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Project C3 - Complement-interacting proteins of relapsing fever Borrelia

PI
Project description

Background: The epidemic louse-borne relapsing fever is caused exclusively by the spirochete Borrelia (B.) recurrentis. The pathogen is transmitted by the human body louse Pediculus humanus humanus, an obligate blood-sucking human ectoparasite. Louse-borne relapsing fever remains seasonally epidemic in states in the Horn of Africa, in particular in the highlands of Ethiopia and adjacent areas of Somalia, Eritrea and the Republic of South Sudan. Humans are the only reservoirs of the disease. Infection with relapsing fever Borrelia leads to a sudden, high fever, which recurs at intervals of several days, separated by short fever-free periods and is often associated with joint, head, chest and limb pain, nausea, and sometimes respiratory distress. The lethality of untreated patients is 50% and higher. At present, no commercial tests are available for the diagnosis of this zoonotic infectious disease.

During acute fever periods, the spirochetes are detectable in high concentrations (~50 cells/ml) in blood, suggesting that these pathogens have developed strategies to escape the human innate immune system, especially the human complement system. Our investigations of the immune evasion of relapsing fever Borrelia revealed that these bacteria exhibit various membrane-exposed molecules on their cell surface that effectively inhibit this first line of defense, either indirectly by binding host-derived complement regulators or directly by interacting with complement components1-4. The number of these different immune evasion mechanisms suggests that B. recurrentis, B. duttonii, and B. miyamotoi (a recently described relapsing fever Borrelia species occurring in Europe, Asia, and North America) possess additional, yet unknown molecules that determine resistance to complement-mediated killing.

Their importance in host-pathogen interactions and immune evasion, as well as their localization on the pathogen surface, make these complement-inhibiting molecules a promising target for the development of novel diagnostic test systems. The aim of this project is to identify and functionally characterize complement-inhibiting molecules of B. recurrentis and to evaluate these proteins as in vitro diagnostic markers of relapsing fever.

 

References C3: 1. Rossmann et al. (2007) J Immunol 178:7292-7301. 2. Grosskinsky et al. (2009) PLoS ONE 4: e4858. 3. Grosskinsky et al. (2010) PLoS Negl Trop Dis 4: e698. 4. Röttgerding et al. (2017) Sci Rep 7:303. 5. Nguyen et al., (2018) Front. Cell. Infect. Microbiol. 8:23.