Extravascular Dermal Trypanosomes in Suspected and Confirmed Cases of gambiense Human African Trypanosomiasis

Abstract

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>The diagnosis of gambiense Human African Trypanosomiasis (gHAT) typically involves two steps: a serological screen, followed by the detection of living trypanosome parasites in the blood or lymph node aspirate. Live parasites can, however, remain undetected in some seropositive individuals, who we hypothesize are infected with Trypanosoma brucei gambiense parasites in their extravascular dermis.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>To test this hypothesis, we conducted a prospective observational cohort study in the gHAT focus of Forecariah, Republic of Guinea. Of the 5,417 subjects serologically screened for gHAT, 66 were enrolled into our study and underwent a dermatological examination. At enrolment, 11 seronegative, 8 unconfirmed seropositive and 18 confirmed seropositive individuals had blood samples and skin biopsies taken and examined for trypanosomes by molecular and immuno-histological methods.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>In seropositive individuals, dermatological symptoms were significantly more frequent, relative to seronegative controls. T.b. gambiense parasites were present in the blood of all confirmed cases (n=18) but not in unconfirmed seropositive individuals (n=8). However, T. brucei parasites were detected in the extravascular dermis of all unconfirmed seropositive individuals and all confirmed cases. Skin biopsies of all treated cases and most seropositive untreated individuals progressively became negative for trypanosomes 6 and 20 months later.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Our results highlight the skin as a potential reservoir for African trypanosomes, with implications for our understanding of this disease’s epidemiology in the context of its planned elimination and underlining the skin as a novel target for gHAT diagnostics.</jats:p> </jats:sec>

Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis

“…effectively reduced over the last decade with the deployment of tiny targets in many disease endemic areas [34]. However, disease reactivation remains a concern due to the potentially high number of asymptomatic individuals carrying tsetse-transmissible parasites in the skin [35][36][37][38]. Nevertheless, before mass treatment of humans with NTBC is considered, caution should be exercised; it should only be used in regions where trypanosomiasis transmission continues despite best efforts in case management.…”

FLAgellum Member 8 modulates extravascular trypanosome distribution in the mammalian host

“…The relevance of skin-dwelling trypanosomes in parasite transmission was demonstrated by xenodiagnosis experiments, early after the infective bite (Caljon et al, 2006), or later in the infection (Capewell et al, 2016), even in the absence of detectable parasitemia. More recently, the presence of extravascular trypanosomes was confirmed in the skin of confirmed and suspected cases of sleeping sickness (Camara et al, 2020). Here, the impaired spreading of FLAM8 -null parasites over the extravascular compartment, especially in the skin, would mathematically reduce the probability for parasites to be ingested by tsetse flies.…”

Vector-borne Trypanosoma brucei parasites develop in artificial human skin and persist as skin tissue forms

“…As the skin interstitial fluid is continuous with the lymphatic system, STF parasites will eventually be drained by suction forces into the lymph, where they start proliferating as BSFs. The skin acts as a reservoir for African trypanosomes (Capewell et al, 2016, Camara et al, 2020 and the hidden, quiescent, but motile STFs could act as a source of parasites that can continuously repopulate the blood. Interestingly, after the initial immune response of the host against the injected metacyclic trypanosomes in the skin, the skin-dwelling parasites appear not to trigger any further major inflammatory cell infiltration (Capewell et al, 2016, Mabille andCaljon, 2020).…”

“…Our discovery of STFs in a close to nature, tractable tissue model might provide an experimental system for tackling the important question as to how the parasites might be slipping under the radar of the inflammation response. In recent years, there has been increasing evidence that trypanosomes persist in the skin of aparasitemic and asymptomatic individuals (Capewell et al, 2016, Camara et al, 2020. It has also been suggested that these individuals contribute to the transmission of the disease (Koffi et al, 2006, Capewell et al, 2019.…”

“…In addition, the skin is now recognized as a reservoir tissue during disease, as trypanosomes have frequently been found in the skin of infected animals and humans, even in aparasitemic (i.e. no trypanosomes detectable in blood) and asymptomatic individuals (Capewell et al, 2016, Casas-Sanchez and Acosta-Serrano, 2016, Kruger et al, 2018, Capewell et al, 2019, Camara et al, 2020. The skin-dwelling parasites of laboratory mice can be transmitted to tsetse flies (Capewell et al, 2016, Caljon et al, 2016, strongly suggesting a contribution to disease transmission.…”