Factor H-related proteins as a protective evolutionary mechanism against microbial infections

Factor H (FH) is the main regulator of the complement alternative pathway, and it is essential to prevent complement-mediated autologous damage. Many pathogens express FH-binding proteins on their surface that recruit human FH as a strategy to avoid or limit their elimination by the host complement. The FH-Related Proteins (FHR-1, FHR-2, FHR-3, FHR-4A, and FHR-5) share sequential and structural homology with FH that result from their common ancestry, but none of them can regulate complement like FH. While the precise contribution of FHRs in human complement is still not completely understood, it has been proposed that these proteins have been conserved along evolution because they outcompete FH binding to the microbial surfaces, thus allowing pathogen elimination. In this review, we recapitulate the current evidence of the interaction between FHRs and pathogens. We describe the results from "in vitro" studies with microbial isolates and purified proteins, and the few studies that have addressed the quantification of FH and FHRs in patients during infection. We also provide an analysis comparing the frequency of common genetic variants, including ΔCFHR3-CFHR1, in different geographical regions, and the incidence of Invasive Meningococcal Disease. All the data are discussed in the context of the role of FHRs as FH-deregulators, and at the light of recent findings supporting a function as complement activators.