A BAFF-ling new role for NK cells in promoting marginal zone antibacterial resistance during chronic virus infection

Abstract

Natural killer (NK) cells are critical for both direct control of virus replication and regulation of potentially pathogenic antiviral responses. Yet, whether NK cells also contribute to immune control of bacterial superinfections during viral infection, a significant clinical cause of morbidity and mortality, remains unknown. We find that NK cells are vital to prevent a near complete loss of B cells and macrophages associated with the marginal zone (MZ) during chronic virus infection in mice. Establishment of chronic infection in the absence of NK cells results in hyper-susceptibility to Listeria monocytogenes infection that cannot be recapitulated by NK-cell depletion prior to bacterial challenge of chronically infected mice. Therefore, we posit that preservation of MZ leukocytes by NK cells, and not direct NK cell activity, curtails post-viral susceptibility toward bacterial superinfection. Mechanistically, we show that NK cells begin expressing the crucial MZ survival factor, B-cell activating factor (BAFF), during chronic virus infection, gradually becoming a prominent source of BAFF in the spleen. In vivo blockade of BAFF in NK-sufficient mice recapitulated the infection-associated loss of MZ cells seen in NK-cell deficient mice. These results reveal a new mechanism whereby NK cells promote bacterial resistance during chronic infection by maintaining BAFF-dependent immune structures. Disruption of this activity of NK cells during certain virus infections in humans may provoke post-viral pneumonia or invasive pneumococcal disease.