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Schuster et al . demonstrated that bloodstream slender forms of African trypanosomes are readily transmissible to young tsetse flies where they can complete their complex life cycle (Schuster et al., 2021). In their experimental conditions, a single slender parasite was sufficient for productive infection. Here, we compared the infectivity of slender and stumpy bloodstream forms in adult flies with a mature immune system, and without using any chemical compounds that would alter the insect immune response and/or promote the infection. After ingestion of slender forms, infected flies were observed only in 1 out of 24 batches of non-immunocompetent teneral flies and with a high number of parasites. In contrast, infected flies were detected in 75% (18/24) of the batches infected with stumpy parasites, and as few as 10 stumpy parasites produced mature infections in immune adult flies. We discuss that, although Schuster et al. have demonstrated the intrinsic capacity of slender form trypanosomes to infect young and naive tsetse flies, highlighting the remarkable plasticity and adaptability of these protists, this phenomenon is unlikely to significantly contribute to the epidemiology of African trypanosomiases. According to both experimental and field observations, stumpy forms appear to be the most adapted forms for African trypanosome transmission from the mammalian host to the tsetse fly vector in natural conditions. Human African Trypanosomiasis – also known as sleeping sickness – is a deadly disease caused by the single-celled parasite Trypanosoma brucei . The parasite has a complex life cycle that involves both humans and tsetse flies. When a tsetse fly bites an infected human, it can take up the parasite and pass it on to other people. Inside the human host, T. brucei exists in two forms: a rapidly dividing ‘slender’ form, and a non-proliferative ‘stumpy’ form that emerges once a high enough density of parasitic cells has been reached. For decades, scientists thought that only the stumpy form can successfully spread from humans to tsetse flies. However, a 2021 study challenged this view, suggesting that the slender form might also be transmissible. To investigate this further, Ngoune et al. examined whether, and under what conditions, the slender and stumpy forms of T. brucei could infect tsetse flies. The team grew both forms of the parasite in the laboratory and fed them to tsetse flies in an environment designed to resemble natural conditions . The midgut and salivary glands of the flies were then dissected four weeks later to assess the level of infection. Ngoune et al. found that slender forms of the parasite were only able to infect one out of 24 batches of young tsetse flies – and only when each fly ingested up to 10,000 parasites. The slender forms also failed to infect adult flies entirely, likely because they have a more robust immune system. In contrast, stumpy forms of the parasite where much more readily transmitted, successfully infecting about 75% of all the tested fly batches, even when as few as 10 parasitic cells were ingested. The study by Ngoune et al. reaffirms the longstanding view that the stumpy form of T. brucei is the primary stage at which the parasite is transmitted from humans to flies. While the slender form of T. brucei may be capable of infecting tsetse flies under certain conditions, these results suggest that it rarely makes this jump and is therefore unlikely to play a significant role in the spread of sleeping sickness.

In the mammalian host, the biology of tissue-dwelling Trypanosoma brucei parasites is not completely understood, especially the mechanisms involved in their extravascular colonization. The trypanosome flagellum is an essential organelle in multiple aspects of the parasites’ development. The flagellar protein termed FLAgellar Member 8 (FLAM8) acts as a docking platform for a pool of cyclic AMP response protein 3 (CARP3) that is involved in signaling. FLAM8 exhibits a stage-specific distribution suggesting specific functions in the mammalian and vector stages of the parasite. Analyses of knockdown and knockout trypanosomes in their mammalian forms demonstrated that FLAM8 is not essential in vitro for survival, growth, motility and stumpy differentiation. Functional investigations in experimental infections showed that FLAM8 -deprived trypanosomes can establish and maintain an infection in the blood circulation and differentiate into insect transmissible forms. However, quantitative bioluminescence imaging and gene expression analysis revealed that FLAM8 -null parasites exhibit a significantly impaired dissemination in the extravascular compartment, that is restored by the addition of a single rescue copy of FLAM8 . In vitro trans-endothelial migration assays revealed significant defects in trypanosomes lacking FLAM8 . FLAM8 is the first flagellar component shown to modulate T . brucei distribution in the host tissues, possibly through sensing functions, contributing to the maintenance of extravascular parasite populations in mammalian anatomical niches, especially in the skin.

The skin is an anatomical reservoir for African trypanosomes, yet the prevalence of extravascular parasite carriage in the population at risk of gambiense Human African Trypanosomiasis (gHAT) remains unclear. Here, we conducted a prospective observational cohort study in the HAT foci of Forecariah and Boffa, Republic of Guinea. Of the 18,916 subjects serologically screened for gHAT, 96 were enrolled into our study. At enrolment and follow-up visits, participants underwent a dermatological examination and had blood samples and superficial skin snip biopsies taken for examination by molecular and immuno-histological methods. In seropositive individuals, dermatological symptoms were significantly more frequent as compared to seronegative controls. Trypanosoma brucei DNA was detected in the blood of 67% of confirmed cases (22/33) and 9% of unconfirmed seropositive individuals (3/32). However, parasites were detected in the extravascular dermis of up to 71% of confirmed cases (25/35) and 41% of unconfirmed seropositive individuals (13/32) by PCR and/or immuno-histochemistry. Six to twelve months after treatment, trypanosome detection in the skin dropped to 17% of confirmed cases (5/30), whereas up to 25% of unconfirmed, hence untreated, seropositive individuals (4/16) were still found positive. Dermal trypanosomes were observed in subjects from both transmission foci, however, the occurrence of pruritus and the PCR positivity rates were significantly higher in unconfirmed seropositive individuals in Forecariah. The lower sensitivity of superficial skin snip biopsies appeared critical for detecting trypanosomes in the basal dermis. These results are discussed in the context of the planned elimination of gHAT.

Schuster et al . demonstrated that bloodstream slender forms of African trypanosomes are readily transmissible to young tsetse flies where they can complete their complex life cycle (Schuster et al., 2021). In their experimental conditions, a single slender parasite was sufficient for productive infection. Here, we compared the infectivity of slender and stumpy bloodstream forms in adult flies with a mature immune system, and without using any chemical compounds that would alter the insect immune response and/or promote the infection. After ingestion of slender forms, infected flies were observed only in 1 out of 24 batches of non-immunocompetent teneral flies and with a high number of parasites. In contrast, infected flies were detected in 75% (18/24) of the batches infected with stumpy parasites, and as few as 10 stumpy parasites produced mature infections in immune adult flies. We discuss that, although Schuster et al. have demonstrated the intrinsic capacity of slender form trypanosomes to infect young and naive tsetse flies, highlighting the remarkable plasticity and adaptability of these protists, this phenomenon is unlikely to significantly contribute to the epidemiology of African trypanosomiases. According to both experimental and field observations, stumpy forms appear to be the most adapted forms for African trypanosome transmission from the mammalian host to the tsetse fly vector in natural conditions. Human African Trypanosomiasis – also known as sleeping sickness – is a deadly disease caused by the single-celled parasite Trypanosoma brucei . The parasite has a complex life cycle that involves both humans and tsetse flies. When a tsetse fly bites an infected human, it can take up the parasite and pass it on to other people. Inside the human host, T. brucei exists in two forms: a rapidly dividing ‘slender’ form, and a non-proliferative ‘stumpy’ form that emerges once a high enough density of parasitic cells has been reached. For decades, scientists thought that only the stumpy form can successfully spread from humans to tsetse flies. However, a 2021 study challenged this view, suggesting that the slender form might also be transmissible. To investigate this further, Ngoune et al. examined whether, and under what conditions, the slender and stumpy forms of T. brucei could infect tsetse flies. The team grew both forms of the parasite in the laboratory and fed them to tsetse flies in an environment designed to resemble natural conditions . The midgut and salivary glands of the flies were then dissected four weeks later to assess the level of infection. Ngoune et al. found that slender forms of the parasite were only able to infect one out of 24 batches of young tsetse flies – and only when each fly ingested up to 10,000 parasites. The slender forms also failed to infect adult flies entirely, likely because they have a more robust immune system. In contrast, stumpy forms of the parasite where much more readily transmitted, successfully infecting about 75% of all the tested fly batches, even when as few as 10 parasitic cells were ingested. The study by Ngoune et al. reaffirms the longstanding view that the stumpy form of T. brucei is the primary stage at which the parasite is transmitted from humans to flies. While the slender form of T. brucei may be capable of infecting tsetse flies under certain conditions, these results suggest that it rarely makes this jump and is therefore unlikely to play a significant role in the spread of sleeping sickness.

Schuster et al. demonstrated that bloodstream slender forms of African trypanosomes are readily transmissible to young tsetse flies where they can complete their complex life cycle (1). In their experimental conditions, a single slender parasite was sufficient for productive infection. Here, we compared the infectivity of slender and stumpy bloodstream forms in adult flies with a mature immune system, and without using any chemical compounds that would alter the insect immune response and/or promote the infection. After ingestion of slender forms, infected flies were observed only in one out of 24 batches of non-immunocompetent teneral flies and with a high number of parasites. In contrast, infected flies were detected in 75% (18/24) of the batches infected with stumpy parasites, and as few as 10 stumpy parasites produced mature infections in immune adult flies. We discuss that, although Schuster et al. have demonstrated the intrinsic capacity of slender form trypanosomes to infect young and naive tsetse flies, highlighting the remarkable plasticity and adaptability of these protists, this phenomenon is unlikely to significantly contribute to the epidemiology of African trypanosomiases. According to both experimental and field observations, stumpy forms appear to be the most adapted forms for African trypanosome transmission from the mammalian host to the tsetse fly vector in natural conditions.Competing Interest StatementThe authors have declared no competing interest.Footnotes* New data as Fig 2 New stat analyses Revised discussion

In the mammalian bloodstream, Trypanosoma brucei, the parasite responsible for sleeping sickness, proliferates as slender forms before undergoing quorum-sensing (QS)-mediated differentiation into cell cycle-arrested stumpy forms (stumpy-QS), a transition that regulates parasitaemia and primes parasites for tsetse fly transmission. Beyond the bloodstream, T. brucei also occupies extravascular, adipose-rich tissues such as the skin, a potential reservoir for transmission. Here, we identify an alternative slender-to-stumpy differentiation pathway driven by glycerol, a host metabolite abundant in adipose-rich tissues, that could resolve the long-standing paradox of successful parasite transmission from human hosts during chronic infection despite low parasitaemia. We show that high (10 mM) and non-physiological glycerol concentrations under low glucose conditions (0.5 mM) induce differentiation, generating distinct stumpy-Glyc forms that resemble stumpy-QS parasites but have an extended lifespan. Under conditions mimicking dermal tissue interstitial fluids (4 mM glucose, 0.25 mM glycerol), we show that glycerol promotes the emergence of proliferative intermediate forms that retain transmission potential and can differentiate into fly host-specific procyclic forms in vitro and within tsetse flies. These findings open the door for reevaluation of the model of T. brucei transmission and supports a dominant role for adipocyte-derived glycerol in the skin in sustaining parasite transmission.

In the mammalian host, the biology of tissue-dwelling Trypanosoma brucei parasites is not completely understood, especially the mechanisms involved in their extravascular colonization. The trypanosome flagellum is an essential organelle in multiple aspects of the parasites' development. The flagellar protein termed FLAgellar Member 8 (FLAM8) acts as a docking platform for a pool of Cyclic AMP response protein 3 (CARP3) that is involved in signaling. FLAM8 exhibits a stage-specific distribution suggesting specific functions in the mammalian and vector stages of the parasite. Analyses of knockdown and knockout trypanosomes in their mammalian forms demonstrated that FLAM8 is not essential in vitro for survival, growth, motility and stumpy differentiation. Functional investigations in experimental infections showed that FLAM8-deprived trypanosomes can establish and maintain an infection in the blood circulation and differentiate into insect transmissible forms. However, quantitative bioluminescence imaging and gene expression analysis revealed that FLAM8-null parasites exhibit a significantly impaired dissemination in the extravascular compartment, that is restored by the addition of a single rescue copy of FLAM8. In vitro trans-endothelial migration assays revealed significant defects in trypanosomes lacking FLAM8, possibly due to cAMP signaling impairments when a pool of CARP3 is not stabilized within FLAM8-related scaffold. FLAM8 is the first flagellar component shown to modulate T. brucei distribution in the host tissues, possibly through sensing functions, contributing to the maintenance of extravascular parasite populations in mammalian anatomical niches, especially in the skin.Competing Interest StatementThe authors have declared no competing interest.

In the mammalian host, the biology of tissue-dwelling Trypanosoma brucei parasites is not completely understood, especially the mechanisms involved in their extravascular colonization. The trypanosome flagellum is an essential organelle in multiple aspects of the parasites’ development. The flagellar protein termed FLAgellar Member 8 (FLAM8) acts as a docking platform for a pool of Cyclic AMP response protein 3 (CARP3) that is involved in signaling. FLAM8 exhibits a stage-specific distribution suggesting specific functions in the mammalian and vector stages of the parasite. Analyses of knockdown and knockout trypanosomes in their mammalian forms demonstrated that FLAM8 is not essential in vitro for survival, growth, motility and stumpy differentiation. Functional investigations in experimental infections showed that FLAM8-deprived trypanosomes can establish and maintain an infection in the blood circulation and differentiate into insect transmissible forms. However, quantitative bioluminescence imaging and gene expression analysis revealed that FLAM8-null parasites exhibit a significantly impaired dissemination in the extravascular compartment, that is restored by the addition of a single rescue copy of FLAM8. In vitro trans-endothelial migration assays revealed significant defects in trypanosomes lacking FLAM8. FLAM8 is the first flagellar component shown to modulate T. brucei distribution in the host tissues, possibly through sensing functions, contributing to the maintenance of extravascular parasite populations in mammalian anatomical niches, especially in the skin. Trypanosoma brucei parasites cause neglected tropical diseases termed human and animal African trypanosomiases. Transmitted by the bite of an infected tsetse fly, upon deposition in the skin of a mammalian host, these parasites occupy both the vasculature and extravascular tissues. Currently, the biology of tissue-resident parasites is not well understood, and the parasite factors that mediate extravascular colonization are not known. Using quantitative in vivo bioluminescence imaging and ex vivo gene expression quantification in host infected tissues and blood, we reveal that the flagellar parasite protein FLAM8 modulates the extravascular dissemination of trypanosomes in the mammalian host. FLAM8 is known to act as a docking platform for signaling complexes in the flagellum, but we observe that it does not influence parasite differentiation into transmissible stages. However, we show that the absence of FLAM8 results in the loss of a key component of the flagellar adenylate cyclase signaling complexes, and reduces parasite migration through endothelial cell monolayers, suggesting that FLAM8 is important for parasite exchanges between the intravascular and the extravascular compartments. This work identifies a key trypanosome flagellar component involved in host-parasite interactions, including the modulation of parasite tropism and extravascular dissemination.