Immune Evasion Strategies of Trypanosoma brucei within the Mammalian Host: Progression to Pathogenicity

Abstract

The diseases caused by African trypanosomes (AT) are of both medical and veterinary importance and have adversely influenced the economic development of sub-Saharan Africa. Moreover, so far not a single field applicable vaccine exists, and chemotherapy is the only strategy available to treat the disease. These strictly extracellular protozoan parasites are confronted with different arms of the host's immune response (cellular as well as humoral) and via an elaborate and efficient (vector)-parasite-host interplay they have evolved efficient immune escape mechanisms to evade/manipulate the entire host immune response. This is of importance, since these parasites need to survive sufficiently long in their mammalian/vector host in order to complete their life cycle/transmission. Here, we will give an overview of the different mechanisms AT (i.e. T. brucei as a model organism) employ, comprising both tsetse fly saliva and parasite-derived components to modulate host innate immune responses thereby sculpturing an environment that allows survival and development within the mammalian host.

Keywords: African trypanosomosis; T. brucei; innate immune response; pathogenicity; tsetse fly.

Figure 1

Saliva components and parasite-derived factors sculpture the skin microenvironment. Upon the bite of a trypanosome-infected tsetse fly, trypanosomes and saliva components are inoculated intradermally leading to modulation of the skin microenvironment into a trypanosome receptive habitat. To this end, saliva components, such as TTI, a 5′Nucleotidase-related apyrase and Adenosine Deaminase-related proteins (ADA) prevent blood coagulation and platelet activation/aggregation, while the TAg5 allergen leads to activation of mast cells. Subsequently, these mast cells degranulate and release histamine and TNF, thereby increasing vasodilatation and allowing extra/intravasation of immune cells [myeloid phagocytic cells (MPC)] as well as parasites. In addition, this will allow infiltration of antibodies as well as complement factors needed for early parasite elimination. Yet, also the complement system (via C3a and C5a) can contribute to (i) increased vasopermeability and (ii) recruitment and activation of immune cells (PMN,…). By contrast, the Gloss2 peptide is able to downregulate inflammatory responses that are triggered upon breaching the skin anatomical barrier and/or encounter of metacyclic trypanosomes. Within the skin, these metacyclic parasites transform into LS bloodstream forms, which is associated with metabolic/structural/morphological changes, including switching of their metacyclic VSG into a blood-stream form VSG, required for survival within the mammalian host. The PAMPs of these pathogens (such as VSG and CpG) can be recognized by tissue-resident MPC or keratinocytes expressing PRR, leading to their activation and subsequent release of innate immune response triggering signals. For instance, release of chemokines will trigger the recruitment of MPC, which can amplify the immune response needed to eliminate skin-associated trypanosomes. Yet, trypanosomes try to dampen the initial pro-inflammatory immune response by (i) releasing TbKHC or (ii) following phagocytosis of altruistic parasites releasing TbAdC, thereby allowing the remaining parasite to survive and proliferate. Within the blood circulation, the parasites encounter the trypanolytic molecules TLF-1 and 2, leading to elimination of non-primate infecting parasites. Yet, HAT-causing parasites express SRA or TgsGP, which inactivate the (ApoL1/HpR) TLF-1/2-mediated trypanolytic effects, thereby allowing proliferation within the blood circulation.

Figure 2

Trypanosome establishment within the mammalian host. Within the blood circulation (several days post infection) the metacyclic trypanosomes give rise to a first small peak (which is not always observed). Subsequently, the metacyclic trypanosomes change their metacyclic VSG coat into the bloodstream VSG, thereby expressing a mosaic VSG that prevents Ab-mediated elimination. This dense VSG coat also prevents recognition of buried epitopes, including binding of complement factors (C3) to their surface. Also Ab-mediated elimination is prevented due to the rapid recycling of these VSG–Ab complexes and VSG shedding (i.e., sVSG release) that in turn scavenges circulating complement. Recognition of sVSG via SR-A on myeloid cells, in concert with CpG recognized via TLR9, results in the activation of MPC, which trigger activation of NK/NKT and T cells. In turn, these cells produce IFN-γ needed for proper activation of myeloid cells (M1 cells) and subsequent release of pro-inflammatory mediators (TNF/NO). Of note, initially, when GIP-sVSG is released via PLC activation due to stress prior to IFN-γ production, there is a weak activation of myeloid cells. Yet, triggering of PRR at the level of B cells (i.e., TLR9 via CpG) can also lead to polyclonal B-cell activation. Subsequently, parasites rapidly multiply as LS forms giving rise to the most prominent parasitemia peak. Trypanosomes also release TLTF that triggers IFN-γ production by CD8⁺ T cells, which in turn stimulates parasite proliferation. However, IFN-γ exposure in concert with GIP-sVSG release will trigger an enhanced production of trypanolytic molecules by myeloid cells, which in concert with anti-VSG antibodies are needed for peak parasitemia control. Upon reaching the peak of parasitemia, the majority of the parasites differentiate into non-proliferative SS forms that are pre-adapted for uptake by tsetse flies, while a minority undergoes antigenic variation. Yet, in the mammalian host, these SS forms are deemed to die, thereby releasing mfVSG as well as CpG. These molecules exert dual functions; (i) the DMG of mfVSG triggers macrophage hyperactivation and LPS-hypersensitivity, while CpG further fuels polyclonal B-cell activation. These B cells can differentiate into short-lived plasmablasts (producing unspecific IgM) and ultimately results in apoptosis/elimination of all B-cell subsets and loss of B-cell memory. At this stage of infection, parasites also release TSIF that further stimulates the production of suppressive M1 and induces T-cell suppression. Once the first peak of parasitemia is controlled, the infection is established and the hosts’ adaptive immune response will develop, whereby the B- and T-cell response are impaired and there is a polarized M1 activation leading the trypanosomosis-associated pathogenicity.