CspA from Borrelia burgdorferi inhibits the terminal complement pathway

Abstract

In order to survive and persist in an immunocompetent human host, Borrelia burgdorferi controls the human immune attack and blocks the damaging effects of the activated complement system. These Gram-negative spirochetes use CspA (CRASP-1) and four additional immune evasion proteins to bind combinations of human plasma regulators, including factor H, factor H-like protein 1 (FHL-1), complement factor H-related protein 1 (CFHR1), CFHR2, CFHR5, and plasminogen. As many microbial immune evasion proteins have multiple functions, we hypothesized that CspA has additional roles in complement or immune control. Here, we identify CspA as a terminal complement inhibitor. Borrelial CspA binds the human terminal complement components C7 and C9 and blocks assembly and membrane insertion of the terminal complement complex (TCC). CspA inhibits TCC assembly at the level of C7, as revealed by hemolytic assays, and inhibits polymerization of C9. CspA, when ectopically expressed on the surface of serum-sensitive Borrelia garinii, blocks TCC assembly on the level of C7 and induces serum resistance in the transformed bacteria. This CspA-mediated serum resistance and terminal complement pathway inhibition allow B. burgdorferi to survive in the hostile environment of human plasma.

Evolutionary genomics of Borrelia burgdorferi sensu lato: Findings, hypotheses, and the rise of hybrids

“…The hypothetical role of vector/host specificity these lp54 genes play is supported by the additional evidence that, except for a24/dbpA , their sequences are conserved within species despite large variations between species. The high variability of lp54 genes (e.g., cspA and a70 ) between species is consistent with their molecular functions of providing resistance against host innate immunity (Hallström et al, 2013b; Koenigs et al, 2013, p. 70), while their conservation within species suggest that they do not interact with host adaptive immunity as directly or strongly as genes like ospC, dbpA , and vlsE .…”

“…The PF54 gene array is the most variable region on the lp54 plasmid and consists of paralogs of a68/cspA , one of the three classes of complement regulator acquiring surface proteins (CRASPs) involved in neutralizing host innate defenses (Gilmore et al, 2008; Hallström et al, 2013a; Hammerschmidt et al, 2014; Koenigs et al, 2013). Besides a64, a65, a66 and a73 , which are present in all strains, the PF54 gene cluster vary in strain-specific (e.g., a67a and a70 within B. burgdorferi s.s.) and species-specific manners (Figure 2).…”

“…In sum, three lines of evidence support the notion that rapid evolution of the PF54 gene array may reflect adaptation to different host species and may contribute to differential clinical manifestations in humans among the three common pathogenic species. Such evidence includes ( i ) strain- and species-specific gene duplications and losses, ( ii ) accelerated amino-acid sequence variations between (but not within) species, and ( iii ) host-resistance functions of PF54 members like CspA and A70 (Caesar et al, 2013; Hallström et al, 2013a; Koenigs et al, 2013). …”

Serum bactericidal antibody assays – The role of complement in infection and immunity

“…Orthologs of CspA Binding of host-derived proteins and/or direct interaction with the formation of the terminal complement complex [5,6] Extraintestinal Escherichia coli (ExPEC) Exopolysaccharide colanic acid Protection from envelope stress whilst cell wall damage is repaired [15] Yersinia pseudotuberculosis Outer membrane protein Ail Recruitment of regulator of classical and lectin pathway (C4b-binding protein), and regulator of alternate pathway (factor H) [16] inability to regulate the alternative pathway. Mutations in the gene are associated with diseases such as atypical hemolytic uraemic syndrome (aHUS) [17].…”

“…Borrelia spp. uses CspA for binding of host-derived proteins and/or direct interaction with the formation of the terminal complement complex, as a mechanism for evasion [5] and [6]. These and other examples, including mechanisms used by N. meningitidis, are shown in Table 1 [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16].…”