Pathogenicity and virulence of African trypanosomes: From laboratory models to clinically relevant hosts

Abstract

African trypanosomes are vector-borne protozoa, which cause significant human and animal disease across sub-Saharan Africa, and animal disease across Asia and South America. In humans, infection is caused by variants of Trypanosoma brucei , and is characterized by varying rate of progression to neurological disease, caused by parasites exiting the vasculature and entering the brain. Animal disease is caused by multiple species of trypanosome, primarily T. congolense , T. vivax, and T. brucei . These trypanosomes also infect multiple species of mammalian host, and this complexity of trypanosome and host diversity is reflected in the spectrum of severity of disease in animal trypanosomiasis, ranging from hyperacute infections associated with mortality to long-term chronic infections, and is also a main reason why designing interventions for animal trypanosomiasis is so challenging. In this review, we will provide an overview of the current understanding of trypanosome determinants of infection progression and severity, covering laboratory models of disease, as well as human and livestock disease. We will also highlight gaps in knowledge and capabilities, which represent opportunities to both further our fundamental understanding of how trypanosomes cause disease, as well as facilitating the development of the novel interventions that are so badly needed to reduce the burden of disease caused by these important pathogens.

Histone divergence inTrypanosoma bruceiresults in unique alterations to nucleosome structure

“…This opens a possible therapeutic avenue for targeting the acidic patch 74,75 allowing specific targeting of kinetoplastids over their human or animal hosts. A global chromatin disruption mechanism would have high utility for combating diseases such as animal trypanosomiasis where the genetic diversity of Trypanosoma species has hindered drug development 17 and drug resistance is a current challenge 16,76 .…”

“…Kinetoplastida includes multiple pathogens, particularly those belonging to the Trypanosoma and Leishmania species. Of these, Trypanosoma brucei is a major clinical target, causing both human and animal trypanosomiasis [16][17][18] . In T. brucei, chromatin accessibility has a direct effect on antigenic variation, a key immune evasion mechanism contributing to its pathogenicity 19 .…”

Cell–cell communication in African trypanosomes

“…In the field, chronic infections of cattle are not uncommon, however, suggesting that rather than selecting for highly virulent trypanosomes, coinfection might actually be important for regulating total parasitaemia, preventing an overwhelming surge of parasitaemia every time an animal is reinfected with infective metacyclics. Alternatively, newly coinfecting trypanosomes could adopt a strategy whereby they 'hide' from the resident trypanosome populations by occupying different niches [114,115]. Indeed, T. brucei cells are prolific in the extravascular tissues [129].…”

“…In most of the above instances of trypanosome-trypanosome communication, the interaction has always been documented between members of the same trypanosome strain/species. In reality however, a population of trypanosomes may not exist in isolation throughout its life cycle [114,115]. Multiple species of African trypanosome with overlapping host ranges and a shared insect vector co-circulate in the field, presenting ample opportunity for interspecies communication at each stage of the parasite's life cycle.…”

Metabolic insights into phosphofructokinase inhibition in bloodstream-form trypanosomes

“…Different subspecies of the protist Trypanosoma brucei cause Human African Trypanosomiasis (HAT), also known as ‘sleeping sickness’ and, together with other Trypanosoma species such as T. congolense , can cause similar diseases in domestic animals in sub-Saharan Africa ( Giordani et al., 2016 ; Büscher et al., 2017 ). The parasites, after having been transmitted between mammalian hosts by the bite of an infected tsetse fly, enter the bloodstream and can subsequently invade extravascular niches of different tissues, including the brain ( Morrison et al., 2023 ). When proliferating in the blood as long-slender forms, T. brucei cells are entirely dependent on the abundantly available glucose for their ATP production.…”