Inactivation of Genes for Antigenic Variation in the Relapsing Fever Spirochete Borrelia hermsii Reduces Infectivity in Mice and Transmission by Ticks

Abstract

Borrelia hermsii, a causative agent of relapsing fever of humans in western North America, is maintained in enzootic cycles that include small mammals and the tick vector Ornithodoros hermsi. In mammals, the spirochetes repeatedly evade the host’s acquired immune response by undergoing antigenic variation of the variable major proteins (Vmps) produced on their outer surface. This mechanism prolongs spirochete circulation in blood, which increases the potential for acquisition by fast-feeding ticks and therefore perpetuation of the spirochete in nature. Antigenic variation also underlies the relapsing disease observed when humans are infected. However, most spirochetes switch off the bloodstream Vmp and produce a different outer surface protein, the variable tick protein (Vtp), during persistent infection in the tick salivary glands. Thus the production of Vmps in mammalian blood versus Vtp in ticks is a dominant feature of the spirochete’s alternating life cycle. We constructed two mutants, one which was unable to produce a Vmp and the other was unable to produce Vtp. The mutant lacking a Vmp constitutively produced Vtp, was attenuated in mice, produced lower cell densities in blood, and was unable to relapse in animals after its initial spirochetemia. This mutant also colonized ticks and was infectious by tick-bite, but remained attenuated compared to wild-type and reconstituted spirochetes. The mutant lacking Vtp also colonized ticks but produced neither Vtp nor a Vmp in tick salivary glands, which rendered the spirochete noninfectious by tick bite. Thus the ability of B. hermsii to produce Vmps prolonged its survival in blood, while the synthesis of Vtp was essential for mammalian infection by the bite of its tick vector.

Variable Major Proteins as Targets for Specific Antibodies against Borrelia miyamotoi

“…While B. hermsii is similarly known to cause a continuous spirochetemia in SCID mice, it usually causes a more consistent pattern of relapse in wild-type mice than we observed for B. miyamotoi (31, 46–49). In that respect, B. miyamotoi is reminiscent of a type of murine relapsing fever that exhibits a similarly short-lived spirochetemia with a limited capacity for relapse (20).…”

“…However, populations can consist of several serotypes, and serotype switching can also occur spontaneously in a small fraction of spirochetes, with an estimated frequency of 10 −3 to 10 −4 per spirochete per generation (30). Thus, infected hosts will clear TBRF spirochetes by IgM directed against one or a few dominant VMPs, leaving outlier spirochetes that express different VMPs to replicate and cause a relapse of spirochetemia (30, 31). Borrelia turicatae Vsps have been described to have a conserved core and a variable exposed dome, explaining why IgM raised against one Vsp is less likely to bind another, and they have been shown to exert different tissue tropisms (27, 32–35).…”

Host associations and genomic diversity of Borrelia hermsii in an endemic focus of tick-borne relapsing fever in western North America

“…Two white mice ( Mus musculus , RML Laboratory Strain) were also fed upon by ticks infected with the two strains of spirochetes to ensure tick infection, as white mice are highly susceptible to infection with these two strains of B. hermsii. [9, 22]. …”

Tick microbiome: the force within

“…Intertwined in this rather challenging life style is the pathogen that cycles between the tick and the vertebrate host. The pathogen enters the tick gut when the larval tick takes a blood meal on an infected vertebrate host and colonizes the tick gut as in the case of Borrelia burgdorferi , the agent of Lyme disease [17]; exits the gut and infects the tick salivary glands as in the case of Anaplasma phagocytophilum that causes anaplasmosis [18]; or Borrelia hermsii , the causative agent of tick-borne relapsing fever [19]. Once the larval tick is infected, the pathogen is maintained through subsequent developmental stages (nymph and adult) of the tick, and the tick essentially remains infected for life [20].…”