Complement evasion mechanisms of the systemic pathogens Yersiniae and Salmonellae

Abstract

Pathogens that colonize deep tissues and spread systemically encounter the innate host resistance mechanism of complement-mediated lysis and complement opsonization leading to engulfment and degradation by phagocytic cells. Yersinia and Salmonella species have developed numerous strategies to block the antimicrobial effects of complement. These include recruitment of complement regulatory proteins factor H, C4BP, and vitronectin (Vn) as well as interference in late maturation events such as assembly of C9 into the membrane attack complex that leads to bacterial lysis. This review will discuss the contributions of various surface structures (proteins, lipopolysaccharide, and capsules) to evasion of complement-mediated immune clearance of the systemic pathogens Yersiniae and Salmonellae. Bacterial proteins required for recruitment of complement regulatory proteins will be described, including the details of their interaction with host regulatory proteins, where known. The potential role of the surface proteases Pla (Yersinia pestis) and PgtE (Salmonella species) on the activity of complement regulatory proteins will also be addressed. Finally, the implications of complement inactivation on host cell interactions and host cell targeting for type 3 secretion will be discussed.

Mutually constructive roles of Ail and LPS in Yersinia pestis serum survival

“…These are likely to have important consequences for the virulence phenotypes that rely on Ail and LPS. The serum resistance function of Ail is thought to depend on its ability to bind elements of the human innate immune system, such as complement components and the blood protein Vitronectin (Bartra et al ., 2015; Krukonis and Thomson, 2020), and these binding events may be expected to rely on the presentation of a competent conformation of Ail at the bacterial cell surface. Moreover, the high abundance of Ail and LPS at the bacterial cell surface suggests that the Ail–LPS interaction network plays an important role in maintaining outer membrane integrity, with implications for resistance to antibiotics and other environmental stressors.…”

“…The acquisition of conformational order could have important implications for the various virulence attributes that rely on the interactions of Ail with human host proteins, specifically, boosting fibrinolysis to create a permissive environment for microbial circulation, promoting host cell adhesion, and evading immune defenses to promote survival in blood by interfering with the assembly of the terminal complement complex (Bartra et al ., 2015; Krukonis and Thomson, 2020). The extracellular loops of Ail, particularly EL2 and EL3, are important for recruiting a range of human factors to the bacterial cell surface (Thomson et al ., 2019), and LPS‐induced conformational order in the Ail loops could have a substantially positive effect on the binding affinity of Ail for its other human host partners by minimizing the conformational entropy loss incurred upon binding.…”

Soluble MAC is primarily released from MAC-resistant bacteria that potently convert complement component C5

“…These findings suggest that detection of sMAC in human serum indicates potent C5 conversion by MAC-resistant bacteria. Increased C5 conversion has previously been associated with MAC-resistance on Gram-negative bacteria [34,35], but this has not yet been directly linked to the detection of sMAC in human serum. Moreover, our study extends on these insights by showing that potent C5 conversion by MAC-resistant E. coli is linked to the expression LPS O-Ag.…”

Lipopolysaccharide of the Yersinia pseudotuberculosis Complex

“…The binding of the core part of LPS to Pla occurs at the amino acid residues Arg 138 and Arg 171 , which induces conformational changes in the active site, affects its stereometry and modulates the activity of Y. pestis plasminogen activator. The substitution of these arginine residues, particularly Arg 138 , reduces the proteolytic activity of Pla and the quantity of Pla in bacteria [92,[100][101][102]. The removal of LPS (lipo-chaperone) results in Pla deactivation.…”