Influenza virus NS1 protein protects against lymphohematopoietic pathogenesis in an in vivo mouse model

Destruction of peripheral lymphocytes and detrimental alterations in hematopoietic precursors are associated with influenza virus infection in birds and humans. A prominent feature among H5N1 influenza-virus-infected patients with a severe or fatal outcome was found to be lymphopenia and reactive hemophagocytosis. We show here that NS1 protein from human H5N1 influenza isolate A/HK/156/97 reduces both systemic and pulmonary pro-inflammatory cytokines in an in vivo mouse model and protects against bone marrow lymphocyte depletion, an effect which has been shown to be mediated by TNFalpha. These data suggest that the outcome of disease-associated lymphohematopoietic pathogenesis with a pathogenic influenza A virus may depend on the balance between the virus-replication-induced generation of pro-inflammatory cytokines which are a crucial component of the host's anti-viral defense and the ability of the NS1 protein, with or without the interaction of other virus proteins, to counteract such cytokine-mediated adverse effects.