Identification of a Novel NK Cell Deficiency in a Genome Wide Screen for Susceptibility to Viral Infection
1. Dept of Human Genetics, McGill University, Montréal, Québec, Canada; 2. Genome Quebec Innovation Center, Montréal, Québec, Canada
Cytomegaloviruses (CMV) are ubiquitous opportunistic pathogens. While acute infection by CMV gives little clinical manifestations, severe morbidity or even mortality can be observed in immuno-incompetent or immature individuals. This is exacerbated by the limited offer in treatment available. A possible approach to fill this gap is the investigation of host genes that are critical for the outcome of host-pathogen interactions. As such, the use of inbred mouse strains that accurately replicate disease and exhibit natural genetic variation in susceptibility has been particularly useful to understand fundamental mechanisms of infectious disease pathogenesis. Further, random chemical mutagenesis of the mouse germline with N-Ethyl-N-Nitrosourea (ENU) is a powerful tool to screen and identify new mutations critical to immunity to CMV infection. Using this approach, we have produced and identified a critical mutation on the highly conversed GTPase GNL1 causing susceptibility to the virus. Despite the unknown role of GNL1, it is believed to be important for cell cycle progression. Our mice GNL1C365X mice are highly susceptibility to murine CMV, but more interestingly, have low immune cells number. The NK cells, which play a non-redundant role in CMV resistance, are especially affected. Although their numbers are greatly reduced, GNL1C365X NK cells remain functional, since their IFNγ production, cytotoxicity activity and proliferation capacity following infection are similar to wild type cells. Nevertheless, mice missing GNL1 show a clear reduction in bone marrow NK early progenitors, which explains the low cell number observed in periphery. Our results suggest that GNL1 is important to the development of NK cells and other immune cells and that impairing GNL1 function leads to a reduction of NK cells numbers, thus causing susceptibility to cytomegalovirus.