conclusions: Collectively, these data demonstrate that a unique gut microbial profile is associated with RSV disease and with severe RSV disease with admission to the pediatric intensive care unit. More mechanistic experiments are needed to determine whether the differences observed in gut microbiota are the cause or consequences of severe RSV disease.

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Section: Discussionmentioning

confidence: 99%

Altered gut microbiota in infants is associated with respiratory syncytial virus disease severity

Harding

Siefker

et al. 2020

BMC Microbiol

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“…Our finding that IFNAR1-SA infant mice are relatively resistant to lethal infection and have reduced levels of pathogenic outcomes is consistent with this idea. IFN-α administration was shown to protect infant mice against respiratory syncytial virus infection and overcome age-related differences in IgA production in response to the infection (63). In another study, agedependent effects of type I IFNs were demonstrated by the observation that type I IFNs protected infant mice treated with TLR ligands from lethal inflammatory responses, whereas they enhanced the same inflammatory response in adult mice (64).…”

Section: Discussionmentioning

confidence: 98%

Age-Dependent Effects of Type I and Type III IFNs in the Pathogenesis of Bordetella pertussis Infection and Disease

Ardanuy

Scanlon

Skerry

et al. 2020

The Journal of Immunology

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Type I and III IFNs play diverse roles in bacterial infections, being protective for some but deleterious for others. Using RNA-sequencing transcriptomics we investigated lung gene expression responses to Bordetella pertussis infection in adult mice, revealing that type I and III IFN pathways may play an important role in promoting inflammatory responses. In B. pertussisinfected mice, lung type I/III IFN responses correlated with increased proinflammatory cytokine expression and with lung inflammatory pathology. In mutant mice with increased type I IFN receptor (IFNAR) signaling, B. pertussis infection exacerbated lung inflammatory pathology, whereas knockout mice with defects in type I IFN signaling had lower levels of lung inflammation than wild-type mice. Curiously, B. pertussis-infected IFNAR1 knockout mice had wild-type levels of lung inflammatory pathology. However, in response to infection these mice had increased levels of type III IFN expression, neutralization of which reduced lung inflammation. In support of this finding, B. pertussis-infected mice with a knockout mutation in the type III IFN receptor (IFNLR1) and double IFNAR1/IFNLR1 knockout mutant mice had reduced lung inflammatory pathology compared with that in wild-type mice, indicating that type III IFN exacerbates lung inflammation. In marked contrast, infant mice did not upregulate type I or III IFNs in response to B. pertussis infection and were protected from lethal infection by increased type I IFN signaling. These results indicate age-dependent effects of type I/III IFN signaling during B. pertussis infection and suggest that these pathways represent targets for therapeutic intervention in pertussis. Pertussis, also referred to as whooping cough, is a highly contagious respiratory disease caused by infection with the bacterial pathogen Bordetella pertussis. There has been a recent resurgence in pertussis, with 48,277 reported cases in the United States in 2012, the most since 1955 (1). In older children and adults, symptoms build up to periods of severe paroxysmal coughing, often for several weeks after onset, but other complications are relatively rare (2, 3). However, for infants, pertussis can be a fatal disease because of

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Section: Discussionmentioning

confidence: 99%

Altered Gut Microbiota in Infants is Associated with Respiratory Syncytial Virus Disease Severity

Harding

Siefker

et al. 2020

Preprint

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Rationale Respiratory syncytial virus (RSV) is the number one cause of lower respiratory tract infections in infants. There are still no vaccines or specific antiviral therapies against RSV, mainly due to the inadequate understanding of RSV pathogenesis. Recent data suggest a role for gut microbiota community structure in determining RSV disease severity.Objectives Our objective was to determine the gut microbial profile associated with severe RSV patients, which could be used to help identify future at-risk patients and develop therapeutically protective microbial assemblages that may stimulate immuno-protection.Methods We enrolled 58 infants hospitalized with RSV, 5 were admitted to the pediatric intensive care unit and thus considered severe, 53 were admitted to the pediatric ward and considered moderate, and 37 healthy controls collected from infants during “well-baby checkups” from 2012 to 2015. We evaluated the composition of gut microbiota within 72 hours of enrollment in these patients via 16s sequencing of fecal DNA.Measurements and Main Results There was a significant enrichment in S24_7, Clostridiales, Odoribacteraceae, Lactobacillaceae, and Actinomyces in RSV vs. controls. Patients with severe RSV disease had slightly lower alpha diversity (richness and evenness of the bacterial community) of the gut microbiota compared to patients with moderate RSV and healthy controls. Beta diversity (overall microbial composition) was significantly different between all RSV patients (severe and moderate) compared to controls and had significant microbial composition separating all three groups (control, moderate RSV, and Severe RSV). Conclusions Collectively, these data indicate that a unique gut microbial profile that is associated with severe RSV disease. More mechanistic experiments are needed to determine whether the differences observed in gut microbiota are the cause or consequences of severe RSV disease.

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Type I Interferon Potentiates IgA Immunity to Respiratory Syncytial Virus Infection During Infancy

Cited by 34 publications

References 56 publications

Altered gut microbiota in infants is associated with respiratory syncytial virus disease severity

Altered gut microbiota in infants is associated with respiratory syncytial virus disease severity

Age-Dependent Effects of Type I and Type III IFNs in the Pathogenesis of Bordetella pertussis Infection and Disease

Altered Gut Microbiota in Infants is Associated with Respiratory Syncytial Virus Disease Severity

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