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1.
PLoS Negl Trop Dis ; 16(3): e0010005, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35333880

RESUMO

BACKGROUND: Onchocerciasis ("river blindness"), is a neglected tropical disease caused by the filarial nematode Onchocerca volvulus and transmitted to humans through repeated bites by infective blackflies of the genus Simulium. Moxidectin was approved by the United States Food and Drug Administration in 2018 for the treatment of onchocerciasis in people at least 12 years of age. The pharmacokinetics of orally administered moxidectin in 18- to 60-year-old men and women infected with Onchocerca volvulus were investigated in a single-center, ivermectin-controlled, double-blind, randomized, single-ascending-dose, ascending severity of infection study in Ghana. METHODOLOGY/PRINCIPAL FINDINGS: Participants were randomized to either a single dose of 2, 4 or 8 mg moxidectin or ivermectin. Pharmacokinetic samples were collected prior to dosing and at intervals up to 12 months post-dose from 33 and 34 individuals treated with 2 and 4 mg moxidectin, respectively and up to 18 months post-dose from 31 individuals treated with 8 mg moxidectin. Moxidectin plasma concentrations were determined using high-performance liquid chromatography with fluorescence detection. Moxidectin plasma AUC0-∞ (2 mg: 26.7-31.7 days*ng/mL, 4 mg: 39.1-60.0 days*ng/mL, 8 mg: 99.5-129.0 days*ng/mL) and Cmax (2mg, 16.2 to17.3 ng/mL, 4 mg: 33.4 to 35.0 ng/mL, 8 mg: 55.7 to 74.4 ng/mL) were dose-proportional and independent of severity of infection. Maximum plasma concentrations were achieved 4 hours after drug administration. The mean terminal half-lives of moxidectin were 20.6, 17.7, and 23.3 days at the 2, 4 and 8 mg dose levels, respectively. CONCLUSION/SIGNIFICANCE: We found no relationship between severity of infection (mild, moderate or severe) and exposure parameters (AUC0-∞ and Cmax), T1/2 and Tmax for moxidectin. Tmax, volume of distribution (V/F) and oral clearance (CL/F) are similar to those in healthy volunteers from Europe. From a pharmacokinetic perspective, moxidectin is an attractive long-acting therapeutic option for the treatment of human onchocerciasis.


Assuntos
Onchocerca volvulus , Oncocercose , Simuliidae , Administração Oral , Adolescente , Adulto , Animais , Feminino , Humanos , Ivermectina/uso terapêutico , Macrolídeos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oncocercose/tratamento farmacológico , Adulto Jovem
2.
Infect Immun ; 84(8): 2175-2184, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27185785

RESUMO

It is unclear whether naturally acquired immunity to Plasmodium falciparum results from the acquisition of antibodies to multiple, diverse antigens or to fewer, highly conserved antigens. Moreover, the specific antibody functions required for malaria immunity are unknown, and hence informative immunological assays are urgently needed to address these knowledge gaps and guide vaccine development. In this study, we investigated whether merozoite-opsonizing antibodies are associated with protection from malaria in a strain-specific or strain-transcending manner by using a novel field isolate and an immune plasma-matched cohort from Papua New Guinea with our validated assay of merozoite phagocytosis. Highly correlated opsonization responses were observed across the 15 parasite strains tested, as were strong associations with protection (composite phagocytosis score across all strains in children uninfected at baseline: hazard ratio of 0.15, 95% confidence interval of 0.04 to 0.63). Opsonizing antibodies had a strong strain-transcending component, and the opsonization of transgenic parasites deficient for MSP3, MSP6, MSPDBL1, or P. falciparum MSP1-19 (PfMSP1-19) was similar to that of wild-type parasites. We have provided the first evidence that merozoite opsonization is predominantly strain transcending, and the highly consistent associations with protection against diverse parasite strains strongly supports the use of merozoite opsonization as a correlate of immunity for field studies and vaccine trials. These results demonstrate that conserved domains within merozoite antigens targeted by opsonization generate strain-transcending immune responses and represent promising vaccine candidates.


Assuntos
Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Malária Falciparum/imunologia , Malária Falciparum/parasitologia , Merozoítos/imunologia , Proteínas Opsonizantes/imunologia , Plasmodium falciparum/imunologia , Adolescente , Anticorpos Antiprotozoários/sangue , Criança , Pré-Escolar , Humanos , Malária Falciparum/sangue , Avaliação de Resultados da Assistência ao Paciente , Fagocitose/imunologia
3.
Cell Rep ; 14(1): 68-81, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26725120

RESUMO

Naturally acquired immunity to malaria develops only after years of repeated exposure to Plasmodium parasites. Despite the key role antibodies play in protection, the cellular processes underlying the slow acquisition of immunity remain unknown. Using mouse models, we show that severe malaria infection inhibits the establishment of germinal centers (GCs) in the spleen. We demonstrate that infection induces high frequencies of T follicular helper (Tfh) cell precursors but results in impaired Tfh cell differentiation. Despite high expression of Bcl-6 and IL-21, precursor Tfh cells induced during infection displayed low levels of PD-1 and CXCR5 and co-expressed Th1-associated molecules such as T-bet and CXCR3. Blockade of the inflammatory cytokines TNF and IFN-γ or T-bet deletion restored Tfh cell differentiation and GC responses to infection. Thus, this study demonstrates that the same pro-inflammatory mediators that drive severe malaria pathology have detrimental effects on the induction of protective B cell responses.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Malária/imunologia , Plasmodium/imunologia , Células Th1/imunologia , Animais , Citocinas/genética , Citocinas/imunologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Malária/genética , Camundongos , Camundongos Knockout , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Proteínas Proto-Oncogênicas c-bcl-6 , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Receptores CXCR5/genética , Receptores CXCR5/imunologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia
4.
J Immunol ; 196(3): 1227-38, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26718341

RESUMO

CXCL10, or IFN-γ-inducible protein 10, is a biomarker associated with increased risk for Plasmodium falciparum-mediated cerebral malaria (CM). Consistent with this, we have previously shown that CXCL10 neutralization or genetic deletion alleviates brain intravascular inflammation and protects Plasmodium berghei ANKA-infected mice from CM. In addition to organ-specific effects, the absence of CXCL10 during infection was also found to reduce parasite biomass. To identify the cellular sources of CXCL10 responsible for these processes, we irradiated and reconstituted wild-type (WT) and CXCL10(-/-) mice with bone marrow from either WT or CXCL10(-/-) mice. Similar to CXCL10(-/-) mice, chimeras unable to express CXCL10 in hematopoietic-derived cells controlled infection more efficiently than WT controls. In contrast, expression of CXCL10 in knockout mice reconstituted with WT bone marrow resulted in high parasite biomass levels, higher brain parasite and leukocyte sequestration rates, and increased susceptibility to CM. Neutrophils and inflammatory monocytes were identified as the main cellular sources of CXCL10 responsible for the induction of these processes. The improved control of parasitemia observed in the absence of CXCL10-mediated trafficking was associated with a preferential accumulation of CXCR3(+)CD4(+) T follicular helper cells in the spleen and enhanced Ab responses to infection. These results are consistent with the notion that some inflammatory responses elicited in response to malaria infection contribute to the development of high parasite densities involved in the induction of severe disease in target organs.


Assuntos
Quimiocina CXCL10/imunologia , Malária Cerebral/imunologia , Malária Cerebral/parasitologia , Monócitos/imunologia , Neutrófilos/imunologia , Animais , Quimiotaxia de Leucócito/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Parasitemia/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
5.
Parasitology ; 143(2): 199-207, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26743747

RESUMO

Malaria is one of the most serious infectious diseases with ~250 million clinical cases annually. Most cases of severe disease are caused by Plasmodium falciparum. The blood stage of Plasmodium parasite is entirely responsible for malaria-associated pathology. Disease syndromes range from fever to more severe complications, including respiratory distress, metabolic acidosis, renal failure, pulmonary oedema and cerebral malaria. The most susceptible population to severe malaria is children under the age of 5, with low levels of immunity. It is only after many years of repeated exposure, that individuals living in endemic areas develop clinical immunity. This form of protection does not result in sterilizing immunity but prevents clinical episodes by substantially reducing parasite burden. Naturally acquired immunity predominantly targets blood-stage parasites and it is known to require antibody responses. A large body of epidemiological evidence suggests that antibodies to Plasmodium antigens are inefficiently generated and rapidly lost in the absence of ongoing exposure, which suggests a defect in the development of B cell immunological memory. This review summarizes the main findings to date contributing to our understanding on cellular processes underlying the slow acquisition of humoral immunity to malaria. Some of the key outstanding questions in the field are discussed.


Assuntos
Interações Hospedeiro-Parasita/imunologia , Imunidade Humoral/imunologia , Malária Falciparum/imunologia , Humanos , Malária Falciparum/parasitologia
6.
PLoS One ; 9(4): e93268, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24691125

RESUMO

BACKGROUND: The Natural Killer Complex (NKC) is a genetic region of highly linked genes encoding several receptors involved in the control of NK cell function. The NKC is highly polymorphic and allelic variability of various NKC loci has been demonstrated in inbred mice, providing evidence for NKC haplotypes. Using BALB.B6-Cmv1r congenic mice, in which NKC genes from C57BL/6 mice were introduced into the BALB/c background, we have previously shown that the NKC is a genetic determinant of malarial pathogenesis. C57BL/6 alleles are associated with increased disease-susceptibility as BALB.B6-Cmv1r congenic mice had increased cerebral pathology and death rates during P. berghei ANKA infection than cerebral malaria-resistant BALB/c controls. METHODS: To investigate which regions of the NKC are involved in susceptibility to experimental cerebral malaria (ECM), intra-NKC congenic mice generated by backcrossing recombinant F2 progeny from a (BALB/c x BALB.B6-Cmv1r) F1 intercross to BALB/c mice were infected with P. berghei ANKA. RESULTS: Our results revealed that C57BL/6 alleles at two locations in the NKC contribute to the development of ECM. The increased severity to severe disease in intra-NKC congenic mice was not associated with higher parasite burdens but correlated with a significantly enhanced systemic IFN-γ response to infection and an increased recruitment of CD8+ T cells to the brain of infected animals. CONCLUSIONS: Polymorphisms within the NKC modulate malarial pathogenesis and acquired immune responses to infection.


Assuntos
Loci Gênicos , Lectinas Tipo C/genética , Malária Cerebral/genética , Receptores de Superfície Celular/genética , Alelos , Animais , Biomarcadores , Modelos Animais de Doenças , Regulação da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Interferon gama/biossíntese , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Malária Cerebral/imunologia , Malária Cerebral/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
7.
J Immunol ; 192(5): 2202-9, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-24489100

RESUMO

Although multiple dendritic cell (DC) subsets have the potential to induce Th17 differentiation in vitro, the key DC that is critical in Th17 induction and Th17-mediated disease remains moot. In this study, we revealed that CCR2(+) monocyte-derived DCs (moDCs), but not conventional DCs, were critical for in vivo Th17 induction and autoimmune inflammation. Functional comparison in vitro indicated that moDCs are the most potent type of Th17-inducing DCs compared with conventional DCs and plasmacytoid DCs. Furthermore, we demonstrated that the importance of GM-CSF in Th17 induction and Th17-mediated disease is its endowment of moDCs to induce Th17 differentiation in vivo, although it has little effect on moDC numbers. Our findings identify the in vivo cellular targets that can be selectively manipulated to ameliorate Th17-mediated inflammatory diseases, as well as the mechanism of GM-CSF antagonism in such diseases.


Assuntos
Doenças Autoimunes/imunologia , Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Monócitos/imunologia , Células Th17/imunologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/patologia , Diferenciação Celular/genética , Células Dendríticas/citologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Camundongos , Camundongos Knockout , Monócitos/citologia , Células Th17/citologia
8.
PLoS One ; 8(9): e74627, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24040299

RESUMO

Naturally acquired humoral immunity to the malarial parasite Plasmodium falciparum can protect against disease, although the precise mechanisms remain unclear. Although antibody levels can be measured by ELISA, few studies have investigated functional antibody assays in relation to clinical outcomes. In this study we applied a recently developed functional assay of antibody-mediated opsonisation of merozoites, to plasma samples from a longitudinal cohort study conducted in a malaria endemic region of Papua New Guinea (PNG). Phagocytic activity was quantified by flow cytometry using a standardized and high-throughput protocol, and was subsequently evaluated for association with protection from clinical malaria and high-density parasitemia. Opsonising antibody responses were found to: i) increase with age, ii) be enhanced by concurrent infection, and iii) correlate with protection from clinical episodes and high-density parasitemia. Stronger protective associations were observed in individuals with no detectable parasitemia at baseline. This study presents the first evidence for merozoite phagocytosis as a correlate of acquired immunity and clinical protection against P. falciparum malaria.


Assuntos
Anticorpos Antiprotozoários/sangue , Malária Falciparum/imunologia , Proteínas Opsonizantes/imunologia , Fagocitose , Adolescente , Antígenos de Protozoários/imunologia , Linhagem Celular , Criança , Pré-Escolar , Seguimentos , Humanos , Imunidade Humoral , Estudos Longitudinais , Malária Falciparum/sangue , Monócitos/parasitologia , Papua Nova Guiné , Parasitemia/sangue , Parasitemia/imunologia , Plasmodium falciparum/metabolismo , Reprodutibilidade dos Testes
9.
J Vis Exp ; (71)2013 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-23329000

RESUMO

We describe a method for isolation and characterization of adherent inflammatory cells from brain blood vessels of P. berghei ANKA-infected mice. Infection of susceptible mouse-strains with this parasite strain results in the induction of experimental cerebral malaria, a neurologic syndrome that recapitulates certain important aspects of Plasmodium falciparum-mediated severe malaria in humans. Mature forms of blood-stage malaria express parasitic proteins on the surface of the infected erythrocyte, which allows them to bind to vascular endothelial cells. This process induces obstructions in blood flow, resulting in hypoxia and haemorrhages and also stimulates the recruitment of inflammatory leukocytes to the site of parasite sequestration. Unlike other infections, i.e neutrotopic viruses, both malaria-parasitized red blood cells (pRBC) as well as associated inflammatory leukocytes remain sequestered within blood vessels rather than infiltrating the brain parenchyma. Thus to avoid contamination of sequestered leukocytes with non-inflammatory circulating cells, extensive intracardial perfusion of infected-mice prior to organ extraction and tissue processing is required in this procedure to remove the blood compartment. After perfusion, brains are harvested and dissected in small pieces. The tissue structure is further disrupted by enzymatic treatment with Collagenase D and DNAse I. The resulting brain homogenate is then centrifuged on a Percoll gradient that allows separation of brain-sequestered leukocytes (BSL) from myelin and other tissue debris. Isolated cells are then washed, counted using a hemocytometer and stained with fluorescent antibodies for subsequent analysis by flow cytometry. This procedure allows comprehensive phenotypic characterization of inflammatory leukocytes migrating to the brain in response to various stimuli, including stroke as well as viral or parasitic infections. The method also provides a useful tool for assessment of novel anti-inflammatory treatments in pre-clinical animal models.


Assuntos
Barreira Hematoencefálica/patologia , Encéfalo/cirurgia , Leucócitos/patologia , Malária/patologia , Animais , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Química Encefálica , Movimento Celular/fisiologia , Modelos Animais de Doenças , Malária/sangue , Malária/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Plasmodium berghei/isolamento & purificação
10.
Immunobiology ; 218(2): 263-71, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22704523

RESUMO

Cerebral malaria (CM) is the most severe syndrome associated with Plasmodium falciparum infections. Experimental evidence suggests that disease results from the sequestration of parasitized-red blood cells (pRBCs) together with inflammatory leukocytes within brain capillaries. We have previously shown that NK cells stimulate migration of CXCR3(+) T cells to the brain of Plasmodium berghei ANKA-infected mice. Here we investigated whether interactions between NK cells and dendritic cells (DCs) are required for the induction of T cell responses involved in disease. For that, NK cell-depleted and control mice were infected with transgenic parasites expressing model T cell epitopes. T cells from TCR transgenic mice specific for those epitopes were adoptively transferred and proliferation was determined. NK cell depletion significantly reduced CD8(+) but not CD4(+) DC-mediated T cell priming. Lack of NK cells did not compromise CD8(+) T cell responses in IL-12(-/-) mice, suggesting that NK cells stimulate IL-12 output by DCs required for optimal T cell priming. The contribution of DCs to NK cell function was also investigated. DC depletion and genetic deletion of IL-12 dramatically reduced NK cell-mediated IFN-γ responses to malaria. Thus NK cells and DCs engage in reciprocal activation for the induction of inflammatory responses involved in severe malaria.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Células Matadoras Naturais/imunologia , Malária Cerebral/imunologia , Plasmodium berghei/imunologia , Transferência Adotiva , Animais , Animais Geneticamente Modificados , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/transplante , Comunicação Celular , Células Cultivadas , Modelos Animais de Doenças , Epitopos de Linfócito T/genética , Humanos , Interferon gama/metabolismo , Interleucina-12/genética , Ativação Linfocitária/genética , Depleção Linfocítica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmodium berghei/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores CXCR3/metabolismo
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