Infections With Extracellular Trypanosomes Require Control by Efficient Innate Immune Mechanisms and Can Result in the Destruction of the Mammalian Humoral Immune System

Abstract

Salivarian trypanosomes are extracellular parasites that affect humans, livestock, and game animals around the world. Through co-evolution with the mammalian immune system, trypanosomes have developed defense mechanisms that allow them to thrive in blood, lymphoid vessels, and tissue environments such as the brain, the fat tissue, and testes. Trypanosomes have developed ways to circumvent antibody-mediated killing and block the activation of the lytic arm of the complement pathway. Hence, this makes the innate immune control of the infection a crucial part of the host-parasite interaction, determining infection susceptibility, and parasitemia control. Indeed, trypanosomes use a combination of several independent mechanisms to avoid clearance by the humoral immune system. First, perpetuated antigenic variation of the surface coat allows to escape antibody-mediated elimination. Secondly, when antibodies bind to the coat, they are efficiently transported toward the endocytosis pathway, where they are removed from the coat proteins. Finally, trypanosomes engage in the active destruction of the mammalian humoral immune response. This provides them with a rescue solution in case antigenic variation does not confer total immunological invisibility. Both antigenic variation and B cell destruction pose significant hurdles for the development of anti-trypanosome vaccine strategies. However, developing total immune escape capacity and unlimited growth capabilities within a mammalian host is not beneficial for any parasite, as it will result in the accelerated death of the host itself. Hence, trypanosomes have acquired a system of quorum sensing that results in density-dependent population growth arrest in order to prevent overpopulating the host. The same system could possibly sense the infection-associated host tissue damage resulting from inflammatory innate immune responses, in which case the quorum sensing serves to prevent excessive immunopathology and as such also promotes host survival. In order to put these concepts together, this review summarizes current knowledge on the interaction between Magez et al.Trypanosomosis and Innate Immune Control trypanosomes and the mammalian innate immune system, the mechanisms involved in population growth regulation, antigenic variation and the immuno-destructive effect of trypanosomes on the humoral immune system. Vaccine trials and a discussion on the role of innate immune modulation in these trials are discussed at the end.

African Trypanosomosis Permanently Obliterates DTPa Vaccine Induced Memory so That Post-treatment Bordetella Pertussis Challenge Fails to Trigger a Protective Recall Response

“…Together, these finding show that anti-trypanosome vaccination should still be considered as the ultimate goal in the fight against both animal and human trypanosomosis, particularly limiting zoonotic transmissions. Unfortunately, despite many promising laboratory reports, no single vaccine-based solution has found its way into field application so far [17].…”

“…These mechanisms have been best studied for T. brucei, with the cloned T. b. brucei AnTat 1.1 parasite serving as one of the most widely implemented in vivo and in vitro laboratory models [14,15]. The assessment of the host-parasite interaction of T. brucei at a molecular level, already accomplished more than 40 years ago, revealed that these parasites use antigenic variation in the variant surface glycoprotein (VSG) coat as a first line of defense against antibody-mediated killing [16][17][18][19][20]. This involves chromosomal recombination, expression site activation/silencing and access to an extensive reservoir of over 1000 genomic VSG genes and pseudogenes, allowing trypanosomes to 'eternally' outrun the mammalian adaptive immune system [21].…”

“…As trypanosomes have a severe detrimental impact on the mammalian adaptive immune response, there has been no progress made towards a field applicable vaccine [17]. The problem of trypanosomosis is exacerbated by the fact that field data have shown infections result in failures of unrelated veterinary vaccines, such as those for classic swine fever [33], foot and mouth disease [34], Pasturella multocida [35], and P. haemolytica [36], and cause overall susceptibility to secondary infections [37].…”

Organotypic endothelial adhesion molecules are key forTrypanosoma bruceitropism and virulence

“…the pancreas. Previous work on intracellular parasites including T. cruzi (Corbett et al, 2002;Dufurrena et al, 2017;Martello et al, 2013), Plasmodium (Abhilash et al, 2016;Glaharn et al, 2018) and Toxoplasma (Nassief Beshay et al, 2018), has reported sequestration in pancreatic blood vessels, pancreatic invasion, and morphological changes in the pancreas, including acute pancreatitis in humans. The fact that the pancreas represents one of the largest reservoirs of an extracellular parasite such as T. brucei is puzzling, as the majority of the organ consists of exocrine tissue which produces pancreatic enzymes for digestion including trypsin and chymotrypsin to digest proteins, amylase to digest carbohydrates, and lipase to break down fats (Shi and Liu, 2014).…”

“…Research in various pathogens including parasites such as Plasmodium and Schistosoma have shown early interactions with these organs which ultimately lead to pathology including hepatosplenomegaly and asplenia. Such pathology may also involve organ remodeling including the loss of specific areas necessary for the generation of adequate immune responses (Cadman et al, 2008;Engwerda et al, 2016;Magez et al, 2020;Martin-Jaular et al, 2011;Oster et al, 1980;Urban et al, 2005). In our work, we observed that this early invasion resulted in very high vascular permeability in the liver, and significant enlargement of the spleen and lymph nodes.…”