Complement therapeutic factor H-IgG proteins as pre-exposure prophylaxes against Lyme borreliae infections

Lyme disease (LD) is the most common vector-borne disease in the northern hemisphere and is caused by the bacteria Borrelia burgdorferi sensu lato (also known as Lyme borreliae) with no effective prevention available. Lyme borreliae evade complement killing, a critical arm of host immune defense, by producing outer surface proteins that bind to a host complement inhibitor, factor H (FH). These outer surface proteins include CspA and CspZ, which bind to the sixth and seventh short consensus repeats (SCR6-7) of FH and the OspE family of proteins (OspE), which bind to the nineteenth and twentieth SCR (SCR19-20). In this study, we produced 2 chimeric proteins, FH-Fc, containing the Fc region of immunoglobulin G (Fc) with SCR6-7 or SCR19-20. We found that both FH-Fc constructs killed B. burgdorferi via bacterial lysis and phagocytosis and reduced bacterial colonization and LD-associated joint inflammation in vivo. While SCR6-7-Fc displayed Lyme borreliae species-specific bacterial killing, SCR19-20-Fc versatilely eradicated all tested bacterial species/strains. This correlated with SCR6-7-Fc binding to select variants of CspA and CspZ, but SCR19-20-Fc binding to all tested OspE variants. Overall, we demonstrated the concept of using FH-Fc constructs to kill Lyme borreliae and defined underlying mechanisms, highlighting the potential of FH-Fc as a pre-exposure prophylaxis against LD infection.