Latent cytomegalovirus disrupts innate NK cell responses to P. falciparum and impairs parasite control in first infection in adults.

NK cells are innate and adaptive responders to malaria, with functional responses underpinned by NK cell heterogeneity. One driver of NK cell heterogeneity is latent CMV infection. Latent CMV infection negatively impacts adaptive immunity to malaria, but whether CMV-mediated changes to the NK cell compartment also impact innate responses to malaria is unknown. We investigated the impact of latent CMV infection on innate NK cell responses to the malaria parasite in vitro in malaria naïve adults, and in vivo NK cell responses during a first controlled human malaria infection. We found that transcriptional activation of NK cells by parasites was attenuated in CMV seropositive individuals. Further, during a first malaria infection, markers of NK cell activation and cytotoxicity were reduced. This attenuated response was not restricted to a single NK phenotype but occurred across diverse NK cell phenotypes. Consistent with a global NK cell attenuation, IL12 production from myeloid cells, a response that supports NK cell activation on exposure to P. falciparum parasites, was lower in CMV infected individuals. Linking NK cell activation to clinical outcomes, NK cell perforin expression was associated with parasite control in CMV seronegative individuals during first malaria infection. Data highlight the interplay between pathogens and the host-immune response that influence clinical outcomes.