Pathogen and Host Response Dynamics in a Mouse Model of Borrelia hermsii Relapsing Fever

Abstract

Most Borrelia species that cause tick-borne relapsing fever utilize rodents as their natural reservoirs, and for decades laboratory-bred rodents have served as informative experimental models for the disease. However, while there has much progress in understanding the pathogenetic mechanisms, including antigenic variation, of the pathogen, the host side of the equation has been neglected. Using different approaches, we studied, in immunocompetent inbred mice, the dynamics of infection with and host responses to North American relapsing fever agent B. hermsii. The spirochete’s generation time in blood of infected mice was between 4–5 h and, after a delay, was matched in rate by the increase of specific agglutinating antibodies in response to the infection. After initiating serotype cells were cleared by antibodies, the surviving spirochetes were a different serotype and, as a population, grew more slowly. The retardation was attributable to the host response and not an inherently slower growth rate. The innate responses at infection peak and immediate aftermath were characterized by elevations of both pro-inflammatory and anti-inflammatory cytokines and chemokines. Immunodeficient mice had higher spirochete burdens and severe anemia, which was accounted for by aggregation of erythrocytes by spirochetes and their partially reversible sequestration in greatly enlarged spleens and elsewhere.

Relapsing Fevers: Neglected Tick-Borne Diseases

“…Asymptomatic incubation in human RF borreliosis is estimated at 3–10 days, probably depending on the 4–5 h generation time of spirochaetes in the blood (mouse model) (Crowder et al, 2016 ). Then, an initial febrile episode followed by a series of relapses (3–5 in LBRF and 9–13 in TBRF) interspaced by a few days remissions are usually described during the course of non-fatal infections in absence of antibiotic treatment (Cutler, 2015 ).…”

Division of the genus Borrelia into two genera (corresponding to Lyme disease and relapsing fever groups) reflects their genetic and phenotypic distinctiveness and will lead to a better understanding of these two groups of microbes (Margos et al. (2016) There is inadequate evidence to support the division of the genus Borrelia. Int. J. Syst. Evol. Microbiol. doi: 10.1099/ijsem.0.001717)

“…The differences in the diseases that occur in humans have their counterparts in natural and experimental infections in mammalian hosts [3,[27][28][29][30]. In comparison with infections by the RF group of species (including B. anserina and B. miyamotoi), infections caused by LD group species tend to be chronic and with higher persistent densities of spirochetes in tissues rather than the blood [31][32][33].…”

Immunological responses to the relapsing fever spirochete Borrelia turicatae in infected Rhesus macaques: implications for pathogenesis and diagnosis.

“…We therefore suspect that we missed the height of the inflammatory response with evaluation commencing after 14 days of infection. In mice infected with B. hermsii , plasma levels of IFN appear to be elevated at the height of spirochetemia, whereas IL-1β is detected after clearance of the infection (50). Directly comparable experiments in mice and primates would be of benefit, but consistent detection of these inflammatory mediators in blood cells exposed to RF spirochetes indicates that they are likely important for pathogenesis.…”