Host Immune Evasion by Lyme and Relapsing Fever Borreliae: Findings to Lead Future Studies for Borrelia miyamotoi

Abstract

The emerging pathogen, Borrelia miyamotoi, is a relapsing fever spirochete vectored by the same species of Ixodes ticks that carry the causative agents of Lyme disease in the US, Europe, and Asia. Symptoms caused by infection with B. miyamotoi are similar to a relapsing fever infection. However, B. miyamotoi has adapted to different vectors and reservoirs, which could result in unique physiology, including immune evasion mechanisms. Lyme Borrelia utilize a combination of Ixodes-produced inhibitors and native proteins [i.e., factor H-binding proteins (FHBPs)/complement regulator-acquiring surface proteins, p43, BBK32, BGA66, BGA71, CD59-like protein] to inhibit complement, while some relapsing fever spirochetes use C4b-binding protein and likely Ornithodoros-produced inhibitors. To evade the humoral response, Borrelia utilize antigenic variation of either outer surface proteins (Osps) and the Vmp-like sequences (Vls) system (Lyme borreliae) or variable membrane proteins (Vmps, relapsing fever borreliae). B. miyamotoi possesses putative FHBPs and antigenic variation of Vmps has been demonstrated. This review summarizes and compares the common mechanisms utilized by Lyme and relapsing fever spirochetes, as well as the current state of understanding immune evasion by B. miyamotoi.

Keywords: Borrelia miyamotoi; Lyme disease; antigenic variation; complement; factor H; immune response; relapsing fever; spirochetes.

Figure 1

Activation and regulation of complement pathways relevant to Borrelia spp. infection. (A) Classical pathway. (B) Mannose–lectin pathway. (C) Alternative pathway. Points of complement inhibition utilized by Borrelia spp. are indicated by red octagons. Red arrows indicate borrelial proteins that interact with host regulatory proteins.

Figure 2

Antigenic variation of Lyme borreliae VlsE and relapsing fever borreliae Vmp systems. (A) VlsE: the expression locus (vlsE) is located near the telomere (open oval) of linear plasmid (lp) 28-1 (blue or green arrow, promoter is indicated by a black arrow). Silent vls cassettes are located upstream and in the opposite orientation of vlsE. Antigenic variation occurs through the random and sequential insertion of silent cassette fragments (labeled 1, 2, and 3). (B) vlp (pink arrows) and vsp (purple arrows) cassettes are located throughout the genome on lp28-1, 28-2, 28-3, 28-4, and 32-1. The expression locus (blue or green arrow, promoter is indicated by a black arrow) is found on lp28-1 near the telomere (open oval). Changing the expressed Vmp cassette is achieved through deletion of the current cassette (blue arrow) followed by insertion of a copy of a new cassette (green arrow via recombination events) resulting in a change in the expressed Vmp on the surface of the bacterium (denoted by blue or green triangles, respectively). Gray arrows indicate non-Vmp ORFs; tan arrows indicate downstream homology sequences (DHS, sequences found throughout the genome and required for mapping recombination events at the Vmp expression locus).