RESUMEN
Humans differ in their susceptibility to infectious disease, partly owing to variation in the immune response after infection. We used single-cell RNA sequencing to quantify variation in the response to influenza infection in peripheral blood mononuclear cells from European- and African-ancestry males. Genetic ancestry effects are common but highly cell type specific. Higher levels of European ancestry are associated with increased type I interferon pathway activity in early infection, which predicts reduced viral titers at later time points. Substantial population-associated variation is explained by cis-expression quantitative trait loci that are differentiated by genetic ancestry. Furthermore, genetic ancestryassociated genes are enriched among genes correlated with COVID-19 disease severity, suggesting that the early immune response contributes to ancestry-associated differences for multiple viral infection outcomes.
Asunto(s)
Negro o Afroamericano/genética , COVID-19/genética , Subtipo H1N1 del Virus de la Influenza A/inmunología , Gripe Humana/genética , Gripe Humana/inmunología , Leucocitos Mononucleares/virología , Población Blanca/genética , Adulto , Anciano , COVID-19/inmunología , COVID-19/fisiopatología , Susceptibilidad a Enfermedades , Regulación de la Expresión Génica , Variación Genética , Humanos , Subtipo H1N1 del Virus de la Influenza A/fisiología , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Sitios de Carácter Cuantitativo , Índice de Severidad de la Enfermedad , Análisis de la Célula Individual , Transcripción Genética , Carga Viral , Adulto JovenRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Neutralizing Abs target the receptor binding domain of the spike (S) protein, a focus of successful vaccine efforts. Concerns have arisen that S-specific vaccine immunity may fail to neutralize emerging variants. We show that vaccination with a human adenovirus type 5 vector expressing the SARS-CoV-2 nucleocapsid (N) protein can establish protective immunity, defined by reduced weight loss and viral load, in both Syrian hamsters and K18-hACE2 mice. Challenge of vaccinated mice was associated with rapid N-specific T cell recall responses in the respiratory mucosa. This study supports the rationale for including additional viral Ags in SARS-CoV-2 vaccines, even if they are not a target of neutralizing Abs, to broaden epitope coverage and immune effector mechanisms.