Yersinia enterocolitica YadA Mediates Complement Evasion by Recruitment and Inactivation of C3 Products

Abstract

Yersinia adhesin A (YadA) is a major virulence factor of Yersinia enterocolitica. YadA mediates host cell binding and autoaggregation and protects the pathogen from killing by the complement system. Previous studies demonstrated that YadA is the most important single factor mediating serum resistance of Y. enterocolitica, presumably by binding C4b binding protein (C4BP) and factor H, which are both complement inhibitors. Factor H acts as a cofactor for factor I-mediated cleavage of C3b into the inactive form iC3b and thus prevents formation of inflammatory effector compounds and the terminal complement complex. In this study, we challenged the current direct binding model of factor H to YadA and show that Y. enterocolitica YadA recruits C3b and iC3b directly, without the need of an active complement cascade or additional serum factors. Enhanced binding of C3b does not decrease survival of YadA-expressing Yersiniae because C3b becomes readily inactivated by factor H and factor I. Binding of factor H to YadA is greatly reduced in the absence of C3. Experiments using Yersinia lacking YadA or expressing YadA with reduced trimeric stability clearly demonstrate that both the presence and full trimeric stability of YadA are essential for complement resistance. A novel mechanism of factor H binding is presented in which YadA exploits recruitment of C3b or iC3b to attract large amounts of factor H. As a consequence, formation of the terminal complement complex is limited and bacterial survival is enhanced. These findings add a new aspect of how Y. enterocolitica effectively evades the host complement system.

Transcriptomic Analysis of Yersinia enterocolitica Biovar 1B Infecting Murine Macrophages Reveals New Mechanisms of Extracellular and Intracellular Survival

“…Despite this general downregulation, the overall expression levels, as indicated by the FPKM values, remain relatively high throughout the course of infection, regardless of the cellular location. The other downregulated gene, yadA, plays a vital role in adherence to host cell surfaces and prevention of complement-mediated inactivation (67,68), functions that have less importance once internalized. One striking observation about the pYV genes upregulated in response to internalization is that half of them have no known function.…”

Vitronectin Binds to a Specific Stretch within the Head Region of <b><i>Yersinia</i></b> Adhesin A and Thereby Modulates <b><i>Yersinia enterocolitica</i></b> Host Interaction

“…1 b). Factor H has been shown to interact with several discontinuous stretches within the stalk domain of YadA [20][21][22]58] . Our data corroborate previous findings that the binding of factor H by Yersinia strains relies on the presence of YadA, but in contrast to Vn, there is no significant difference in binding efficiency in the various serotypes tested.…”

“…Recently, we demonstrated a novel mechanism that contributes to serum resistance in Ye O:8 WA-314, and amended the current model of direct factor H binding to YadA 0: 3 and YadA 0: 9 . We have shown that Ye binds C3b or iC3b and thereby attracts high amounts of factor H to the bacterial surface [21] . This is different from the direct binding of factor H, which was shown earlier [19,20,22] .…”

Heterologous Expression of Bartonella Adhesin A in Escherichia coli by Exchange of Trimeric Autotransporter Adhesin Domains Results in Enhanced Adhesion Properties and a Pathogenic Phenotype

“…It was observed that an exchange of the YadA membrane anchor domain with that of Hia, EibA, or UspA1 from other gammaproteobacteria leads to comparable surface expression of such chimeric YadA proteins in Y. enterocolitica whereas virulence of these chimeric-protein-expressing strains was reduced for unclear reasons compared to wild-type YadA-expressing Y. enterocolitica (20). Accordingly, the exact locus of YadA mediating complement resistance of Y. enterocolitica by C3b and subsequent factor H binding could not be assigned in a recent study (33).…”

“…For instance, recombinant BadA HN23 hybrid 3 expression did not confer complement resistance when bacteria were exposed to human serum for 2 h (data not shown). Although complement resistance has been excluded for B. henselae in a previous publication (46), it is well known that TAAs (such as YadA [33,47] or UspA [48]) confer serum resistance. From this, we conclude at least that the membrane anchor of YadA and truncated and hererologously expressed BadA do not contribute to serum resistance.…”