Immune Evasion Strategies of Relapsing Fever Spirochetes

Abstract

Relapsing fever (RF) is claimed a neglected arthropod-borne disease caused by a number of diverse human pathogenic Borrelia (B.) species. These RF borreliae are separated into the groups of tick-transmitted species including B. duttonii, B. hermsii, B. parkeri, B. turicatae, B. hispanica, B. persica, B. caucasica, and B. myiamotoi, and the louse-borne Borrelia species B. recurrentis. As typical blood-borne pathogens achieving high cell concentrations in human blood, RF borreliae (RFB) must outwit innate immunity, in particular complement as the first line of defense. One prominent strategy developed by RFB to evade innate immunity involves inactivation of complement by recruiting distinct complement regulatory proteins, e.g., C1 esterase inhibitor (C1-INH), C4b-binding protein (C4BP), factor H (FH), FH-like protein-1 (FHL-1), and factor H-related proteins FHR-1 and FHR-2, or binding of individual complement components and plasminogen, respectively. A number of multi-functional, complement and plasminogen-binding molecules from distinct Borrelia species have previously been identified and characterized, exhibiting considerable heterogeneity in their sequences, structures, gene localization, and their capacity to bind host-derived proteins. In addition, RFB possess a unique system of antigenic variation, allowing them to change the composition of surface-exposed variable major proteins, thus evading the acquired immune response of the human host. This review focuses on the current knowledge of the immune evasion strategies by RFB and highlights the role of complement-interfering and infection-associated molecules for the pathogenesis of RFB.

Interaction between Borrelia miyamotoi variable major proteins Vlp15/16 and Vlp18 with plasminogen and complement

“…Diverse bacterial plasminogen-binding proteins as well as plasmin(ogen) play a role in inactivating complement 33 , 47 , 57 , 58 . We thus aimed to examine the ability of all three variable major proteins (Vlp15/16, Vlp18, and Vsp1) in inhibiting the activation of complement cascades.…”

“…A sophisticated strategy developed by RF borreliae, including B. miyamotoi, to escape complement and fibrinolytic pathway is to produce several outer surface proteins that bind to complement inhibitors or plasminogen [42][43][44][45][46][47] . Such binding down-regulates complement-mediated killing and activates plasminogenmediated ECM component degradation, which is thought to confer efficient dissemination.…”

Vitronectin binding protein, BOM1093, confers serum resistance on Borrelia miyamotoi

“…Erps (ErpP, ErpC, and ErpA) can also bind to FH and contribute to serum resistance of Lyme disease borreliae; however, the biological significance of these interactions remains unclear. RF borreliae also express complement regulator-binding proteins on their surface 25 . BHA007 ( B. hermsii ) and CihC ( B. recurrentis and B. duttonii ) can bind C4BP.…”

Large-Scale Sequencing of Borreliaceae for the Construction of Pan-Genomic-Based Diagnostics

“…In both dissemination routes, the spirochetes mitigate the host immune response to prevent recognition by the innate immune system and ultimately delay and distort the development of a T-cell-dependent B-cell response [ 49 , 150 , 151 , 152 , 153 ]. In addition, Borreliaceae spirochetes, can also evade the host immune system through various other means [ 154 ]. Both Borrelieceae can utilize the antigenic variation system, vls , present within the genome to evade the complement cascade.…”

“…While Lyme borreliosis has become highly prevalent, the impact of elapsing fever (Rf) still remains a significant health concern. The RF-causing Borrelia genus can be transmitted either by ticks or lice around the world [ 154 , 162 , 163 , 164 ]. Within the United States, this infectious disease has remained endemic solely within western mountainous regions [ 164 ].…”