RESUMO
BACKGROUND: In the 20th century, epidemics of human African trypanosomiasis (HAT) ravaged communities in a number of African countries. The latest surge in disease transmission was recorded in the late 1990s, with more than 35,000 cases reported annually in 1997 and 1998. In 2013, after more than a decade of sustained control efforts and steady progress, the World Health Assembly resolved to target the elimination of HAT as a public health problem by 2020. We report here on recent progress towards this goal. METHODOLOGY/PRINCIPAL FINDINGS: With 992 and 663 cases reported in 2019 and 2020 respectively, the first global target was amply achieved (i.e. fewer than 2,000 HAT cases/year). Areas at moderate or higher risk of HAT, where more than 1 case/10,000 people/year are reported, shrunk to 120,000 km2 for the five-year period 2016-2020. This reduction of 83% from the 2000-2004 baseline (i.e. 709,000 km2) is slightly below the target (i.e. 90% reduction). As a result, the second global target for HAT elimination as a public health problem cannot be considered fully achieved yet. The number of health facilities able to diagnose and treat HAT expanded (+9.6% compared to a 2019 survey), thus reinforcing the capacity for passive detection and improving epidemiological knowledge of the disease. Active surveillance for gambiense HAT was sustained. In particular, 2.8 million people were actively screened in 2019 and 1.6 million in 2020, the decrease in 2020 being mainly caused by COVID-19-related restrictions. Togo and Côte d'Ivoire were the first countries to be validated for achieving elimination of HAT as a public health problem at the national level; applications from three additional countries are under review by the World Health Organization (WHO). CONCLUSIONS/SIGNIFICANCE: The steady progress towards the elimination of HAT is a testament to the power of multi-stakeholder commitment and coordination. At the end of 2020, the World Health Assembly endorsed a new road map for 2021-2030 that set new bold targets for neglected tropical diseases. While rhodesiense HAT remains among the diseases targeted for elimination as a public health problem, gambiense HAT is targeted for elimination of transmission. The goal for gambiense HAT is expected to be particularly arduous, as it might be hindered by cryptic reservoirs and a number of other challenges (e.g. further integration of HAT surveillance and control into national health systems, availability of skilled health care workers, development of more effective and adapted tools, and funding for and coordination of elimination efforts).
Assuntos
Trypanosoma brucei brucei/patogenicidade , Trypanosoma brucei gambiense/patogenicidade , Trypanosoma brucei rhodesiense/patogenicidade , Tripanossomíase Africana/prevenção & controle , África Subsaariana/epidemiologia , Animais , Doenças Endêmicas , Humanos , Controle de Insetos , Insetos Vetores/parasitologia , Tripanossomíase Africana/epidemiologia , Moscas Tsé-Tsé/parasitologia , Organização Mundial da SaúdeRESUMO
The protozoan Trypanosoma brucei rhodesiense causes Human African Trypanosomiasis, also known as sleeping sickness, and penetrates the central nervous system, leading to meningoencephalitis. The Cathepsin L-like cysteine peptidase of T. b. rhodesiense has been implicated in parasite penetration of the blood-brain barrier and its activity is modulated by the chagasin-family endogenous inhibitor of cysteine peptidases (ICP). To investigate the role of ICP in T. b. rhodesiense bloodstream form, ICP-null (Δicp) mutants were generated, and lines re-expressing ICP (Δicp:ICP). Lysates of Δicp displayed increased E-64-sensitive cysteine peptidase activity and the mutant parasites traversed human brain microvascular endothelial cell (HBMEC) monolayers in vitro more efficiently. Δicp induced E-selectin in HBMECs, leading to the adherence of higher numbers of human neutrophils. In C57BL/6 mice, no Δicp parasites could be detected in the blood after 6 days, while mice infected with wild-type (WT) or Δicp:ICP displayed high parasitemia, peaking at day 12. In mice infected with Δicp, there was increased recruitment of monocytes to the site of inoculation and higher levels of IFN-γ in the spleen. At day 14, mice infected with Δicp exhibited higher preservation of the CD4+, CD8+, and CD19+ populations in the spleen, accompanied by sustained high IFN-γ, while NK1.1+ populations receded nearly to the levels of uninfected controls. We propose that ICP helps to downregulate inflammatory responses that contribute to the control of infection.
Assuntos
Proteínas de Protozoários , Trypanosoma brucei rhodesiense , Tripanossomíase Africana , Animais , Camundongos , Camundongos Endogâmicos C57BL , Trypanosoma brucei rhodesiense/patogenicidade , Tripanossomíase Africana/parasitologia , Virulência , Proteínas de Protozoários/metabolismoRESUMO
Trypanosoma brucei rhodesiense is the causative agent for Rhodesian human African trypanosomiasis. The disease is considered acute, but varying clinical outcomes including chronic infections have been observed. The basis for these different clinical manifestations is thought to be associated with a combination of parasite and host factors. In the current study, Trypanosoma brucei rhodesiense strains responsible for varying infection outcomes were sought using mouse model. Clinical rHAT parasite isolates were subjected to PCR tests to confirm presence of the serum resistance associated (SRA) gene. Thereafter, four T. b. rhodesiense isolates were subjected to a comparative pathogenicity study using female Swiss white mice; the parasite strains were compared on the basis of parasitaemia, host survival time, clinical and postmortem biomarkers of infection severity. Isolates identified to cause acute and chronic disease were compared for establishment in insect vector, tsetse fly. The mouse survival time was significantly different (Log-rankp = 0.0001). With mice infected with strain KETRI 3801 exhibiting the shortest survival time (20 days) as compared to those infected with KETRI 3928 that, as controls, survived past the 60 days study period. In addition, development of anaemia was rapid in KETRI 3801 and least in KETRI 3928 infections, and followed the magnitude of survival time. Notably, hepatosplenomegaly was pronounced with longer survival. Mouse weight and feed intake reduced (KETRI 3801 > KETRI 2636 > EATRO 1762) except in KETRI 3928 infections which remained similar to controls. Comparatively, acute to chronic infection outcomes is in the order of KETRI 3801 > KETRI 2636 > EATRO 1762 > KETRI 3928, indicative of predominant role of strain dependent factors. Further, KETRI 3928 strain established better in tsetse as compared to KETRI 3801, suggesting that transmission of strains causing chronic infections could be common. In sum, we have identified Trypanosoma brucei rhodesiense strains that cause acute and chronic infections in mice, that will be valuable in investigating pathogen - host interactions responsible for varying disease outcomes and transmission in African trypanosomiasis.
Assuntos
Trypanosoma brucei rhodesiense/patogenicidade , Tripanossomíase Africana/parasitologia , Moscas Tsé-Tsé/parasitologia , Animais , Ingestão de Alimentos , Feminino , Modelos Lineares , Fígado/patologia , Masculino , Camundongos , Tamanho do Órgão , Parasitemia/parasitologia , Baço/patologia , Trypanosoma brucei rhodesiense/isolamento & purificação , VirulênciaRESUMO
Trypanosoma brucei rhodesiense is one of the causative agents of Human African Trypanosomiasis (HAT), known as sleeping sickness. The parasite invades the central nervous system and causes severe encephalitis that is fatal if left untreated. We have previously identified ecotin-like inhibitors of serine peptidases, named ISPs, in trypanosomatid parasitic protozoa. Here, we investigated the role of ISP2 in bloodstream form T. b. rhodesiense. We generated gene-deficient mutants lacking ISP2 (Δisp2), which displayed a growth profile in vitro similar to that of wild-type (WT) parasites. C57BL/6 mice infected with Δisp2 displayed lower blood parasitemia, a delayed hind leg pathological phenotype and survived longer. The immune response was examined at two time-points that corresponded with two peaks of parasitemia. At 4 days, the spleens of Δisp2-infected mice had a greater percentage of NOS2+ myeloid cells, IFN-γ+-NK cells and increased TNF-α compared to those infected with WT and parasites re-expressing ISP2 (Δisp2:ISP2). By 13 days the increased NOS2+ population was sustained in Δisp2-infected mice, along with increased percentages of monocyte-derived dendritic cells, as well as CD19+ B lymphocytes, and CD8+ and CD4+ T lymphocytes. Taken together, these findings indicate that ISP2 contributes to T. b. rhodesiense virulence in mice and attenuates the inflammatory response during early infection.
Assuntos
Inibidores de Serina Proteinase/metabolismo , Trypanosoma brucei rhodesiense/genética , Trypanosoma brucei rhodesiense/patogenicidade , Tripanossomíase Africana/imunologia , Animais , Animais Geneticamente Modificados , Anticorpos Monoclonais , Feminino , Inflamação , Camundongos Endogâmicos C57BL , Inibidores de Serina Proteinase/genética , Baço/parasitologia , VirulênciaRESUMO
Suramin is 100 years old and is still being used to treat the first stage of acute human sleeping sickness, caused by Trypanosoma bruceirhodesiense Suramin is a multifunctional molecule with a wide array of potential applications, from parasitic and viral diseases to cancer, snakebite, and autism. Suramin is also an enigmatic molecule: What are its targets? How does it get into cells in the first place? Here, we provide an overview of the many different candidate targets of suramin and discuss its modes of action and routes of cellular uptake. We reason that, once the polypharmacology of suramin is understood at the molecular level, new, more specific, and less toxic molecules can be identified for the numerous potential applications of suramin.
Assuntos
Suramina/uso terapêutico , Tripanossomicidas/uso terapêutico , Tripanossomíase Africana/tratamento farmacológico , Animais , Humanos , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Trypanosoma brucei rhodesiense/patogenicidade , Tripanossomíase Africana/parasitologiaRESUMO
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.
Assuntos
Doenças Negligenciadas/diagnóstico , Doenças Negligenciadas/epidemiologia , Trypanosoma brucei gambiense/patogenicidade , Trypanosoma brucei rhodesiense/patogenicidade , Tripanossomíase Africana/diagnóstico , Tripanossomíase Africana/epidemiologia , Animais , Antiprotozoários/administração & dosagem , Antiprotozoários/uso terapêutico , Barreira Hematoencefálica/parasitologia , Encéfalo/parasitologia , Diagnóstico Tardio , Humanos , Incidência , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/prevenção & controle , Pentamidina/administração & dosagem , Pentamidina/uso terapêutico , Índice de Gravidade de Doença , Suramina/administração & dosagem , Suramina/uso terapêutico , Resultado do Tratamento , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/prevenção & controleRESUMO
BACKGROUND: This paper presents the development of an agent-based model (ABM) to incorporate climatic drivers which affect tsetse fly (G. m. morsitans) population dynamics, and ultimately disease transmission. The model was used to gain a greater understanding of how tsetse populations fluctuate seasonally, and investigate any response observed in Trypanosoma brucei rhodesiense human African trypanosomiasis (rHAT) disease transmission, with a view to gaining a greater understanding of disease dynamics. Such an understanding is essential for the development of appropriate, well-targeted mitigation strategies in the future. METHODS: The ABM was developed to model rHAT incidence at a fine spatial scale along a 75 km transect in the Luangwa Valley, Zambia. The model incorporates climatic factors that affect pupal mortality, pupal development, birth rate, and death rate. In combination with fine scale demographic data such as ethnicity, age and gender for the human population in the region, as well as an animal census and a sample of daily routines, we create a detailed, plausible simulation model to explore tsetse population and disease transmission dynamics. RESULTS: The seasonally-driven model suggests that the number of infections reported annually in the simulation is likely to be a reasonable representation of reality, taking into account the high levels of under-detection observed. Similar infection rates were observed in human (0.355 per 1000 person-years (SE = 0.013)), and cattle (0.281 per 1000 cattle-years (SE = 0.025)) populations, likely due to the sparsity of cattle close to the tsetse interface. The model suggests that immigrant tribes and school children are at greatest risk of infection, a result that derives from the bottom-up nature of the ABM and conditioning on multiple constraints. This result could not be inferred using alternative population-level modelling approaches. CONCLUSIONS: In producing a model which models the tsetse population at a very fine resolution, we were able to analyse and evaluate specific elements of the output, such as pupal development and the progression of the teneral population, allowing the development of our understanding of the tsetse population as a whole. This is an important step in the production of a more accurate transmission model for rHAT which can, in turn, help us to gain a greater understanding of the transmission system as a whole.
Assuntos
Clima , Estações do Ano , Trypanosoma brucei rhodesiense/patogenicidade , Tripanossomíase Africana/epidemiologia , Tripanossomíase Africana/transmissão , Moscas Tsé-Tsé/fisiologia , Adolescente , Adulto , Fatores Etários , Animais , Coeficiente de Natalidade , Bovinos , Criança , Pré-Escolar , Etnicidade , Feminino , Mapeamento Geográfico , Humanos , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Mortalidade , Dinâmica Populacional , Chuva , Instituições Acadêmicas , Fatores Sexuais , Temperatura , Tripanossomíase Africana/mortalidade , Adulto Jovem , ZâmbiaRESUMO
African trypanosomes, which divide their life cycle between mammals and tsetse flies, are confronted with environments that differ widely in temperature, nutrient availability and host responses to infection. In particular, since trypanosomes cannot predict when they will be transmitted between hosts, it is vital for them to be able to sense and adapt to their milieu. Thanks to technical advances, significant progress has been made in understanding how the parasites perceive external stimuli and react to them. There is also a growing awareness that trypanosomes use a variety of mechanisms to exchange information with each other, thereby enhancing their chances of survival.
Assuntos
Meio Ambiente , Interações Hospedeiro-Patógeno/fisiologia , Estágios do Ciclo de Vida/fisiologia , Mamíferos/parasitologia , Trypanosoma brucei gambiense/fisiologia , Trypanosoma brucei rhodesiense/fisiologia , Moscas Tsé-Tsé/parasitologia , Animais , Insetos Vetores/parasitologia , Percepção de Quorum/fisiologia , Trypanosoma brucei brucei/patogenicidade , Trypanosoma brucei gambiense/patogenicidade , Trypanosoma brucei rhodesiense/patogenicidade , Tripanossomíase Africana/parasitologiaRESUMO
Human African trypanosomiasis (HAT) is a major tropical disease for which few drugs for treatment are available, driving the need for novel active compounds. Recently, morpholino-substituted benzyl amides of the fluoroquinolone-type antibiotics were identified to be compounds highly active against Trypanosoma brucei brucei Since the lead compound GHQ168 was challenged by poor water solubility in previous trials, the aim of this study was to introduce structural variations to GHQ168 as well as to formulate GHQ168 with the ultimate goal to increase its aqueous solubility while maintaining its in vitro antitrypanosomal activity. The pharmacokinetic parameters of spray-dried GHQ168 and the newly synthesized compounds GHQ242 and GHQ243 in mice were characterized by elimination half-lives ranging from 1.5 to 3.5 h after intraperitoneal administration (4 mice/compound), moderate to strong human serum albumin binding for GHQ168 (80%) and GHQ243 (45%), and very high human serum albumin binding (>99%) for GHQ242. For the lead compound, GHQ168, the apparent clearance was 112 ml/h and the apparent volume of distribution was 14 liters/kg of body weight (BW). Mice infected with T. b. rhodesiense (STIB900) were treated in a stringent study scheme (2 daily applications between days 3 and 6 postinfection). Exposure to spray-dried GHQ168 in contrast to the control treatment resulted in mean survival durations of 17 versus 9 days, respectively, a difference that was statistically significant. Results that were statistically insignificantly different were obtained between the control and the GHQ242 and GHQ243 treatments. Therefore, GHQ168 was further profiled in an early-treatment scheme (2 daily applications at days 1 to 4 postinfection), and the results were compared with those obtained with a control treatment. The result was statistically significant mean survival times exceeding 32 days (end of the observation period) versus 7 days for the GHQ168 and control treatments, respectively. Spray-dried GHQ168 demonstrated exciting antitrypanosomal efficacy.
Assuntos
Amidas/uso terapêutico , Quinolonas/uso terapêutico , Tripanossomicidas/uso terapêutico , Amidas/administração & dosagem , Amidas/farmacocinética , Animais , Feminino , Humanos , Injeções Intraperitoneais , Masculino , Camundongos , Quinolonas/administração & dosagem , Quinolonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Tripanossomicidas/administração & dosagem , Tripanossomicidas/farmacocinética , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei brucei/patogenicidade , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Trypanosoma brucei rhodesiense/patogenicidadeRESUMO
Human African Trypanosomiasis (HAT) transmitted by the tsetse fly continues to be a public health issue, despite more than a century of research. There are two types of the disease, the chronic gambiense and the acute rhodesiense-HAT. Fly abundance and distribution have been affected by changes in land-use patterns and climate. However, disease transmission still continues. Here, we review some aspects of HAT ecoepidemiology in the context of altered infestation patterns and maintenance of the transmission cycle as well as emerging options in disease and vector control.
Assuntos
Insetos Vetores , Tripanossomíase Africana/epidemiologia , Moscas Tsé-Tsé/patogenicidade , Animais , Congo , Humanos , Trypanosoma brucei gambiense/patogenicidade , Trypanosoma brucei rhodesiense/patogenicidade , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/transmissão , Moscas Tsé-Tsé/parasitologiaAssuntos
Técnicas Citológicas/métodos , Testes Hematológicos/métodos , Trypanosoma brucei rhodesiense/patogenicidade , Tripanossomíase Africana/sangue , Tripanossomíase Africana/diagnóstico , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Espanha , Viagem , Tripanossomíase Africana/parasitologiaRESUMO
Intercellular communication between parasites and with host cells provides mechanisms for parasite development, immune evasion, and disease pathology. Bloodstream African trypanosomes produce membranous nanotubes that originate from the flagellar membrane and disassociate into free extracellular vesicles (EVs). Trypanosome EVs contain several flagellar proteins that contribute to virulence, and Trypanosoma brucei rhodesiense EVs contain the serum resistance-associated protein (SRA) necessary for human infectivity. T. b. rhodesiense EVs transfer SRA to non-human infectious trypanosomes, allowing evasion of human innate immunity. Trypanosome EVs can also fuse with mammalian erythrocytes, resulting in rapid erythrocyte clearance and anemia. These data indicate that trypanosome EVs are organelles mediating non-hereditary virulence factor transfer and causing host erythrocyte remodeling, inducing anemia.
Assuntos
Vesículas Extracelulares/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Protozoários/metabolismo , Trypanosoma brucei rhodesiense/citologia , Trypanosoma brucei rhodesiense/imunologia , Tripanossomíase Africana/patologia , Tripanossomíase Africana/parasitologia , Fatores de Virulência/metabolismo , Anemia/patologia , Animais , Eritrócitos/parasitologia , Flagelos/metabolismo , Humanos , Evasão da Resposta Imune , Camundongos , Proteoma/metabolismo , Rodaminas/análise , Trypanosoma brucei rhodesiense/metabolismo , Trypanosoma brucei rhodesiense/patogenicidadeRESUMO
Humans resist infection by the African parasite Trypanosoma brucei owing to the trypanolytic activity of the serum apolipoprotein L1 (APOL1). Following uptake by endocytosis in the parasite, APOL1 forms pores in endolysosomal membranes and triggers lysosome swelling. Here we show that APOL1 induces both lysosomal and mitochondrial membrane permeabilization (LMP and MMP). Trypanolysis coincides with MMP and consecutive release of the mitochondrial TbEndoG endonuclease to the nucleus. APOL1 is associated with the kinesin TbKIFC1, of which both the motor and vesicular trafficking VHS domains are required for MMP, but not for LMP. The presence of APOL1 in the mitochondrion is accompanied by mitochondrial membrane fenestration, which can be mimicked by knockdown of a mitochondrial mitofusin-like protein (TbMFNL). The BH3-like peptide of APOL1 is required for LMP, MMP and trypanolysis. Thus, trypanolysis by APOL1 is linked to apoptosis-like MMP occurring together with TbKIFC1-mediated transport of APOL1 from endolysosomal membranes to the mitochondrion.
Assuntos
Apolipoproteínas/metabolismo , Cinesinas/metabolismo , Lipoproteínas HDL/metabolismo , Lisossomos/metabolismo , Membranas Mitocondriais/metabolismo , Proteínas de Protozoários/metabolismo , Apolipoproteína L1 , Apoptose , Transporte Biológico , Endocitose , Humanos , Membranas Intracelulares/metabolismo , Permeabilidade , Trypanosoma brucei brucei/metabolismo , Trypanosoma brucei brucei/patogenicidade , Trypanosoma brucei gambiense/metabolismo , Trypanosoma brucei gambiense/patogenicidade , Trypanosoma brucei rhodesiense/metabolismo , Trypanosoma brucei rhodesiense/patogenicidadeRESUMO
We evaluated Mastomys natelensis rat as an animal model for Rhodesian sleeping sickness. Parasitaemia, clinical and pathological characteristics induced by T. b. rhodesiense isolates, KETRI 3439, 3622 and 3637 were compared in Mastomys rats and Swiss white mice. Each isolate was intra-peritonially injected in mice and rat groups (n=12) at 1×10(4) trypanosomes/0.2mL. Pre-patent period (PP) range for KETRI 3439 and KETRI 3622-groups was 3-6 days for mice and 4-5 days for rats while for KETRI 3637-infected mice and rats was 5-9 and 4-12 days, respectively. Pairwise comparison between PP of mice and rats separately infected with either isolate showed no significant difference (p>0.05). The PP's of KETRI 3637-infected mice were significantly (p>0.01) longer than those infected with KETRI 3439 or KETRI 3622, a trend also observed in rats. The second parasitaemic wave was more prominent in mice. Clinical signs included body weakness, dyspnoea, peri-orbital oedema and extreme emaciation which were more common in rats. Survival time for KETRI 3439 and 3622-infected groups was significantly (p<0.05) longer in mice than rats but similar in KETRI 3637-infected groups. Inflammatory lesions were more severe in rats than mice. All mice and KETRI 3622-infected rats had splenomegaly, organ congestion with rats additionally showing prominent lymphadenopathy. KETRI 3439-infected rats showed hemorrhagic pneumonia, enteritis with moderate splenomegaly and lymphadenopathy. KETRI 3637-infected rats had the most severe lesions characterized by prominent splenomegaly, lymphadenopathy, hepatomegaly, enlarged adrenal glands, organ congestion, generalized oedemas, gastroenteritis, pneumonia and brain congestion. KETRI 3637-infected Mastomys is a suitable model for studying pathophysiology of HAT.
Assuntos
Trypanosoma brucei rhodesiense/patogenicidade , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Parasitemia/patologia , Ratos , Especificidade da Espécie , Tripanossomíase Africana/patologiaRESUMO
A third of African Americans with sporadic focal segmental glomerulosclerosis (FSGS) or HIV-associated nephropathy (HIVAN) do not carry APOL1 renal risk genotypes. This raises the possibility that other APOL1 variants may contribute to kidney disease. To address this question, we sequenced all APOL1 exons in 1437 Americans of African and European descent, including 464 patients with biopsy-proven FSGS/HIVAN. Testing for association with 33 common and rare variants with FSGS/HIVAN revealed no association independent of strong recessive G1 and G2 effects. Seeking additional variants that might have been under selection by pathogens and could represent candidates for kidney disease risk, we also sequenced an additional 1112 individuals representing 53 global populations. Except for G1 and G2, none of the 7 common codon-altering variants showed evidence of selection or could restore lysis against trypanosomes causing human African trypanosomiasis. Thus, only APOL1 G1 and G2 confer renal risk, and other common and rare APOL1 missense variants, including the archaic G3 haplotype, do not contribute to sporadic FSGS and HIVAN in the US population. Hence, in most potential clinical or screening applications, our study suggests that sequencing APOL1 exons is unlikely to bring additional information compared to genotyping only APOL1 G1 and G2 risk alleles.
Assuntos
Nefropatia Associada a AIDS/genética , Apolipoproteínas/genética , Glomerulosclerose Segmentar e Focal/genética , Lipoproteínas HDL/genética , Polimorfismo de Nucleotídeo Único , Nefropatia Associada a AIDS/diagnóstico , Nefropatia Associada a AIDS/etnologia , Negro ou Afro-Americano/genética , Apolipoproteína L1 , Apolipoproteínas/sangue , Biópsia , Estudos de Casos e Controles , Éxons , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Glomerulosclerose Segmentar e Focal/diagnóstico , Glomerulosclerose Segmentar e Focal/etnologia , Haplótipos , Interações Hospedeiro-Parasita , Humanos , Lipoproteínas HDL/sangue , Masculino , Fenótipo , Medição de Risco , Fatores de Risco , Análise de Sequência de DNA , Trypanosoma brucei gambiense/metabolismo , Trypanosoma brucei gambiense/patogenicidade , Trypanosoma brucei rhodesiense/metabolismo , Trypanosoma brucei rhodesiense/patogenicidade , Estados Unidos/epidemiologia , População Branca/genéticaRESUMO
Treatment of late-stage sleeping sickness requires drugs that can cross the blood-brain barrier (BBB) to reach the parasites located in the brain. We report here the synthesis and evaluation of four new N-hydroxy and 12 new N-alkoxy derivatives of bisimidazoline leads as potential agents for the treatment of late-stage sleeping sickness. These compounds, which have reduced basicity compared to the parent leads (i.e., are less ionized at physiological pH), were evaluated in vitro against Trypanosoma brucei rhodesiense and in vivo in murine models of first- and second-stage sleeping sickness. Resistance profile, physicochemical parameters, in vitro BBB permeability, and microsomal stability also were determined. The N-hydroxy imidazoline analogues were the most effective in vivo, with 4-((1-hydroxy-4,5-dihydro-1H-imidazol-2-yl)amino)-N-(4-((1-hydroxy-4,5-dihydro-1H-imidazol-2-yl)amino)phenyl)benzamide (14d) showing 100% cures in the first-stage disease, while 15d, 16d, and 17d appeared to slightly improve survival. In addition, 14d showed weak activity in the chronic model of central nervous system infection in mice. No evidence of reduction of this compound with hepatic microsomes and mitochondria was found in vitro, suggesting that N-hydroxy imidazolines are metabolically stable and have intrinsic activity against T. brucei. In contrast to its unsubstituted parent compound, the uptake of 14d in T. brucei was independent of known drug transporters (i.e., T. brucei AT1/P2 and HAPT), indicating a lower predisposition to cross-resistance with other diamidines and arsenical drugs. Hence, the N-hydroxy bisimidazolines (14d in particular) represent a new class of promising antitrypanosomal agents.
Assuntos
Tripanossomicidas/uso terapêutico , Trypanosoma brucei brucei/patogenicidade , Trypanosoma brucei rhodesiense/patogenicidade , Tripanossomíase Africana/tratamento farmacológico , Animais , Modelos Animais de Doenças , Feminino , Imidazolinas/uso terapêutico , Camundongos , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei rhodesiense/efeitos dos fármacosRESUMO
This paper reports an evaluation of a melamino nitroheterocycle, a potential lead for further development as an agent against human African trypanosomiasis (HAT). Studies on its efficacy, physicochemical and biopharmaceutical properties, and potential for toxicity are described. The compound previously had been shown to possess exceptional activity against Trypanosoma brucei in in vitro assays comparable to that of melarsoprol. Here, we demonstrate that the compound also was curative in the stringent acute mouse model T. brucei rhodesiense STIB 900 when given intraperitoneally at 40 mg/kg of body weight. Nevertheless, activity was only moderate when the oral route was used, and no cure was obtained when the compound was tested in a stage 2 rodent model of infection. Genotoxic profiling revealed that the compound induces DNA damage by a mechanism apparently independent from nitroreduction and involving the introduction of base pair substitutions (Ames test), possibly caused by oxidative damage of the DNA (comet test). No significant genotoxicity was observed at the chromosome level (micronucleus assay). The lack of suitable properties for oral and central nervous system uptake and the genotoxic liabilities prevent the progression of this melamine nitroheterocycle as a drug candidate for HAT. Further modification of the compound is required to improve the pharmacokinetic properties of the molecule and to separate the trypanocidal activity from the toxic potential.
Assuntos
Tripanossomicidas/uso terapêutico , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Trypanosoma brucei rhodesiense/patogenicidade , Tripanossomíase Africana/tratamento farmacológico , Animais , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Testes de Sensibilidade ParasitáriaRESUMO
African sleeping sickness is a neglected tropical disease transmitted by tsetse flies. New and better drugs are still needed especially for its second stage, which is fatal if untreated. 28DAP010, a dipyridylbenzene analogue of DB829, is the second simple diamidine found to cure mice with central nervous system infections by a parenteral route of administration. 28DAP010 showed efficacy similar to that of DB829 in dose-response studies in mouse models of first- and second-stage African sleeping sickness. The in vitro time to kill, determined by microcalorimetry, and the parasite clearance time in mice were shorter for 28DAP010 than for DB829. No cross-resistance was observed between 28DAP010 and pentamidine on the tested Trypanosoma brucei gambiense isolates from melarsoprol-refractory patients. 28DAP010 is the second promising preclinical candidate among the diamidines for the treatment of second-stage African sleeping sickness.
Assuntos
Amidinas/farmacologia , Piridinas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei gambiense/efeitos dos fármacos , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Amidinas/síntese química , Amidinas/farmacocinética , Animais , Relação Dose-Resposta a Droga , Feminino , Humanos , Melarsoprol/farmacocinética , Melarsoprol/farmacologia , Camundongos , Pentamidina/farmacocinética , Pentamidina/farmacologia , Piridinas/síntese química , Piridinas/farmacocinética , Relação Estrutura-Atividade , Tripanossomicidas/síntese química , Tripanossomicidas/farmacocinética , Trypanosoma brucei gambiense/crescimento & desenvolvimento , Trypanosoma brucei gambiense/patogenicidade , Trypanosoma brucei rhodesiense/crescimento & desenvolvimento , Trypanosoma brucei rhodesiense/patogenicidade , Tripanossomíase Africana/parasitologiaRESUMO
Tsetse flies (Glossina spp.) vector pathogenic African trypanosomes, which cause sleeping sickness in humans and nagana in domesticated animals. Additionally, tsetse harbors 3 maternally transmitted endosymbiotic bacteria that modulate their host's physiology. Tsetse is highly resistant to infection with trypanosomes, and this phenotype depends on multiple physiological factors at the time of challenge. These factors include host age, density of maternally-derived trypanolytic effector molecules present in the gut, and symbiont status during development. In this study, we investigated the molecular mechanisms that result in tsetse's resistance to trypanosomes. We found that following parasite challenge, young susceptible tsetse present a highly attenuated immune response. In contrast, mature refractory flies express higher levels of genes associated with humoral (attacin and pgrp-lb) and epithelial (inducible nitric oxide synthase and dual oxidase) immunity. Additionally, we discovered that tsetse must harbor its endogenous microbiome during intrauterine larval development in order to present a parasite refractory phenotype during adulthood. Interestingly, mature aposymbiotic flies (Gmm(Apo)) present a strong immune response earlier in the infection process than do WT flies that harbor symbiotic bacteria throughout their entire lifecycle. However, this early response fails to confer significant resistance to trypanosomes. Gmm(Apo) adults present a structurally compromised peritrophic matrix (PM), which lines the fly midgut and serves as a physical barrier that separates luminal contents from immune responsive epithelial cells. We propose that the early immune response we observe in Gmm(Apo) flies following parasite challenge results from the premature exposure of gut epithelia to parasite-derived immunogens in the absence of a robust PM. Thus, tsetse's PM appears to regulate the timing of host immune induction following parasite challenge. Our results document a novel finding, which is the existence of a positive correlation between tsetse's larval microbiome and the integrity of the emerging adult PM gut immune barrier.
Assuntos
Microbiota , Trypanosoma brucei rhodesiense/imunologia , Moscas Tsé-Tsé/imunologia , Moscas Tsé-Tsé/parasitologia , Animais , Proteínas de Transporte/biossíntese , Feminino , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/parasitologia , Proteínas de Insetos/biossíntese , NADPH Oxidases/biossíntese , Óxido Nítrico Sintase Tipo II/biossíntese , Simbiose , Trypanosoma brucei rhodesiense/patogenicidade , Tripanossomíase Africana/transmissão , Moscas Tsé-Tsé/crescimento & desenvolvimento , Moscas Tsé-Tsé/microbiologiaRESUMO
Human African trypanosomiasis, or sleeping sickness, is caused by infection with parasites of the genus Trypanosoma, transmitted by the tsetse fly. The disease has two forms, Trypanosoma brucei (T b) rhodesiense and T b gambiense; and is almost always fatal if untreated. Despite a recent reduction in the number of reported cases, patients with African trypanosomiasis continue to present major challenges to clinicians. Because treatment for CNS-stage disease can be very toxic, diagnostic staging to distinguish early-stage from late-stage disease when the CNS in invaded is crucial but remains problematic. Melarsoprol is the only available treatment for late-stage T b rhodesiense infection, but can be lethal to 5% of patients owing to post-treatment reactive encephalopathy. Eflornithine combined with nifurtimox is the first-line treatment for late-stage T b gambiense. New drugs are in the pipeline for treatment of CNS human African trypanosomiasis, giving rise to cautious optimism.