Highly pathogenic H5N1 influenza virus continues to circulate in South-East Asia and Africa. Since 2003, over 550 human cases of H5 N1 infections have been reported and approximately 50% of those cases have died. Although the exact number of H5N1 infected persons is unknown, the severity of the resulting disease in those that have been identified is driven by a combination of viral and host factors. Evidence shows that host genetic polymorphisms are involved in H5N1 pathogenesis and identifying them, and the affected host genes, will reveal important biological properties of H5N1 virus infections and resulting disease. Such information will provide a framework for the rationale design of new treatments and measures to reduce the burden of disease. We have previously utilized the genetic variation between inbred mouse strain s to identify virologic and immunologic hallmarks of severe influenza disease. These studies provided the data supporting our hypothesis that host polymorphisms have substantial impact on influenza virus disease by modulating early viral replication kinetics. To identify the specific host genetic polymorphisms involved, we utilized the fact that the A/J mouse strain was more susceptible to H5N1 influenza virus than the C57B L/6 strain. Furthering this observation, we have now localized the genetic factors behind the increased disease in A/J mice to a single chromosome. Consomic C57BL/6 mice containing this A/ J chromosome were more susceptible to highly pathogenic H5N1 influenza A virus and influenza B virus infection as compared to C57BL/6 wild type controls. Susceptibility to H5N1 virus was associated with higher viral loads in the lungs and increased production of pro-inflammatory cytokines;all hallmarks of a severe H5N1 infection in humans. To identify the host gene responsible for the disparity in pathogenesis, we will (1) define the genetic locus associated with the increased mortality and higher viral loads using congenic mouse strains, and (2) identify the mechanism of increased viral load in the susceptible animals. Finally, we will perform candidate host gene analysis and assess their role on influenza virus infection and replication. At the conclusion of the proposed studies, we will have identified a novel host gene associated with severe influenza.
Highly pathogenic H5N1 influenza virus causes severe disease and death in humans and represents a considerable threat to public health. This project will identify a host gene containing a genetic polymorphism that is associated with severe H5N1 disease. The discovery of host genes modulating influenza disease will provide much needed insight into H5N1 virus biology and uncover new treatment options for this deadly disease.