Gene signature of children with severe respiratory syncytial virus infection.

BACKGROUND: The limited treatment options for children with severe respiratory syncytial virus (RSV) infection highlights the need for a comprehensive understanding of the host cellular response during infection. We aimed to identify host genes that are associated with severe RSV disease and to identify drugs that can be repurposed for the treatment of severe RSV infection. METHODS: We examined clinical data and blood samples from 37 hospitalized children (29 mild and 8 severe) with RSV infection. We tested RNA from blood samples using next-generation sequencing to profile global mRNA expression and identify cellular processes. RESULTS: Retractions, decreased breath sounds, and tachypnea were associated with disease severity. We observed upregulation of genes related to neutrophil, inflammatory response, blood coagulation, and downregulation of genes related to T cell response in children with severe RSV. Using network-based approach, 43 drugs were identified that are predicted to interact with the gene products of these differentially expressed genes. CONCLUSIONS: These results suggest that the changes in the expression pattern in the innate and adaptive immune responses may be associated with RSV clinical severity. Compounds that target these cellular processes can be repositioned as candidate drugs in the treatment of severe RSV. IMPACT: Neutrophil, inflammation, and blood coagulation genes are upregulated in children with severe RSV infection. Expression of T cell response genes are suppressed in cases of severe RSV. Genes identified in this study can contribute in understanding the pathogenesis of RSV disease severity. Drugs that target cellular processes associated with severe RSV can be repositioned as potential therapeutic options.

Norovirus-specific immunoglobulin A in breast milk for protection against norovirus-associated diarrhea among infants.

BACKGROUND: Norovirus (NV) causes acute gastroenteritis in infants. Humoral and fecal immunoglobulin A (IgA) responses have been correlated with protection against NV; however, the role of breast milk IgA against NV infection and associated diarrhea is still unknown. This study aimed to evaluate the protective role of NV-specific IgA (NV-IgA) in breast milk. METHODS: Ninety-five breast milk samples collected from mothers enrolled in a 2016-2017 Peruvian birth cohort study were tested for total IgA and NV-IgA by ELISA using GII·4 variants and non-GII·4 genotype virus-like particles (VLPs). Breast milk samples were grouped according to the NV infection and diarrheal status of infants: NV positive with diarrhea (NV+D+, n=18); NV positive without diarrhea (NV+D-, n=37); and NV negative without diarrhea (NV-D-, n=40). The percent positivity and titer of NV-IgA were compared among groups. The cross-reactivity was estimated based on the correlation of ratio between NV-IgA against GII·4 variants and non-GII·4 genotype VLPs. FINDINGS: NV-IgA had high positivity rates against different VLPs, especially against GII (89-100%). The NV+D- group had higher percent positivity (89% vs. 61%, p=0·03) and median titer (1:100 vs 1:50, p=0·03) of NV-IgA than the NV+D+ group against GI·1 VLPs. A relatively high correlation between different GII·4 variants (0·87) and low correlation between genogroups (0·23-0·37) were observed. INTERPRETATION: Mothers with high positivity rates and titers of NV-IgA in breast milk had NV infected infants with reduced diarrheal symptoms. Antigenic relatedness to the genetic diversity of human norovirus was suggested.Funding National Institute of Allergy and Infectious Diseases, National Institute of Health: 1R01AI108695-01A1 and the Japan Society for the Promotion of Science (Fostering Joint International Research B):19KK0241.