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Salmonella enterica serovar Typhi (S. Typhi) causes typhoid fever, a bacterial disease killing hundreds of thousands of people annually. Unlike other Salmonella, S. Typhi only infects humans. The inability of S. Typhi to infect other animal species depends at least partially on a host-defence pathway regulated by the RAB32 GTPase. It was therefore assumed that a RAB32-associated pathway was absent or inactive as a host-defence pathway in humans. Here we show that RAB32 and its guanine-nucleotide exchange factor Biogenesis of Lysosome-related Organelle Complex-3 (BLOC-3) control S. Typhi replication in human macrophages, as inactivating RAB32 or removing BLOC-3 by CRISPR-Cas9 targeting increases S. Typhi replication. We also report that, to survive in human macrophages, S. Typhi actively counteracts the RAB32/BLOC-3 pathway through its Salmonella pathogenicity island-1-encoded type III secretion system. These findings indicate that the RAB32/BLOC-3 pathway is a general host-defence pathway protecting mammalian species from bacterial infections and that S. Typhi has evolved specific strategies to neutralize this pathway.