Abstract
Seasonal influenza virus infections cause mild illness in healthy adults, as timely viral clearance is mediated by the functions of cytotoxic T cells. However, avian H5N1 influenza virus infections can result in prolonged and fatal illness across all age groups, which has been attributed to the overt and uncontrolled activation of host immune responses. Here, we investigate how excessive innate immune responses to H5N1 impair subsequent adaptive T cell responses in the lungs. Using recombinant H1N1 and H5N1 strains sharing 6 internal genes, we demonstrate that H5N1 (2:6) infection in mice causes higher stimulation and increased migration of lung dendritic cells to the draining lymph nodes, resulting in greater numbers of virus-specific T cells in the lungs. Despite robust T cell responses in the lungs, H5N1 (2:6)-infected mice showed inefficient and delayed viral clearance compared with H1N1-infected mice. In addition, we observed higher levels of inhibitory signals, including increased PD-1 and interleukin-10 (IL-10) expression by cytotoxic T cells in H5N1 (2:6)-infected mice, suggesting that delayed viral clearance of H5N1 (2:6) was due to the suppression of T cell functions in vivo Importantly, H5N1 (2:6)-infected mice displayed decreased numbers of tissue-resident memory T cells compared with H1N1-infected mice; however, despite the decreased number of tissue-resident memory T cells, H5N1 (2:6) was protected against a heterologous challenge from H3N2 virus (X31). Taken together, our study provides mechanistic insight for the prolonged viral replication and protracted illness observed in H5N1-infected patients.IMPORTANCE Influenza viruses cause upper respiratory tract infections in humans. In healthy adults, seasonal influenza virus infections result in mild disease. Occasionally, influenza viruses endemic in domestic birds can cause severe and fatal disease even in healthy individuals. In avian influenza virus-infected patients, the host immune system is activated in an uncontrolled manner and is unable to control infection in a timely fashion. In this study, we investigated why the immune system fails to effectively control a modified form of avian influenza virus. Our studies show that T cell functions important for clearing virally infected cells are impaired by higher negative regulatory signals during modified avian influenza virus infection. In addition, memory T cell numbers were decreased in modified avian influenza virus-infected mice. Our studies provide a possible mechanism for the severe and prolonged disease associated with avian influenza virus infections in humans.