Natural genetic variation impacts complement inhibitory activity of PFam54 orthologs of Asian Borrelia bavariensis

European and Asian populations of Borrelia (B.) bavariensis, a causative agent of Lyme borreliosis, substantially differ in their infection dynamics. This is argued to be a byproduct of the unique demographic history of B. bavariensis in relation to colonizing Europe from a highly diverse, ancestral Asian population. Whether genetic factors related to human disease could be unique traits associated with the demographic history of the European population though remains largely unclear. European B. bavariensis possesses at least two anti-complement determinants, BGA66 and BGA71 encoding by genes of the PFam54 gene array. In Asian B. bavariensis populations, the composition of this gene array is highly diverse. To assess functional integrity of PFam54 orthologs, two Asian B. bavariensis isolates, NT24 and JHM1114, were investigated. Despite the substantial observed genetic diversity, the complement-inhibitory and cell-protective function of BGA66 and BGA71 orthologs are largely conserved among European and Asian populations. We also identified two novel PFam54 orthologs of Asian origin, BGA67b and BGA71b, both of which display anti-complement activity on the terminal pathway and confer serum resistance. Taken together, our findings highlight the importance of studying natural variation of proteins potentially involved in immune escape, pathogenesis, and host adaptation.