Clinical and Neuropathogenetic Aspects of Human African Trypanosomiasis

Abstract

Trypanosomiasis has been recognized as a scourge in sub-Saharan Africa for centuries. The disease, caused by protozoan parasites of the Trypanosoma genus, is a major cause of mortality and morbidity in animals and man. Human African trypanosomiasis (HAT), or sleeping sickness, results from infections with T. brucei (b.) gambiense or T. b. rhodesiense with T. b. gambiense accounting for over 95% of infections. Historically there have been major epidemics of the infection, followed by periods of relative disease control. As a result of concerted disease surveillance and treatment programmes, implemented over the last two decades, there has been a significant reduction in the number of cases of human disease reported. However, the recent identification of asymptomatic disease carriers gives cause for some concern. The parasites evade the host immune system by switching their surface coat, comprised of variable surface glycoprotein (VSG). In addition, they have evolved a variety of strategies, including the production of serum resistance associated protein (SRA) and T. b. gambiense-specific glycoprotein (TgsGP) to counter host defense molecules. Infection with either disease variant results in an early haemolymphatic-stage followed by a late encephalitic-stage when the parasites migrate into the CNS. The clinical features of HAT are diverse and non-specific with early-stage symptoms common to several infections endemic within sub-Saharan Africa which may result in a delayed or mistaken diagnosis. Migration of the parasites into the CNS marks the onset of late-stage disease. Diverse neurological manifestations can develop accompanied by a neuroinflammatory response, comprised of astrocyte activation, and inflammatory cell infiltration. However, the transition between the early and late-stage is insidious and accurate disease staging, although crucial to optimize chemotherapy, remains problematic with neurological symptoms and neuroinflammatory changes recorded in early-stage infections. Further research is required to develop better diagnostic and staging techniques as well as safer more efficacious drug regimens. Clearer information is also required concerning disease pathogenesis, specifically regarding asymptomatic carriers and the mechanisms employed by the trypanosomes to facilitate progression to the CNS and precipitate late-stage disease. Without progress in these areas it may prove difficult to maintain current control over this historically episodic disease.

Update on human African trypanosomiasis (sleeping sickness)

“…This result has been achieved as a result of the combined and coordinated work of WHO, African governments, non-governmental organisations, charities and other bodies ( 1). Thus, in 2009 WHO estimated that there were as few as 9878 new HAT cases per year , and by 2014 the number of reported cases was reduced to 3796 cases ( with <15,000 estimated new cases) (2,8) , and by 2016 the figure was further reduced to 2184 new cases per year (9). It is therefore not surprising that WHO perceives as realistic goals both the elimination of sleeping sickness as a public health problem by 2020 and the achievement of interruption of its transmission by 2030 (9).…”

“…Thus, in 2009 WHO estimated that there were as few as 9878 new HAT cases per year , and by 2014 the number of reported cases was reduced to 3796 cases ( with <15,000 estimated new cases) (2,8) , and by 2016 the figure was further reduced to 2184 new cases per year (9). It is therefore not surprising that WHO perceives as realistic goals both the elimination of sleeping sickness as a public health problem by 2020 and the achievement of interruption of its transmission by 2030 (9). It should be appreciated, however, that HAT caused by T.b.rhodesiense will be extremely difficult to eliminate in the future because cattle are the animal reservoirs of the human parasites ( as opposed to the human reservoir of the parasites causing T.b.gambiense ) and mass culling of cattle is neither desirable nor probably achievable .…”

Invisible Designers: Brain Evolution Through the Lens of Parasite Manipulation

“…An interesting case study is the protozoan Trypanosoma brucei, the agent of sleeping sickness (Lundkvist et al 2004;Mogk et al 2017). There is still considerable uncertainty on how this parasite manages to enter the CNS (Kennedy and Rodgers 2019). Trypanosoma stimulates the release of various cytokines by lymphocytes and neurons; the same cytokines (including IFN-γ) facilitate the passage of immune cells from the blood to the brain, a mechanism that may be exploited by the parasite to cross the barrier (Grab and Ken-nedy 2008;Rodgers 2010;Kennedy and Rodgers 2019;Masocha and Kristensson 2019).…”

“…There is still considerable uncertainty on how this parasite manages to enter the CNS (Kennedy and Rodgers 2019). Trypanosoma stimulates the release of various cytokines by lymphocytes and neurons; the same cytokines (including IFN-γ) facilitate the passage of immune cells from the blood to the brain, a mechanism that may be exploited by the parasite to cross the barrier (Grab and Ken-nedy 2008;Rodgers 2010;Kennedy and Rodgers 2019;Masocha and Kristensson 2019). Other data suggest that this parasite may bypass the BBB entirely, and penetrate through the blood-cerebrospinal fluid barrier in the choroid plexus-a site of intense cellular trafficking where leukocytes enter the CNSand/or in the circumventricular organs (Mogk et al 2017;Kennedy and Rodgers 2019).…”

“…Trypanosoma stimulates the release of various cytokines by lymphocytes and neurons; the same cytokines (including IFN-γ) facilitate the passage of immune cells from the blood to the brain, a mechanism that may be exploited by the parasite to cross the barrier (Grab and Ken-nedy 2008;Rodgers 2010;Kennedy and Rodgers 2019;Masocha and Kristensson 2019). Other data suggest that this parasite may bypass the BBB entirely, and penetrate through the blood-cerebrospinal fluid barrier in the choroid plexus-a site of intense cellular trafficking where leukocytes enter the CNSand/or in the circumventricular organs (Mogk et al 2017;Kennedy and Rodgers 2019). This illustrates the principle that parasites should evolve to target the inevitable "weak spots" in the barrier, which include passages for cranial nerves (e.g., the olfactory nerve; Masocha and Kristensson 2012) and several regions of relatively high permeability (e.g., around the pineal gland and the median eminence of the hypothalamus; Daneman and Prat 2015).…”