V‐antigen homologs in pathogenic gram‐negative bacteria

Abstract

Gram-negative bacteria cause many types of infections in animals from fish and shrimps to humans. Bacteria use Type III secretion systems (TTSSs) to translocate their toxins directly into eukaryotic cells. The V-antigen is a multifunctional protein required for the TTSS in Yersinia and Pseudomonas aeruginosa. V-antigen vaccines and anti-V-antigen antisera confer protection against Yersinia or P. aeruginosa infections in animal models. The V-antigen forms a pentameric cap structure at the tip of the Type III secretory needle; this structure, which has evolved from the bacterial flagellar cap structure, is indispensable for toxin translocation. Various pathogenic gram-negative bacteria such as Photorhabdus luminescens, Vibrio spp., and Aeromonas spp. encode homologs of the V-antigen. Because the V-antigens of pathogenic gram-negative bacteria play a key role in toxin translocation, they are potential therapeutic targets for combatting bacterial virulence. In the USA and Europe, these vaccines and specific antibodies against V-antigens are in clinical trials investigating the treatment of Yersinia or P. aeruginosa infections. Pathogenic gram-negative bacteria are of great interest because of their ability to infect fish and shrimp farms, their potential for exploitation in biological terrorism attacks, and their ability to cause opportunistic infections in humans. Thus, elucidation of the roles of the V-antigen in the TTSS and mechanisms by which these functions can be blocked is critical to facilitating the development of improved anti-V-antigen strategies.

The prophylactic effects of human IgG derived from sera containing high anti-PcrV titers against pneumonia-causingPseudomonas aeruginosa

“…Our target is PcrV, which forms the tip of the type III secretion apparatus responsible for the delivery of type III secretory toxins (i.e., ExoS, ExoT, ExoU, and ExoY) into target cells. 12 Based on the preclinical data for the mAb166 murine anti-PcrV monoclonal antibody in various animal models, 19,20,22,39 a humaneered anti-PcrV monoclonal antibody (KB001-A, KaloBios Pharmaceuticals) has been developed 23 and tested for treating P. aeruginosa pneumonia in patients with cystic fibrosis and in mechanically ventilated patients in Phase II studies in the United States 24 and France. 25 Although Figure 10.…”

“…11 In the type III secretion system of P. aeruginosa, PcrV, a cap structure on the tip of the type III secretory apparatus, is a key molecule through which cytotoxic P. aeruginosa delivers lethal cytotoxic toxins into its target eukaryotic cells. 12 We have previously reported that the blockade of PcrV by specific antibodies can inhibit translocation of type III secretory toxins. 10,13,14 Active immunization with recombinant PcrV protects animals from lethal P. aeruginosa infections [14][15][16] , and anti-PcrV antibodies also protect infected animals from acute lung injury, bacteremia, and sepsis.…”

Use of bioengineered human commensal gut bacteria-derived microvesicles for mucosal plague vaccine delivery and immunization

“…Conservation of the TTSS has been discussed and demonstrated in other studies [34][35][36][37]. Assessment of the health records of the study subjects did not uncover any unreported health conditions and no veterinary adverse health observations were made.…”

Immunomodulatory Yersinia outer proteins (Yops)–useful tools for bacteria and humans alike

“…208 Subsequently, this plasmid-encoded secreted protein was also identified in all human pathogenic Yersinia (for recent review see ref. 209 ). Interestingly, homologs of LcrV are also expressed by several other bacteria employing a T3SS such as P. aeruginosa, V. cholerae, Photorhabdus luminescens and Aeromonas spp.…”

“…Interestingly, homologs of LcrV are also expressed by several other bacteria employing a T3SS such as P. aeruginosa, V. cholerae, Photorhabdus luminescens and Aeromonas spp. 209 However, quite surprisingly neither any possible intracellular target(s) nor an enzymatic activity has been associated with LcrV yet. Furthermore, LcrV has been intensely studied as part of candidate vaccines against Yersinia infections and has been shown to confer protection in animal models.…”