Trypanosomes Expressing a Mosaic Variant Surface Glycoprotein Coat Escape Early Detection by the Immune System

Abstract

Host resistance to African trypanosomiasis is partially dependent on an early and strong T-independent B-cell response against the variant surface glycoprotein (VSG) coat expressed by trypanosomes. The repetitive array of surface epitopes displayed by a monotypic surface coat, in which identical VSG molecules are closely packed together in a uniform architectural display, cross-links cognate B-cell receptors and initiates T-independent B-cell activation events. However, this repetitive array of identical VSG epitopes is altered during the process of antigenic variation, when former and nascent VSG proteins are transiently expressed together in a mosaic surface coat. Thus, T-independent B-cell recognition of the trypanosome surface coat may be disrupted by the introduction of heterologous VSG molecules into the coat structure. To address this hypothesis, we transformed Trypanosoma brucei rhodesiense LouTat 1 with the 117 VSG gene from Trypanosoma brucei brucei MiTat 1.4 in order to produce VSG double expressers; coexpression of the exogenous 117 gene along with the endogenous LouTat 1 VSG gene resulted in the display of a mosaic VSG coat. Results presented here demonstrate that the host's ability to produce VSG-specific antibodies and activate B cells during early infection with VSG double expressers is compromised relative to that during infection with the parental strain, which displays a monotypic coat. These findings suggest a previously unrecognized mechanism of immune response evasion in which coat-switching trypanosomes fail to directly activate B cells until coat VSG homogeneity is achieved. This process affords an immunological advantage to trypanosomes during the process of antigenic variation.The variant surface glycoprotein (VSG) coat covering the membrane of African trypanosomes consists of a densely packed array of 10 7 identical molecules that determine the antigenic phenotype of the parasite. VSG molecules are 55-to 65-kDa glycoproteins that contain internal antiparallel A and B ␣-helices that lend rigidity to the folded structure (29); the molecules are displayed as homodimers oriented with the hydrophilic N-terminal portion of the protein toward the extracellular space and with glycosylphosphatidylinositol anchors tethering the C terminus to the plasma membrane (9,11,29). Together, these characteristics permit a highly ordered packing of VSG molecules into the surface coat structure. Despite extensive primary sequence variation among different VSGs, secondary and tertiary structural features of these molecules are highly conserved (11,12,29,31), perhaps ensuring that all VSG molecules are packaged similarly into a surface coat structure during the process of antigenic variation.Stringent allelic exclusion ensures that only 1 of approximately 1,000 different VSG genes in the genome is transcribed at any given time from a chromosome telomere (reviewed in references 10, 13, and 17). Thus, normally only one species of VSG molecule is present within the trypanosome surface coat, resulting in the homo...

Bartonella henselae exists as a mosaic of different genetic variants in the infected host

“…Emergence of genetic variants may lead to a more effective adaptation to an individual host and specific niches within a host, as shown for Helicobacter and Bacteroides (Kraft et al, 2006;Cerdeno-Tarraga et al, 2005). Antigenic variation may alter surface-coat proteins and contribute to the evasion of specific immune responses such as B cell recognition (Dubois et al, 2005), which can result in prolonged bacteraemia and a more effective transmission to other hosts. Our results suggest that B. henselae undergoes genetic and therefore may undergo antigenic variation in the mammalian host.…”

“…(Dubois et al, 2005), Helicobacter pylori (Kraft et al, 2006) and Anaplasma marginale (Brayton et al, 2005) to circumvent the host specific immune responses and maintain a persistent infection. Several studies suggest that B. henselae may display a marked genetic and antigenic variability.…”

Parasite-intrinsic factors can explain ordered progression of trypanosome antigenic variation

“…Another possibility, that order arises from differential efficiencies of variant-specific immune responses, is negated by the observation that different variants are cleared in vivo by the immune system with closely similar dynamics (22). The suggestion that transient expression of two VSGs by a trypanosome, such as during switching, could enhance sensitivity to antibodies and therefore influence order (21) is not supported by the normal in vivo growth and reduced immunogenicity of artificially created double expressors (23,24). Antigenic ''crossreactivity'' on the basis of common, invariant antigens (25,26) is unlikely to cause order, because such molecules do not elicit protective responses against trypanosomes (27)(28)(29).…”

An optimized in vitro blood–brain barrier model reveals bidirectional transmigration of African trypanosome strains

“…T. b. gambiense and T. b. rhodesiense are human pathogens and multiply within the blood circulation system. Therein, the parasites evade the host immune system by different strategies, for instance by switching their surface-coat antigens (Dubois et al, 2005). As the disease progresses, the parasites infect the central nervous system (CNS), leading to the severe outcome of the disease.…”