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1.
EBioMedicine ; 105: 105188, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38848649

RESUMO

BACKGROUND: The Global Program to Eliminate Lymphatic Filariasis (GPELF) is the largest public health program based on mass drug administration (MDA). Despite decades of MDA, ongoing transmission in some countries remains a challenge. To optimise interventions, it is critical to differentiate between recrudescence and new infections. Since adult filariae are inaccessible in humans, deriving a method that relies on the offspring microfilariae (mf) is necessary. METHODS: We developed a genome amplification and kinship analysis-based approach using Brugia malayi samples from gerbils, and applied it to analyse Wuchereria bancrofti mf from humans in Côte d'Ivoire. We examined the pre-treatment genetic diversity in 269 mf collected from 18 participants, and further analysed 1-year post-treatment samples of 74 mf from 4 participants. Hemizygosity of the male X-chromosome allowed for direct inference of haplotypes, facilitating robust maternal parentage inference. To enrich parasite DNA from samples contaminated with host DNA, a whole-exome capture panel was created for W. bancrofti. FINDINGS: By reconstructing and temporally tracking sibling relationships across pre- and post-treatment samples, we differentiated between new and established maternal families, suggesting reinfection in one participant and recrudescence in three participants. The estimated number of reproductively active adult females ranged between 3 and 11 in the studied participants. Population structure analysis revealed genetically distinct parasites in Côte d'Ivoire compared to samples from other countries. Exome capture identified protein-coding variants with ∼95% genotype concordance rate. INTERPRETATION: We have generated resources to facilitate the development of molecular genetic tools that can estimate adult worm burdens and monitor parasite populations, thus providing essential information for the successful implementation of GPELF. FUNDING: This work was financially supported by the Bill and Melinda Gates Foundation (https://www.gatesfoundation.org) under grant OPP1201530 (Co-PIs PUF & Gary J. Weil). B. malayi parasite material was generated with support of the Foundation for Barnes Jewish Hospital (PUF). In addition, the development of computational methods was supported by the National Institutes of Health under grants AI144161 (MM) and AI146353 (MM). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Assuntos
Filariose Linfática , Recidiva , Reinfecção , Wuchereria bancrofti , Filariose Linfática/parasitologia , Filariose Linfática/epidemiologia , Filariose Linfática/diagnóstico , Filariose Linfática/genética , Humanos , Animais , Wuchereria bancrofti/genética , Feminino , Masculino , Reinfecção/parasitologia , Brugia Malayi/genética , Gerbillinae/parasitologia , Variação Genética , Microfilárias/genética , Adulto , Haplótipos , Côte d'Ivoire/epidemiologia
2.
PLoS Negl Trop Dis ; 15(10): e0009806, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34610025

RESUMO

BACKGROUND: Infectious disease risk is driven by three interrelated components: exposure, hazard, and vulnerability. For schistosomiasis, exposure occurs through contact with water, which is often tied to daily activities. Water contact, however, does not imply risk unless the environmental hazard of snails and parasites is also present in the water. By increasing reliance on hazardous activities and environments, socio-economic vulnerability can hinder reductions in exposure to a hazard. We aimed to quantify the contributions of exposure, hazard, and vulnerability to the presence and intensity of Schistosoma haematobium re-infection. METHODOLOGY/PRINCIPAL FINDINGS: In 13 villages along the Senegal River, we collected parasitological data from 821 school-aged children, survey data from 411 households where those children resided, and ecological data from all 24 village water access sites. We fit mixed-effects logistic and negative binomial regressions with indices of exposure, hazard, and vulnerability as explanatory variables of Schistosoma haematobium presence and intensity, respectively, controlling for demographic variables. Using multi-model inference to calculate the relative importance of each component of risk, we found that hazard (Æ©wi = 0.95) was the most important component of S. haematobium presence, followed by vulnerability (Æ©wi = 0.91). Exposure (Æ©wi = 1.00) was the most important component of S. haematobium intensity, followed by hazard (Æ©wi = 0.77). Model averaging quantified associations between each infection outcome and indices of exposure, hazard, and vulnerability, revealing a positive association between hazard and infection presence (OR = 1.49, 95% CI 1.12, 1.97), and a positive association between exposure and infection intensity (RR 2.59-3.86, depending on the category; all 95% CIs above 1). CONCLUSIONS/SIGNIFICANCE: Our findings underscore the linkages between social (exposure and vulnerability) and environmental (hazard) processes in the acquisition and accumulation of S. haematobium infection. This approach highlights the importance of implementing both social and environmental interventions to complement mass drug administration.


Assuntos
Reinfecção/parasitologia , Schistosoma haematobium/fisiologia , Esquistossomose Urinária/parasitologia , Vulnerabilidade Social , Adolescente , Animais , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Reinfecção/epidemiologia , Reinfecção/psicologia , População Rural/estatística & dados numéricos , Schistosoma haematobium/genética , Schistosoma haematobium/isolamento & purificação , Esquistossomose Urinária/epidemiologia , Esquistossomose Urinária/psicologia , Senegal/epidemiologia , Populações Vulneráveis/estatística & dados numéricos , Água/parasitologia
3.
PLoS Negl Trop Dis ; 15(5): e0009340, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33983946

RESUMO

The current approaches to reduce the burden of chronic helminth infections in endemic areas are adequate sanitation and periodic administration of deworming drugs. Yet, resistance against some deworming drugs and reinfection can still rapidly occur even after treatment. A vaccine against helminths would be an effective solution at preventing reinfection. However, vaccines against helminth parasites have yet to be successfully developed. While T helper cells and innate lymphoid cells have been established as important components of the protective type 2 response, the roles of B cells and antibodies remain the most controversial. Here, we review the roles of B cells during intestinal helminth infection. We discuss the potential factors that contribute to the context-specific roles for B cells in protection against diverse intestinal helminth parasite species, using evidence from well-defined murine model systems. Understanding the precise roles of B cells during resistance and susceptibility to helminth infection may offer a new perspective of type 2 protective immunity.


Assuntos
Anticorpos Anti-Helmínticos/imunologia , Linfócitos B/imunologia , Helmintíase/imunologia , Helmintos/imunologia , Enteropatias Parasitárias/imunologia , Animais , Anti-Helmínticos/uso terapêutico , Centro Germinativo/imunologia , Helmintíase/tratamento farmacológico , Helmintíase/parasitologia , Helmintos/efeitos dos fármacos , Humanos , Enteropatias Parasitárias/tratamento farmacológico , Enteropatias Parasitárias/parasitologia , Camundongos , Vacinas Protozoárias/imunologia , Reinfecção/parasitologia , Reinfecção/prevenção & controle , Linfócitos T Auxiliares-Indutores/imunologia
4.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 32(6): 569-576, 2020 Nov 23.
Artigo em Chinês | MEDLINE | ID: mdl-33325190

RESUMO

OBJECTIVE: To investigate the disease progression and immunoprotective characteristics in mice re-infected with homogeneous/heterogeneous Plasmodium strains following cure of Plasmodium infections with chloroquine at the peak of parasitemia. METHODS: C57BL/6 mice were infected with the non-lethal P. yoelii 17XNL strain, and half of mice were given treatment with chloroquine at the peak of parasitemia (9 days post-infection), while the other mice were self-cured naturally. Then, all cured mice were re-infected with the equivalent lethal P. yoelii 17XL or P. berghei ANKA strain 90 days following primary Plasmodium infections. The parasitemia levels during primary infections and reinfections were measured by microscopic examinations of Giemsa-stained thin blood films, and the levels of the IgG antibody in sera and the percentages of memory T cell subsets in spleen cells were detected in mice using ELISA and flow cytometry before and after parasite reinfections, respectively. RESULTS: Following primary infections with the P. yoelii 17XNL strain, the serum IgG antibody levels were (5.047 ± 0.924) pg/mL in the selfcured mice and (4.429 ± 0.624) pg/mL in the chloroquine-treated mice, respectively (t = 0.437, P > 0.05), which were both significantly higher than that in the uninfected mice (1.624 pg/mL ± 0.280 pg/mL) (F = 22.522, P < 0.01). There was no significant difference in the serum IgG antibody level among self-cured and chloroquine-treated mice re-infected with the P. yoelii 17XL strain or the P. berghei ANKA strain (F = 0.542, P > 0.05); however, the serum IgG antibody levels were all significantly higher in selfcured and chloroquine-treated mice re-infected with the P. yoelii 17XLstrain[(15.487±1.173)pg/mLand(15.965±1.150)pg/mL] or the P. berghei ANKA strain [(14.644 ± 1.523) pg/mL and (15.185 ± 1.333) pg/mL] relative to primary infections (F = 67.383, P < 0.01). There was no significant difference in the proportion of CD4+ [(34.208 ± 2.106), (32.820 ± 1.930), (34.023 ± 2.289), (35.608 ± 1.779) pg/mL] or CD8+ T memory cells [(17.935 ± 2.092), (18.918 ± 2.823), (17.103 ± 1.627), (17.873 ± 1.425) pg/mL] in self-cured and chloroquine-treated mice with primary infections with the P. yoelii 17XNL strain followed by re-infections with the P. yoelii 17XL strain or the P. berghei ANKA strain (F = 0.944 and 0.390, both P > 0.05); however, the proportions of the CD4+ or CD8+ T memory cells were significantly greater in self-cured and chloroquine-treated mice with primary infections with the P. yoelii 17XNL strain followed by re-infections with the P. yoelii 17XL strain or the P. berghei ANKA strain than in mice with primary infections (F = 50.532 and 21.751, both P < 0.01). CONCLUSIONS: The cure of murine Plasmodium infections with chloroquine does not affect the production of effective immune protections in mice during parasite re-infections. Following a primary infection, mice show a protection against re-infections with either homogeneous or heterogeneous Plasmodium strains, and a higher-level resistance to re-infections with homogeneous parasite strains is found than with heterogeneous strains.


Assuntos
Cloroquina/uso terapêutico , Malária , Plasmodium yoelii , Reinfecção/parasitologia , Animais , Anticorpos Antiprotozoários/sangue , Imunoglobulina G/sangue , Malária/tratamento farmacológico , Malária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/imunologia
5.
Pediatr Infect Dis J ; 39(9): e283-e284, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32740452

RESUMO

We present a case of a 22-month-old girl who had 2 episodes of cutaneous larva migrans 2 months apart after returning from a tropical area, despite a single exposure period.


Assuntos
Larva Migrans/diagnóstico , Reinfecção/diagnóstico , Reinfecção/parasitologia , Administração Tópica , Antiparasitários/uso terapêutico , Feminino , Humanos , Lactente , Ivermectina/uso terapêutico , Larva Migrans/tratamento farmacológico , Pele/parasitologia , Pele/patologia , Viagem , Resultado do Tratamento , Clima Tropical
6.
Artigo em Inglês | MEDLINE | ID: mdl-31932376

RESUMO

Antimalarial drugs have long half-lives, so clinical trials to monitor their efficacy require long periods of follow-up to capture drug failure that may become patent only weeks after treatment. Reinfections often occur during follow-up, so robust methods of distinguishing drug failures (recrudescence) from emerging new infections are needed to produce accurate failure rate estimates. Molecular correction aims to achieve this by comparing the genotype of a patient's pretreatment (initial) blood sample with that of any infection that occurs during follow-up, with matching genotypes indicating drug failure. We use an in silico approach to show that the widely used match-counting method of molecular correction with microsatellite markers is likely to be highly unreliable and may lead to gross under- or overestimates of the true failure rates, depending on the choice of matching criterion. A Bayesian algorithm for molecular correction was previously developed and utilized for analysis of in vivo efficacy trials. We validated this algorithm using in silico data and showed it had high specificity and generated accurate failure rate estimates. This conclusion was robust for multiple drugs, different levels of drug failure rates, different levels of transmission intensity in the study sites, and microsatellite genetic diversity. The Bayesian algorithm was inherently unable to accurately identify low-density recrudescence that occurred in a small number of patients, but this did not appear to compromise its utility as a highly effective molecular correction method for analyzing microsatellite genotypes. Strong consideration should be given to using Bayesian methodology to obtain accurate failure rate estimates during routine monitoring trials of antimalarial efficacy that use microsatellite markers.


Assuntos
Antimaláricos/uso terapêutico , Biologia Computacional/métodos , Malária Falciparum/tratamento farmacológico , Repetições de Microssatélites/genética , Plasmodium falciparum/efeitos dos fármacos , Algoritmos , Combinação Arteméter e Lumefantrina/uso terapêutico , Artesunato/uso terapêutico , Simulação por Computador , Interpretação Estatística de Dados , Feminino , Humanos , Masculino , Mefloquina/uso terapêutico , Plasmodium falciparum/genética , Reinfecção/genética , Reinfecção/parasitologia , Falha de Tratamento
7.
Commun Biol ; 3: 7, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31909199

RESUMO

Plasmodium vivax malaria is characterized by repeated episodes of blood stage infection (relapses) resulting from activation of dormant stages in the liver, so-called hypnozoites. Transition of hypnozoites into developing schizonts has never been observed. A barrier for studying this has been the lack of a system in which to monitor growth of liver stages. Here, exploiting the unique strengths of the simian hypnozoite model P. cynomolgi, we have developed green-fluorescent (GFP) hypnozoites that turn on red-fluorescent (mCherry) upon activation. The transgenic parasites show full liver stage development, including merozoite release and red blood cell infection. We demonstrate that individual hypnozoites actually can activate and resume development after prolonged culture, providing the last missing evidence of the hypnozoite theory of relapse. The few events identified indicate that hypnozoite activation in vitro is infrequent. This system will further our understanding of the mechanisms of hypnozoite activation and may facilitate drug discovery approaches.


Assuntos
Genes Reporter , Malária/parasitologia , Plasmodium cynomolgi/fisiologia , Reinfecção/parasitologia , Proteínas de Fluorescência Verde/genética , Fígado/parasitologia , Microrganismos Geneticamente Modificados/genética , Microrganismos Geneticamente Modificados/fisiologia , Plasmodium cynomolgi/genética
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