Human African Trypanosomiasis Presenting at Least 29 Years after Infection—What Can This Teach Us about the Pathogenesis and Control of This Neglected Tropical Disease?

Sudarshi, Darshan; Lawrence, Simon; Pickrell, William Owen; Eligar, Vinay; Walters, R. J.; Quaderi, Shumonta; Walker, Zuzana; Capewell, Paul; Clucas, Caroline; Vincent, Angela; Checchi, Francesco; MacLeod, Annette; Brown, Michael J.

doi:10.1371/journal.pntd.0003349

Cited by 72 publications

(47 citation statements)

References 26 publications

(26 reference statements)

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“…It is also important to consider that there is a lengthy lag in outbreaks of the disease after periods of conflict or socio-political instability [6]. Concern is currently raised by outbreaks in the Ivory Coast [7] and South Sudan [8], by the discovery of the presence of asymptomatic carriers [9, 10], and by the resurgence of an old focus in Zambia [11]. …”

Section: Introductionmentioning

confidence: 99%

Trypanosoma brucei Invasion and T-Cell Infiltration of the Brain Parenchyma in Experimental Sleeping Sickness: Timing and Correlation with Functional Changes

et al. 2016

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BackgroundThe timing of Trypanosoma brucei entry into the brain parenchyma to initiate the second, meningoencephalitic stage of human African trypanosomiasis or sleeping sickness is currently debated and even parasite invasion of the neuropil has been recently questioned. Furthermore, the relationship between neurological features and disease stage are unclear, despite the important diagnostic and therapeutic implications.MethodologyUsing a rat model of chronic Trypanosoma brucei brucei infection we determined the timing of parasite and T-cell neuropil infiltration and its correlation with functional changes. Parasite DNA was detected using trypanosome-specific PCR. Body weight and sleep structure alterations represented by sleep-onset rapid eye movement (SOREM) periods, reported in human and experimental African trypanosomiasis were monitored. The presence of parasites, as well as CD4+ and CD8+ T-cells in the neuropil was assessed over time in the brain of the same animals by immunocytochemistry and quantitative analyses.Principal findingsTrypanosome DNA was present in the brain at day 6 post-infection and increased more than 15-fold by day 21. Parasites and T-cells were observed in the parenchyma from day 9 onwards. Parasites traversing blood vessel walls were observed in the hypothalamus and other brain regions. Body weight gain was reduced from day 7 onwards. SOREM episodes started in most cases early after infection, with an increase in number and duration after parasite neuroinvasion.ConclusionThese findings demonstrate invasion of the neuropil over time, after an initial interval, by parasites and lymphocytes crossing the blood-brain barrier, and show that neurological features can precede this event. The data thus challenge the current clinical and cerebrospinal fluid criteria of disease staging.

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Section: Introductionmentioning

confidence: 99%

Trypanosoma brucei Invasion and T-Cell Infiltration of the Brain Parenchyma in Experimental Sleeping Sickness: Timing and Correlation with Functional Changes

et al. 2016

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“…Latent infections of T. b. gambiense have only recently been identified and there has been little investigation into the genetic factors that may play a role in determining disease outcome in such individuals (Sudarshi et al 2014;Ilboudo et al 2011;Jamonneau et al 2012). These latent infections likely represent an overlooked and hidden reservoir that will hamper ongoing control efforts for African trypanosomiasis.…”

Section: Discussionmentioning

confidence: 99%

“…gambiense have recently been identified, contradicting more than a century of dogma that the disease is invariably fatal if untreated (Sudarshi et al 2014;Ilboudo et al 2011;Jamonneau et al 2012). Individuals with latent infections appear able to tolerate the parasite without obvious symptoms for a prolonged period, with one recent case persisting for 29 years without symptoms (Sudarshi et al 2014). Latent infections are primarily identified using serological methods due to low observable parasitemia.…”

Section: Introductionmentioning

confidence: 99%

T cell activation and the HLA locus associate with latent infections of human African trypanosomiasis

Capewell

Bucheton²,

Clucas

et al. 2017

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Infections by many pathogens can result in a wide range of phenotypes, from severe to mild, or even asymptomatic. Understanding the genetic basis of these phenotypes can lead to better tools to treat patients or detect reservoirs. To identify human genetic factors that contribute to symptoms diversity, we examined the range of disease severities caused by the parasite T. b. gambiense, the primary cause of human African trypanosomiasis (HAT). We analyzed the transcriptomes of immune cells from both symptomatic HAT cases and individuals with latent infections. Our analysis identified several genes and pathways that associated with the latent phenotype, primarily suggesting increased T and B cell activation in HAT patients relative to latent infections.We also used these transcriptome data to conduct an exome-wide single nucleotide polymorphism (SNP) association study. This suggested that SNPs in the human major histocompatibility locus (HLA) associate with severity, supporting the transcription data and suggesting that T cell activation is a determining factor in outcome. Finally, to establish if T cell activation controls disease severity, we blocked co-stimulatory dependent T cell activation in an animal model for HAT. This showed that reducing T cell activation during trypanosome infection improves symptoms and reduces parasitemia. Our data has used a combination of transcriptome-wide analysis and an in vivo model to reveal that T cell activation and the HLA locus associate with the development of symptoms during HAT. This may open new avenues for the development of new therapeutics and prognostics.

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“…The latency with which trypanosomes are detected in the central nervous system (CNS) varies considerably. A chronic stage with eventual exacerbation is now thought to exist after several case reports emerged describing patients who showed progression after more than a decade (reviewed in Sudarshi et al., ). From the CSF trypanosomes spread to susceptible tissues close to the ventricular system that do not have the BBB.…”

Section: Symptoms Observed In Sleeping Sicknessmentioning

confidence: 99%

African trypanosomes and brain infection – the unsolved question

et al. 2016

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African trypanosomes induce sleeping sickness. The parasites are transmitted during the blood meal of a tsetse fly and appear primarily in blood and lymph vessels, before they enter the central nervous system. During the latter stage, trypanosomes induce a deregulation of sleep-wake cycles and some additional neurological disorders. Historically, it was assumed that trypanosomes cross the blood-brain barrier and settle somewhere between the brain cells. The brain, however, is a strictly controlled and immune-privileged area that is completely surrounded by a dense barrier that covers the blood vessels: this is the blood-brain barrier. It is known that some immune cells are able to cross this barrier, but this requires a sophisticated mechanism and highly specific cell-cell interactions that have not been observed for trypanosomes within the mammalian host. Interestingly, trypanosomes injected directly into the brain parenchyma did not induce an infection. Likewise, after an intraperitoneal infection of rats, Trypanosoma brucei brucei was not observed within the brain, but appeared readily within the cerebrospinal fluid (CSF) and the meninges. Therefore, the parasite did not cross the blood-brain barrier, but the blood-CSF barrier, which is formed by the choroid plexus, i.e. the part of the ventricles where CSF is produced from blood. While there is no question that trypanosomes are able to invade the brain to induce a deadly encephalopathy, controversy exists about the pathway involved. This review lists experimental results that support crossing of the blood-brain barrier and of the blood-CSF barrier and discuss the implications that either pathway would have on infection progress and on the survival strategy of the parasite. For reasons discussed below, we prefer the latter pathway and suggest the existence of an additional distinct meningeal stage, from which trypanosomes could invade the brain via the Virchow-Robin space thereby bypassing the blood-brain barrier. We also consider healthy carriers, i.e. people living symptomless with the disease for up to several decades, and discuss implications the proposed meningeal stage would have for new anti-trypanosomal drug development. Considering the re-infection of blood, a process called relapse, we discuss the likely involvement of the newly described glymphatic connection between the meningeal space and the lymphatic system, that seems also be important for other infectious diseases.

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Human African Trypanosomiasis Presenting at Least 29 Years after Infection—What Can This Teach Us about the Pathogenesis and Control of This Neglected Tropical Disease?

Cited by 72 publications

References 26 publications

Trypanosoma brucei Invasion and T-Cell Infiltration of the Brain Parenchyma in Experimental Sleeping Sickness: Timing and Correlation with Functional Changes

Trypanosoma brucei Invasion and T-Cell Infiltration of the Brain Parenchyma in Experimental Sleeping Sickness: Timing and Correlation with Functional Changes

T cell activation and the HLA locus associate with latent infections of human African trypanosomiasis

African trypanosomes and brain infection – the unsolved question

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