Salmonella entericaserovar Typhi uses two type 3 secretion systems to replicate in human macrophages and to colonize humanized mice

Abstract

AbstractSalmonella entericaserovar Typhi (S.Typhi) is a human-restricted pathogen that replicates in macrophages. In this study, we investigated the roles of theS.Typhi Type 3 secretion systems (T3SSs) encoded onSalmonellaPathogenicity Islands (SPI) -1 (T3SS-1) and -2 (T3SS-2) during human macrophage infection. We found that mutants ofS. Typhi deficient for both T3SSs were defective for intramacrophage replication as measured by flow cytometry, viable bacterial counts, and live time-lapse microscopy. T3SS-secreted proteins PipB2 and SifA contributed toS.Typhi replication and were translocated into the cytosol of human macrophages through both T3SS-1 and -2, demonstrating functional redundancy for these secretion systems. Importantly, anS. Typhi mutant strain that is deficient for both T3SS-1 and -2 was severely attenuated in the ability to colonize systemic tissues in a humanized mouse model of typhoid fever. Overall, this study establishes a critical role forS.Typhi T3SSs during its replication within human macrophages and during systemic infection of humanized mice.ImportanceSalmonella entericaserovar Typhi is a human-restricted pathogen that causes typhoid fever. Understanding the key virulence mechanisms that facilitateS.Typhi replication in human phagocytes will enable rational vaccine and antibiotic development to limit spread of this pathogen. WhileS.Typhimurium replication in murine models has been studied extensively, there is limited information available aboutS.Typhi replication in human macrophages, some of which directly conflicts with findings fromS.Typhimurium murine models. This study establishes that both ofS.Typhi’s two Type 3 Secretion Systems (T3SS-1 and -2) contribute to intramacrophage replication and virulence.