Regulation of innate and acquired immunity in African trypanosomiasis

Abstract

African trypanosomes are well known for their ability to avoid immune elimination by switching the immunodominant variant surface glycoprotein (VSG) coat during infection. However, antigenic variation is only one of several means by which trypanosomes manipulate the immune system of their hosts. In this article, the role of parasite factors such as GPI anchor residues of the shed VSG molecule and the release of CpG DNA, in addition to host factors such as IFN-gamma, in regulating key aspects of innate and acquired immunity during infection is examined. The biological relevance of these immunoregulatory events is discussed in the context of host and parasite survival.

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

“…Hence, immunosuppressive effects reported in model hosts (40) are not relevant to antigenic variation, certainly up to the terminal stages of infection. There is another VSGtriggered immune response, which activates macrophages to yield trypanocidal agents (38), but it is not known whether this response kills trypanosomes variant-specifically. Because this response is mainly extravascular (43), and order is not influenced by trypanosomes in that compartment (17,39), it is unlikely to (37), switching between variants and the density-dependent variables of differentiation to the nonproliferating stumpy stage (33), immune response onset (46,47), and removal of variants.…”

“…Although the antitrypanosome immune response is complex (38), the dynamics of antibody production and variant killing strongly correlate, and it is empirical data regarding antibody thresholds on which we base the model. Hosts are not directly involved in switching, which is parasite-intrinsic (41) and independent of host species (17); the host acts solely to select new variants by killing old ones.…”

“…Factors known to exert significant influence on the course of infection include the density-dependent, parasite-triggered differentiation to the nondividing short stumpy stage (33,34), density-dependent general growth interference between trypanosomes (37) (which is likely to include any indirect immune system effects, such as reported in model host infections; ref. 38), and the VSG-specific antibody responses. All these have been quantified experimentally, permitting inclusion in mathematical modeling.…”

Structural basis for trypanosomal haem acquisition and susceptibility to the host innate immune system

“…The parasites are protozoan hemoflagellates transmitted by tsetse flies to the host blood where they proliferate. Evasion of the host immune system is achieved by antigenic variation, in which a coating of variable surface glycoproteins (VSGs) on the parasite surface is constantly changing within the population 2,3 . Trypanosomes are deficient in haem biosynthesis and require uptake of exogenous haem 4 .…”

Biological Variation Among African Trypanosomes: I. Clonal Expression of Virulence Is Not Linked to the Variant Surface Glycoprotein or the Variant Surface Glycoprotein Gene Telomeric Expression Site

“…However, from the studies presented here it is apparent not only that the VSG molecules themselves are not virulence factors but also that the VSG gene and the VSG gene ES are not linked to virulence expression in the LouTat 1 serodeme of T. brucei rhodesiense. This conclusion is underscored by this work from our laboratory in which VATs derived from the highly virulent LouTat 1A expressed different VSG phenotypes and genes, as well as utilized different ES, but did not alter their virulence phenotypes (Inverso et al, 1988;Mansfield and Paulnock, 2005;Mansfield, 2006). Overall, therefore, we predict that the virulence phenotype of African trypanosomes, as well as clonal changes in relative virulence for a host species, are regulated by genes mapping outside the VSG gene ES and are expressed independently of VSG gene expression.…”