Infection history of the blood-meal host dictates pathogenic potential of the Lyme disease spirochete within the feeding tick vector

Abstract

Lyme disease in humans is caused by several genospecies of the Borrelia burgdorferi sensu lato (s.l.) complex of spirochetal bacteria, including B. burgdorferi, B. afzelii and B. garinii. These bacteria exist in nature as obligate parasites in an enzootic cycle between small vertebrate hosts and Ixodid tick vectors, with humans representing incidental hosts. During the natural enzootic cycle, infected ticks in endemic areas feed not only upon naïve hosts, but also upon seropositive infected hosts. In the current study, we considered this environmental parameter and assessed the impact of the immune status of the blood-meal host on the phenotype of the Lyme disease spirochete within the tick vector. We found that blood from a seropositive host profoundly attenuates the infectivity (>104 fold) of homologous spirochetes within the tick vector without killing them. This dramatic neutralization of vector-borne spirochetes was not observed, however, when ticks and blood-meal hosts carried heterologous B. burgdorferi s.l. strains, or when mice lacking humoral immunity replaced wild-type mice as blood-meal hosts in similar experiments. Mechanistically, serum-mediated neutralization does not block induction of host-adapted OspC+ spirochetes during tick feeding, nor require tick midgut components. Significantly, this study demonstrates that strain-specific antibodies elicited by B. burgdorferi s.l. infection neutralize homologous bacteria within feeding ticks, before the Lyme disease spirochetes enter a host. The blood meal ingested from an infected host thereby prevents super-infection by homologous spirochetes, while facilitating transmission of heterologous B. burgdorferi s.l. strains. This finding suggests that Lyme disease spirochete diversity is stably maintained within endemic populations in local geographic regions through frequency-dependent selection of rare alleles of dominant polymorphic surface antigens.

Maternal Antibodies Provide Bank Voles with Strain-Specific Protection against Infection by the Lyme Disease Pathogen

“…ospC is the most polymorphic gene in the genome of B. burgdorferi sensu lato (11)(12)(13) and encodes outer surface protein C (OspC). Studies have shown that OspC induces a strain-specific antibody response that protects rodents from tick bite (21)(22)(23)30). The two ospC alleles used in this study (the A3 and A10 alleles) have a genetic distance of 23.19% and an amino acid distance of 62.57%.…”

“…There is no vertical transmission of B. burgdorferi sensu lato in either the tick (17) or the vertebrate host (18)(19)(20). In nature, vertebrate hosts develop a strong antibody response against B. burgdorferi sensu lato (18,19), and infection studies in rodents have shown that this antibody response is strain specific (21)(22)(23)(24). This antibody response is not effective at clearing the pathogen, which is why rodent hosts remain infected for months or even years (25)(26)(27)(28).…”

Protective Immunity and New Vaccines for Lyme Disease

“…Many strains of B. burgdorferi are maintained in the same local populations of infected mice and ticks, and host responses to 1 strain do not prevent infection with a different strain. It was recently found that the blood from a seropositive host profoundly attenuates the infectivity of homologous bacteria within the tick vector without killing them, thus preventing superinfection by homologous bacteria while facilitating transmission of heterologous B. burgdorferi strains [ 13 ]. In this section, we discuss how lipid immunogens, outer surface proteins, and live-mutant vaccines have been investigated for their potential to induce protective immune responses to B. burgdorferi infection and how any new Lyme disease host-targeted vaccines need to account for species and strain variability.…”

“…Synthesis of OspC is induced during the blood meal while spirochetes reside in the tick midgut, and it is required by B. burgdorferi for host colonization [ 11 , 14 , 15 ]. Antibody-mediated immunity to OspC can prevent dissemination of homologous B. burgdorferi to the host [ 13 , 16 ] during early infection. However, due to OspC diversity, such protection is strain specific.…”

Identification and quantification of Lyme pathogen strains by deep sequencing of outer surface protein C (ospC) amplicons

“…Rather than strains actively facilitating each other in establishing infections, however, strain 372 aggregation in ticks may be a reflection of reservoir hosts being either free of spirochetes (in the 373 case of resistant and healthy hosts) or infected by multiple strains (in the case of susceptible and 374 weakened hosts). Regardless, it appears that once a host is infected by a strain, it becomes 375 susceptible for super-infection by additional, immunologically distinct strains (Bhatia et al, 2018). To summarize, we have established a next-generation sequencing-based, taxonomically 387 broad procedure that has the potential to become a standard protocol for detecting and quantifying…”