Salmonella Pathogenicity Island 1-Independent Induction of Apoptosis in Infected Macrophages by Salmonella enterica Serotype Typhimurium

Abstract

The enteric pathogen Salmonella enterica serotype Typhimurium induces apoptosis in infected macrophages. This process is rapid, specific, and depends on the type III protein secretion system encoded within Salmonella pathogenicity island 1 (SPI1). Here, we demonstrate that serotype Typhimurium can activate programmed macrophage cell death independently of SPI1. SPI1 independent induction of apoptosis in infected macrophages is observed as early as 12 to 13 h postinfection, even in the absence of intracellular bacterial replication. Delayed activation of programmed macrophage cell death is not observed with serotype Typhimurium strains mutated in ompR or SPI2. Even though SPI2 mutants have a defect in intracellular proliferation, our results indicate that long-term intracellular survival and growth are not required for delayed macrophage killing per se, since Salmonella mutants that are severely defective in intracellular growth still induce delayed apoptosis. Inactivation of genes required for either rapid or delayed induction of apoptosis results in a conditional noncytotoxic phenotype, whereas simultaneous inactivation of genes required for both rapid and delayed induction of apoptosis renders serotype Typhimurium noncytotoxic under all conditions tested. Our hypothesis is that differential activation of programmed macrophage cell death by serotype Typhimurium occurs under discrete physiological conditions at distinct locations within an infected host.

The lipopolysaccharide modification regulator PmrA limitsSalmonellavirulence by repressing the type three-secretion system Spi/Ssa

“…Control experiments showed reduced cell death in macrophages infected with the ssrB mutant (Fig. 6), in agreement with previous reports (38). These data indicate that the PmrA protein delays macrophage death induced by wild-type Salmonella.…”

Redox sensor SsrB Cys 203 enhances Salmonella fitness against nitric oxide generated in the host immune response to oral infection

“…Therefore, we do not favor the idea that SsrB Cys 203 helps Salmonella sense RNS in the gastrointestinal lumen. Second, RNS inhibit Salmonella-induced apoptosis (3), in which the SPI2 type III secretion system plays a critical role (27). In this context, the inhibition of phagocyte cell death by the RNSdependent repression of SPI2 may be advantageous later in the course of infection.…”

Salmonella Rapidly Kill Dendritic Cells via a Caspase-1- Dependent Mechanism

“…Indeed, longterm residence and replication within phagocytic cells appear to be essential for Salmonella virulence because mutant bacteria that cannot survive or multiply inside macrophages are attenuated for systemic infection in mice (10). The complex nature of this hostpathogen interaction is further illustrated by recent evidence that Salmonella can kill macrophages via at least two distinct mechanisms, resulting in the rapid activation of host caspase-1 and caspase-2 (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Caspase-1 is a member of a family of cysteinecontaining aspartate-specific proteases that play an important role in apoptosis (22,23).…”