Modulation of mucosal immunity and tissue resident memory formation by NS1-deficient influenza A virus

Abstract

Abstract Recurrent influenza A virus (IAV) epidemics and occasional pandemics as a result of viral genome reassortment and human adaptation pose significant health burdens globally. The non-structural protein 1 (NS1) mediates attenuation of host response and facilitates viral replication in the nucleus. While intranasal vaccination using NS1-deleted live attenuated virus has been shown to induce pulmonary mucosal immunity in animal models, the immunological details have not been fully studied. In vivo mouse infection using wild type (WSN/WT) and NS1-deleted WSN (WSN/Del) showed WSN/Del induced massive type I interferon response in murine lungs, whereas pulmonary inflammation was minimal. Skewed migration of CD103+ dendritic cells (DC) to mediastinal lymph nodes upon WSN/Del infection was observed with enhanced formation and persistence of tissue resident influenza-specific memory CD8 T cells (T RM). After rechallenge, while influenza-specific T RMin both groups expanded comparably, more polyfunctionality was seen in T RMfrom WSN/Del immunized mice than WSN/WT recovered mice. Single cell RNA-seq of migratory DC in initial immunization showed differential gene programs associated with WSN/Del infection. Ongoing work is undertaken to identify the signals provided by DC that may lead to preferential priming of T cells to tissue resident lineage. Since T RMhave been illustrated to confer heterosubtypic protection, knowledge on the specific physiological cues that facilitate T RMformation and retention will be useful to vaccine development.