Resistance of Yersinia pestis to Complement-Dependent Killing Is Mediated by the Ail Outer Membrane Protein

Abstract

Yersinia pestis, the causative agent of plague, must survive in blood in order to cause disease and to be transmitted from host to host by fleas. Members of the Ail/Lom family of outer membrane proteins provide protection from complement-dependent killing for a number of pathogenic bacteria. The Y. pestis KIM genome is predicted to encode four Ail/Lom family proteins. Y. pestis mutants specifically deficient in expression of each of these proteins were constructed using lambda Red-mediated recombination. The Ail outer membrane protein was essential for Y. pestis to resist complement-mediated killing at 26 and 37°C. Ail was expressed at high levels at both 26 and 37°C, but not at 6°C. Expression of Ail in Escherichia coli provided protection from the bactericidal activity of complement. High-level expression of the three other Y. pestis Ail/Lom family proteins (the y1682, y2034, and y2446 proteins) provided no protection against complement-mediated bacterial killing. A Y. pestis ail deletion mutant was rapidly killed by sera obtained from all mammals tested except mouse serum. The role of Ail in infection of mice, Caenorhabditis elegans, and fleas was investigated.

Role of immune response in Yersinia pestis infection

“…In addition, to survive and grow in blood for transmission between its flea vector and the mammalian host, Y. pestis has developed resistance to complement-mediated lysis [23,24,25]. In contrast to enteropathogenic yersiniae, which are resistant to complement when grown at 37°C but not when grown at 26°C, Y. pestis is resistant to complement at both temperatures [23].…”

The Yersinia pseudotuberculosis Outer Membrane Protein Ail Recruits the Human Complement Regulatory Protein Factor H

“…All three pathogenic Yersinia species express a chromosomally encoded outer membrane protein, Ail, which was shown to mediate resistance to serum or complement-mediated killing (3)(4)(5). Ail belongs to a family of highly conserved 17-19-kDa outer membrane proteins found in the Enterobacteriaceae, including Rck (Salmonella typhimurium and S. enteritidis), PagC (typhoid and nontyphoid Salmonella, Escherichia coli O157:H7), and OmpX (E. coli and Enterobacter cloacae) (6, 7).…”

Functional Recruitment of the Human Complement Inhibitor C4BP to Yersinia pseudotuberculosis Outer Membrane Protein Ail

“…Similar to the Ail proteins in the enteropathogenic Yersiniae, the Ail protein from Y. pestis was shown to mediate serum resistance (11). Although C4BP binding to Y. pestis was demonstrated (23), it remains to be shown whether Ail is responsible for this interaction.…”

“…Double point mutations in the second surfaceexposed loop of Ail, D67G/V68G, or D67A/V68R resulted in loss of the serum-resistance phenotype when the respective proteins were expressed in E. coli DH5a (22). Ail was also shown to mediate serum resistance in both Y. pestis and Y. pseudotuberculosis, although the precise mechanisms have not been characterized (10,11). Although binding of C4BP to Y. pestis was demonstrated (23), it is not known whether Ail is responsible for this interaction.…”

“…The human pathogenic Yersinia species possess a chromosomally encoded gene, ail, which was shown to mediate serum resistance or resistance to complement-mediated killing (10)(11)(12). Ail belongs to a family of highly conserved 17-19-kDa outer membrane proteins found in the Enterobacteriaceae, including Rck (Salmonella typhimurium and enteritidis), PagC (typhoid and nontyphoid Salmonella, Escherichia coli O157:H7), and OmpX (E. coli and Enterobacter cloacae) (13,14).…”