Structural evolution of an immune evasion determinant shapes Lyme borreliae host tropism

Abstract

Lyme disease presents a suitable model for the investigation of host tropism – a pathogen’s ability to colonize and survive in different host species – since its causative agent, the spirochete Borrelia burgdorferi (Bb) is transmitted by ticks and maintained in rodent and bird reservoir hosts. In order to survive in vertebrates and escape from killing by complement, a first-line host immune defense, Bb produces the outer surface protein CspZ that binds the complement inhibitor factor H (FH) to promote infection. Protein sequence conservation seems to be linked to FH-binding activity divergence, raising the hypothesis that even minor variation can confer host-specific, FH-binding-mediated infectivity. Our work shows that that this minor variation is located in a loop in the CspZ protein localized in the CspZ-FH binding interface. Our functional experiments prove that this loop promotes bird- or rodent-specific FH-binding activity and infectivity. Swapping loops between rodent- and bird-associated CspZ variants alters their capability to confer host-specific dissemination. We further investigated the evolutionary mechanisms driving the emergence of the CspZ loop-mediated, host-dependent complement evasion. This multifaceted work demonstrates how a single, short protein motif can significantly impact host tropism.

Comparative reservoir competence ofPeromyscus leucopus, C57BL/6J, and C3H/HeN forBorrelia burgdorferiB31

“…has emphasized that there are substantial differences among B. burgdorferi strains in their ability to infect ticks from C3H/HeJ mice [33], raising the possibility that other strains may be better or worse adapted to P. leucopus . In line with this, there is evidence of strain specificity within different reservoir hosts [19, 45, 46]. Screening additional B. burgdorferi strains in P. leucopus could enable identification of variable spirochete loci that associate with higher transmission.…”

“…Recent work has highlighted that there are bacterial strain dependent differences in the ability for B. burgdorferi to transmit from C3H/HeJ mice to I. scapularis [24], raising the possibility that other strains may be better or worse adapted to P. leucopus . In line with this, there is some evidence of strain specificity within different reservoir hosts [29, 32, 35], despite B. burgdorferi ’s reputation as a generalist. Screening additional strains in P. leucopus could enable identification of variable loci that associate with higher transmission.…”

“…Recent work by Zinck et al . has shown that there are substantial differences among B. burgdorferi strains in their ability to infect ticks from C3H/HeJ mice (33) and other work has demonstrated that there is strain specificity within different reservoir hosts (39, 43, 44). These data raise the possibility that some strains may be better or worse adapted to P. leucopus .…”

Lizards and the enzootic cycle of Borrelia burgdorferi sensu lato

“…species or strains is partly mediated by their distinct propensity to circumvent complement-mediated killing (Kurtenbach et al, 2002). This hypothesis has been recently tested in numerous mammalian and avian hosts (Combs et al, 2022;Hart et al, 2018Hart et al, , 2021Lin et al, 2022;Marcinkiewicz et al, 2023). Consistent with this concept, lower levels of survival were reported for several strains within the B. burgdorferi s.s. species in the sera from North American lizards (i.e., eastern and western fence lizards) (Lane & Quistad, 1998;Ullmann et al, 2003).…”

Co-infection of Ehrlichia with B. burgdorferi drives emergency myelopoiesis and promotes Lyme arthritis

“…qPCR was then performed to quantify Bb loads. Spirochete genomic equivalents were calculated using an ABI 7500 Real-Time PCR System (ThermoFisher Scientific) in conjunction with PowerUp SYBR Green Master Mix (ThermoFisher Scientific) based on amplification of the Lyme borreliae recA gene (Table S1) with the amplification cycle as described previously (33). The number of recA copies was calculated by establishing a threshold cycle standard curve of a known number of recA gene extracted from cultured B31-A3.…”