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

Abstract

29The global public health impact of relapsing fever (RF) spirochetosis is significant, as the 30 pathogens exist on five of seven continents. The hallmark sign of infection is episodic fever and 31 the greatest threat is to the unborn. With the goal of better understanding the specificity of B cell 32 responses and the role of immune responses in pathogenicity, we infected Rhesus macaques with 33 Borrelia turicatae (a new world RF spirochete species) by tick bite and monitored the immune 34 responses generated in response to the pathogen. Specifically, we evaluated inflammatory 35 mediator induction by the pathogen, host antibody responses to specific antigens, and peripheral 36 lymphocyte population dynamics. Our results indicate that B. turicatae elicits from peripheral 37 blood cells key inflammatory response mediators (IL-1β and TNF-α) which are associated with 38 pre-term abortion. Moreover, a global decline in peripheral B cell populations was observed in 39 all animals at 14 days post-infection. Serological responses were also evaluated to assess the 40 antigenicity of three surface proteins, BipA, BrpA and Bta112. Interestingly, a distinction was 41 observed between antibodies generated in non-human primates (NHPs) and mice. Our results 42 provide support for the nonhuman primate model not only in studies of prenatal pathogenesis, 43 but for diagnostic and vaccine antigen identification and testing. 44 45 46Relapsing Fever (RF) spirochetosis is a neglected global disease. In parts of Africa, RF 47 spirochetosis is a common bacterial infection [1], and the disease is a significant cause of 48 hospital admissions and child mortality [2][3][4][5][6]. The causative agents are Borrelia species that are 49 transmitted by the human body louse, or ixodid and argasid ticks (1-4). The manifestation of 50 disease in humans includes recurrent febrile episodes, rigors, vomiting, severe headache, 51 neurological symptoms, muscle and joint aches and tachycardia (1). Antibiotic treatment may 52 result in the Jarisch-Herxheimer reaction, which is caused by a cytokine release leading to shock 53 (5) and even death (6, 7). Mortality of tick-borne RF spirochetosis is 4-10% and is associated 54 with the burden of spirochetes in the blood (8). RF borreliosis is particularly devastating on fetal 55 and neonatal health (9, 10). For example, in Tanzania a perinatal mortality rate of 436/1000 was 56 reported for Borrelia duttonii (11). The disease also has a severe impact in developing countries 57 because of the nonspecific, malaria-like clinical manifestation of the disease. Importantly, with 58 the geographic distribution of RF spirochetes largely overlapping with malaria (12) and studies 59 indicating an often misdiagnosis (13, 14), the true morbidity of RF is underappreciated. 60The reduction in spirochete levels and eventual clearance has been shown in animal 61 models to be a direct result of the antibody response, especially IgM and IgG3 isotypes (15, 16). 62The clearance by lymphocytic response was established by Newm...