Human genetic susceptibility to intracellular pathogens

Summary:  Intracellular pathogens contribute to a significant proportion of infectious disease morbidity and mortality worldwide. Increasing evidence points to a major role for host genetics in explaining inter‐individual variation in susceptibility to infectious diseases. A number of monogenic disorders predisposing to infectious disease have been reported, including susceptibility to intracellular pathogens in association with mutations in genes of the interleukin‐12/interleukin‐23/interferon‐γ axis. Common genetic variants have also been demonstrated to regulate susceptibility to intracellular infection, for example the CCR5Δ32 polymorphism that modulates human immunodeficiency virus‐1 (HIV‐1) disease progression. Genome‐wide association study approaches are being increasingly utilized to define genetic variants underlying susceptibility to major infectious diseases. This review focuses on the current state‐of‐the‐art in genetics and genomics as pertains to understanding the genetic contribution to human susceptibility to infectious diseases caused by intracellular pathogens such as tuberculosis, leprosy, HIV‐1, hepatitis, and malaria, with a particular emphasis on insights from recent genome‐wide approaches. The results from these studies implicate common genetic variants in novel molecular pathways involved in human immunity to specific pathogens.