Abstract
BackgroundRelapsing fever (RF) spirochetes are notable for multiphasic antigenic variation of polymorphic outer membrane lipoproteins, a phenomenon responsible for immune evasion. An additional role in tissue localization is suggested by the finding that isogenic serotypes 1 (Bt1) and 2 (Bt2) of the RF spirochete Borrelia turicatae, which differ only in the Vsp they express, exhibit marked differences in clinical disease severity and tissue localization during infection.Methodology/Principal FindingsHere we used known vsp DNA sequences encoding for B. turicatae and Borrelia hermsii Vsp proteins with variable regions and then studied whether there are differences in disease expression and tissue localization of their corresponding serotypes during mouse infection. For sequence and structural comparisons we focused exclusively on amino acid residues predicted to project away from the spirochetes surface, referred to as the Vsp dome. Disease severity and tissue localization were studied during persistent infection with individual or mixed serotypes in SCID mice. The results showed that all Vsp domes clustered into 3 main trunks, with the domes for B. turicatae Vsp1 (BtVsp1) and BtVsp2 clustering into separate ones. B. hermsii serotypes whose Vsp domes clustered with the BtVsp1 dome were less virulent but localized to the brain more. The BtVsp2 dome was the oddball among all and Bt2 was the only serotype that caused severe arthritis.Conclusion/SignificanceThese findings indicate that there is significant variability in Vsp dome structure, disease severity, and tissue localization among serotypes of B. hermsii.
Highlights
Relapsing fever (RF) is an arthropod-borne, spirochetal disease of humans caused by infection with different Borrelia species [1]
Computer homology modeling of variable small proteins (Vsp) dome regions We began the study by examining the differences between Vsp1 (BtVsp1) and Vsp2 (BtVsp2) of B. turicatae by computer homology modeling
In most aspects the clinical manifestations of infection with B. hermsii serotypes resembled those observed with B. turicatae, one notable exception was tibiotarsal arthritis which occurs to a significant degree only with Bt2 (Figure 3B and Table 3)
Summary
Relapsing fever (RF) is an arthropod-borne, spirochetal disease of humans caused by infection with different Borrelia species [1]. A characteristic feature of RF is two or more periods of high fever and bacteremia separated by afebrile periods during low bacteremia This pattern of relapses and remissions is explained by the sequential spontaneous appearance and clearance of isogenic serotypes that are antigenically distinct from the previous ones and from the ones that follow them [1,2]. Major outer membrane lipoproteins that are highly variable in sequence and are the target of antibody-mediated clearance define the serotype [3,4] These proteins in the new world RF spirochetes B. hermsii (Bh) and B. turicatae (Bt) come in two sizes, variable small proteins (Vsp) of ,22 kDa and variable large proteins (Vlp) of ,37 kDa [5,6]. An additional role in tissue localization is suggested by the finding that isogenic serotypes 1 (Bt1) and 2 (Bt2) of the RF spirochete Borrelia turicatae, which differ only in the Vsp they express, exhibit marked differences in clinical disease severity and tissue localization during infection
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