Abstract
Salmonella causes disease in humans and animals ranging from mild self-limiting gastroenteritis to potentially life-threatening typhoid fever. Salmonellosis remains a considerable cause of morbidity and mortality globally, and hence imposes a huge socio-economic burden worldwide. A key property of all pathogenic Salmonella strains is the ability to invade non-phagocytic host cells. The major determinant of this invasiveness is a Type 3 Secretion System (T3SS), a molecular syringe that injects virulence effector proteins directly into target host cells. These effectors cooperatively manipulate multiple host cell signaling pathways to drive pathogen internalization. Salmonella does not only rely on these injected effectors, but also uses several other T3SS-independent mechanisms to gain entry into host cells. This review summarizes our current understanding of the methods used by Salmonella for cell invasion, with a focus on the host signaling networks that must be coordinately exploited for the pathogen to achieve its goal.
Highlights
Salmonella enterica is a leading cause of morbidity and mortality in both humans and animals
SPI1 has been the subject of decades of research, which has shown it to encode a Type Three Secretion System (T3SS), a molecule syringe that directly delivers a cohort of virulence effector proteins into host cells (Deng et al, 2017)
It is well-established that the same pathway promotes the pronounced membrane ruffling associated with Salmonella entry (Hanisch et al, 2010), and recent work has identified the multiplicity of signaling events that must be coordinated by Salmonella in order to correctly subvert WAVE Regulatory Complex (WRC) function (Figure 2)
Summary
Salmonella enterica is a leading cause of morbidity and mortality in both humans and animals. SPI1 has been the subject of decades of research, which has shown it to encode a Type Three Secretion System (T3SS), a molecule syringe that directly delivers a cohort of virulence effector proteins (encoded both within SPI1 and elsewhere in the Salmonella chromosome) into host cells (Deng et al, 2017) These effectors both drive the forced uptake of the pathogen by non-phagocytic cells, and manipulate host cell signaling pathways, especially those involved in the inflammatory response (McGhie et al, 2009). Infection of cultured cells leads to a SopB-dependent increase in phosphatidylinositol-3-phosphate (PI3P), phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2)and phosphatidylinositol-3,4,5-triphosphate (PI(3,4,5)P3) (Mallo et al, 2008) The production of these lipids allows the recruitment of various host proteins, e.g., SGEF, which in turn activates RhoG, which may be important for Salmonella entry (Patel and Galan, 2006). SipA mutants have small, but significant, decrease in invasiveness, suggesting that SipA enhances Salmonella entry but is not strictly required (Jepson et al, 2001)
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