Influenza A virus (IAV) is a major human respiratory pathogen that causes seasonal epidemics and occasional pandemics. The virus is a segmented, negative stranded RNA virus that, unlike most other RNA viruses, replicates its genome in the nucleus of infected cells. Genome replication yields a complementary RNA (cRNA) and a viral genomic RNA (vRNA). Both cRNA and vRNA contain a 5' triphosphate (ppp) which is recognized by the innate immune system by pattern recognition receptors (PRRs). Cytosolic sensors have been implicated in the specific recognition of influenza virus. Whether IAV can also be recognized in the nucleus is unknown. To address this, we screened nuclear proteins that, based on enzymatic features, may recognize viral RNA. Our preliminary results indicate that the protein DXO, a nuclear enzyme with 5'->3' pyrophosphohydrolase activity, can both recognize and degrade IAV RNA in vitro and in infected cells. We will study the mechanism and impact of DXO activity using biochemical and gene expression studies (Aims 1-2). We will examine DXO activity in vivo using a knock-out mouse model that we recently generated (Aim 3). These studies will provide novel mechanistic insights into how viral RNA expression is controlled along with elucidating the role of viral RNA catabolism in IAV pathogenesis, thus instructing new therapeutic avenues for disease eradication.

Public Health Relevance

Influenza virus infection represents a significant burden on society and a profound public health concern. The proposed research aims to understand a novel mechanism by which the host immune response antagonizes influenza virus infection by virtue of a specific recognition and degradation of the pathogen RNA. The knowledge that will be generated from this research project will instruct new therapeutic approaches for disease control and eradication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI143840-03
Application #
10078852
Study Section
Virology - A Study Section (VIRA)
Program Officer
Bozick, Brooke Allison
Project Start
2019-01-10
Project End
2023-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029