Lung NK cells are sufficient to control viral dissemination during respiratory MCMV infection

Murine cytomegalovirus (MCMV) respiratory dissemination schemes, which mimic natural infection routes, have only recently become an area of investigation. Using an intratracheal (i.t.) infection method, we discovered that the respiratory infection route yields differential infection kinetics compared to the widely used intraperitoneal (i.p.) infection method. Remarkably, we find that respiratory infection results in limited dissemination, with the virus being mostly contained in the pulmonary tissue. Importantly, using Rag1, Ly49H, and natural killer (NK) cell-deficient animals, we find that lung conventional NK (cNK) cells play a critical role in preventing MCMV-induced morbidity. Mechanistically, we show that indirect activation of lung NK cells via interleukin (IL)-12 and type 1 interferon (IFN) inflammatory cytokines is dispensable, while direct activation via Ly49H is essential in preventing morbidity from i.t. infection. Additionally, we did not find a significant role for ILC2 or tissue-resident NK (trNK) cells in the prevention of viral dissemination, and we did not observe an increase in the abundance of these cells. These findings uncover an unanticipated role for pulmonary cNK cells in preventing viral dissemination from infected lungs.