RESUMEN
The 1990s saw the rapid reemergence of malaria in Amazonia, where it remains an important public health priority in South America. The Amazonian International Center of Excellence in Malaria Research (ICEMR) was designed to take a multidisciplinary approach toward identifying novel malaria control and elimination strategies. Based on geographically and epidemiologically distinct sites in the Northeastern Peruvian and Western Brazilian Amazon regions, synergistic projects integrate malaria epidemiology, vector biology, and immunology. The Amazonian ICEMR's overarching goal is to understand how human behavior and other sociodemographic features of human reservoirs of transmission-predominantly asymptomatically parasitemic people-interact with the major Amazonian malaria vector, Nyssorhynchus (formerly Anopheles) darlingi, and with human immune responses to maintain malaria resilience and continued endemicity in a hypoendemic setting. Here, we will review Amazonian ICEMR's achievements on the synergies among malaria epidemiology, Plasmodium-vector interactions, and immune response, and how those provide a roadmap for further research, and, most importantly, point toward how to achieve malaria control and elimination in the Americas.
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Anopheles , Malaria , Animales , Anopheles/fisiología , Biología , Brasil/epidemiología , Humanos , Malaria/epidemiología , Malaria/prevención & control , Mosquitos Vectores/fisiología , Perú/epidemiologíaRESUMEN
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RESUMEN
Earlier studies indicate that either the canonical or non-canonical pathways of inflammasome activation have a limited role on malaria pathogenesis. Here, we report that caspase-8 is a central mediator of systemic inflammation, septic shock in the Plasmodium chabaudi-infected mice and the P. berghei-induced experimental cerebral malaria (ECM). Importantly, our results indicate that the combined deficiencies of caspases-8/1/11 or caspase-8/gasdermin-D (GSDM-D) renders mice impaired to produce both TNFα and IL-1ß and highly resistant to lethality in these models, disclosing a complementary, but independent role of caspase-8 and caspases-1/11/GSDM-D in the pathogenesis of malaria. Further, we find that monocytes from malaria patients express active caspases-1, -4 and -8 suggesting that these inflammatory caspases may also play a role in the pathogenesis of human disease.
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Caspasa 8/metabolismo , Inflamación/patología , Malaria Cerebral/enzimología , Animales , Encéfalo/patología , Caspasa 1/metabolismo , Células Dendríticas/metabolismo , Activación Enzimática , Matriz Extracelular/metabolismo , Regulación de la Expresión Génica , Humanos , Interferón gamma/metabolismo , Interleucina-1beta/metabolismo , Lipopolisacáridos , Malaria Cerebral/genética , Ratones Endogámicos C57BL , Monocitos/metabolismo , Plasmodium chabaudi/fisiología , Bazo/metabolismo , Receptores Toll-Like/metabolismoRESUMEN
Plasmodium vivax infection, the predominant cause of malaria in Asia and Latin America, affects ~14 million individuals annually, with considerable adverse effects on wellbeing and socioeconomic development. A clinical hallmark of Plasmodium infection, the paroxysm, is driven by pyrogenic cytokines produced during the immune response. Here, we review studies on the role of specific immune cell types, cognate innate immune receptors, and inflammatory cytokines on parasite control and disease symptoms. This review also summarizes studies on recurrent infections in individuals living in endemic regions as well as asymptomatic infections, a serious barrier to eliminating this disease. We propose potential mechanisms behind these repeated and subclinical infections, such as poor induction of immunological memory cells and inefficient T effector cells. We address the role of antibody-mediated resistance to P. vivax infection and discuss current progress in vaccine development. Finally, we review immunoregulatory mechanisms, such as inhibitory receptors, T regulatory cells, and the anti-inflammatory cytokine, IL-10, that antagonizes both innate and acquired immune responses, interfering with the development of protective immunity and parasite clearance. These studies provide new insights for the clinical management of symptomatic as well as asymptomatic individuals and the development of an efficacious vaccine for vivax malaria.
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Interacciones Huésped-Parásitos/inmunología , Inmunidad , Malaria Vivax/inmunología , Malaria Vivax/parasitología , Plasmodium vivax/fisiología , Inmunidad Adaptativa , Anticuerpos Antiprotozoarios/inmunología , Antígenos de Protozoos/inmunología , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Interacciones Huésped-Parásitos/genética , Humanos , Inmunidad Innata , Mediadores de Inflamación/metabolismo , Vacunas contra la Malaria/inmunología , Malaria Vivax/genética , Malaria Vivax/metabolismo , Plasmodium vivax/crecimiento & desarrollo , Receptores Toll-Like/metabolismoRESUMEN
UNLABELLED: High levels of circulating immunocomplexes (ICs) are found in patients with either infectious or sterile inflammation. We report that patients with either Plasmodium falciparum or Plasmodium vivax malaria have increased levels of circulating anti-DNA antibodies and ICs containing parasite DNA. Upon stimulation with malaria-induced ICs, monocytes express an NF-κB transcriptional signature. The main source of IC-induced proinflammatory cytokines (i.e., tumor necrosis factor alpha [TNF-α] and interleukin-1ß [IL-1ß])in peripheral blood mononuclear cells from acute malaria patients was found to be a CD14(+) CD16 (FcγRIIIA)(+) CD64 (FcγRI)(high) CD32 (FcγRIIB)(low) monocyte subset. Monocytes from convalescent patients were predominantly of the classical phenotype (CD14(+) CD16(-)) that produces high levels of IL-10 and lower levels of TNF-α and IL-1ß in response to ICs. Finally, we report a novel role for the proinflammatory activity of ICs by demonstrating their ability to induce inflammasome assembly and caspase-1 activation in human monocytes. These findings illuminate our understanding of the pathogenic role of ICs and monocyte subsets and may be relevant for future development of immunity-based interventions with broad applications to systemic inflammatory diseases. IMPORTANCE: Every year, there are approximately 200 million cases of Plasmodium falciparum and P. vivax malaria, resulting in nearly 1 million deaths, most of which are children. Decades of research on malaria pathogenesis have established that the clinical manifestations are often a consequence of the systemic inflammation elicited by the parasite. Recent studies indicate that parasite DNA is a main proinflammatory component during infection with different Plasmodium species. This finding resembles the mechanism of disease in systemic lupus erythematosus, where host DNA plays a central role in stimulating an inflammatory process and self-damaging reactions. In this study, we disclose the mechanism by which ICs containing Plasmodium DNA activate innate immune cells and consequently stimulate systemic inflammation during acute episodes of malaria. Our results further suggest that Toll-like receptors and inflammasomes have a central role in malaria pathogenesis and provide new insights toward developing novel therapeutic interventions for this devastating disease.
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Complejo Antígeno-Anticuerpo/metabolismo , Citocinas/metabolismo , ADN Protozoario/inmunología , Inflamasomas/metabolismo , Malaria Falciparum/patología , Malaria Vivax/patología , Monocitos/metabolismo , Complejo Antígeno-Anticuerpo/sangre , Antígenos CD/análisis , Humanos , Inmunofenotipificación , Malaria Falciparum/inmunología , Malaria Vivax/inmunología , Monocitos/química , Multimerización de ProteínaRESUMEN
Infection with Plasmodium vivax results in strong activation of monocytes, which are important components of both the systemic inflammatory response and parasite control. The overall goal of this study was to define the role of monocytes during P. vivax malaria. Here, we demonstrate that P. vivax-infected patients display significant increase in circulating monocytes, which were defined as CD14(+)CD16- (classical), CD14(+)CD16(+) (inflammatory), and CD14loCD16(+) (patrolling) cells. While the classical and inflammatory monocytes were found to be the primary source of pro-inflammatory cytokines, the CD16(+) cells, in particular the CD14(+)CD16(+) monocytes, expressed the highest levels of activation markers, which included chemokine receptors and adhesion molecules. Morphologically, CD14(+) were distinguished from CD14lo monocytes by displaying larger and more active mitochondria. CD14(+)CD16(+) monocytes were more efficient in phagocytizing P. vivax-infected reticulocytes, which induced them to produce high levels of intracellular TNF-α and reactive oxygen species. Importantly, antibodies specific for ICAM-1, PECAM-1 or LFA-1 efficiently blocked the phagocytosis of infected reticulocytes by monocytes. Hence, our results provide key information on the mechanism by which CD14(+)CD16(+) cells control parasite burden, supporting the hypothesis that they play a role in resistance to P. vivax infection.
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Eritrocitos/inmunología , Inflamación/inmunología , Receptores de Lipopolisacáridos/inmunología , Malaria Vivax/inmunología , Mitocondrias/inmunología , Monocitos/inmunología , Plasmodium vivax/inmunología , Receptores de IgG/inmunología , Enfermedad Aguda , Adolescente , Adulto , Anciano , Femenino , Citometría de Flujo , Humanos , Inmunofenotipificación , Malaria Vivax/metabolismo , Malaria Vivax/parasitología , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , Mitocondrias/patología , Monocitos/metabolismo , Monocitos/parasitología , Fagocitosis , Especies Reactivas de Oxígeno/metabolismo , Adulto JovenRESUMEN
Excessive release of proinflammatory cytokines by innate immune cells is an important component of the pathogenic basis of malaria. Proinflammatory cytokines are a direct output of Toll-like receptor (TLR) activation during microbial infection. Thus, interference with TLR function is likely to render a better clinical outcome by preventing their aberrant activation and the excessive release of inflammatory mediators. Herein, we describe the protective effect and mechanism of action of E6446, a synthetic antagonist of nucleic acid-sensing TLRs, on experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA. We show that in vitro, low doses of E6446 specifically inhibited the activation of human and mouse TLR9. Tenfold higher concentrations of this compound also inhibited the human TLR8 response to single-stranded RNA. In vivo, therapy with E6446 diminished the activation of TLR9 and prevented the exacerbated cytokine response observed during acute Plasmodium infection. Furthermore, severe signs of ECM, such as limb paralysis, brain vascular leak, and death, were all prevented by oral treatment with E6446. Hence, we provide evidence that supports the involvement of nucleic acid-sensing TLRs in malaria pathogenesis and that interference with the activation of these receptors is a promising strategy to prevent deleterious inflammatory responses that mediate pathogenesis and severity of malaria.
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Hidrocarburos Aromáticos/farmacología , Malaria Cerebral/prevención & control , Malaria Cerebral/terapia , Ácidos Nucleicos/metabolismo , Receptores Toll-Like/antagonistas & inhibidores , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/patología , Humanos , Hidrocarburos Aromáticos/química , Inflamación/complicaciones , Inflamación/patología , Lipopolisacáridos/farmacología , Malaria Cerebral/inducido químicamente , Malaria Cerebral/parasitología , Ratones , Ratones Endogámicos C57BL , Plasmodium chabaudi/efectos de los fármacos , Plasmodium chabaudi/fisiología , Choque Séptico/inducido químicamente , Choque Séptico/complicaciones , Receptores Toll-Like/metabolismoRESUMEN
Malaria-induced sepsis is associated with an intense proinflammatory cytokinemia for which the underlying mechanisms are poorly understood. It has been demonstrated that experimental infection of humans with Plasmodium falciparum primes Toll-like receptor (TLR)-mediated proinflammatory responses. Nevertheless, the relevance of this phenomenon during natural infection and, more importantly, the mechanisms by which malaria mediates TLR hyperresponsiveness are unclear. Here we show that TLR responses are boosted in febrile patients during natural infection with P. falciparum. Microarray analyses demonstrated that an extraordinary percentage of the up-regulated genes, including genes involving TLR signaling, had sites for IFN-inducible transcription factors. To further define the mechanism involved in malaria-mediated "priming," we infected mice with Plasmodium chabaudi. The human data were remarkably predictive of what we observed in the rodent malaria model. Malaria-induced priming of TLR responses correlated with increased expression of TLR mRNA in a TLR9-, MyD88-, and IFNgamma-dependent manner. Acutely infected WT mice were highly susceptible to LPS-induced lethality while TLR9(-/-), IL12(-/-) and to a greater extent, IFNgamma(-/-) mice were protected. Our data provide unprecedented evidence that TLR9 and MyD88 are essential to initiate IL12 and IFNgamma responses and favor host hyperresponsiveness to TLR agonists resulting in overproduction of proinflammatory cytokines and the sepsis-like symptoms of acute malaria.
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Inmunidad Innata , Interferón gamma/inmunología , Interleucina-12/inmunología , Malaria/inmunología , Factor 88 de Diferenciación Mieloide/inmunología , Receptores Toll-Like/inmunología , Animales , Citocinas , Fiebre , Perfilación de la Expresión Génica , Humanos , Inflamación , Ratones , Plasmodium chabaudi , Plasmodium falciparum , Sepsis/parasitología , Sepsis/patología , Receptor Toll-Like 9/inmunología , Receptores Toll-Like/genética , Factores de Transcripción , Regulación hacia Arriba/genéticaRESUMEN
TLR9 is critical in parasite recognition and host resistance to experimental infection with Trypanosoma cruzi. However, no information is available regarding nucleotide sequences and cellular events involved on T. cruzi recognition by TLR9. In silico wide analysis associated with in vitro screening of synthetic oligonucleotides demonstrates that the retrotransposon VIPER elements and mucin-like glycoprotein (TcMUC) genes in the T. cruzi genome are highly enriched for CpG motifs that are immunostimulatory for mouse and human TLR9, respectively. Importantly, infection with T. cruzi triggers high levels of luciferase activity under NF-kappaB-dependent transcription in HEK cells cotransfected with human TLR9, but not in control (cotransfected with human MD2/TLR4) HEK cells. Further, we observed translocation of TLR9 to the lysosomes during invasion/uptake of T. cruzi parasites by dendritic cells. Consistently, potent proinflammatory activity was observed when highly unmethylated T. cruzi genomic DNA was delivered to the endo-lysosomal compartment of host cells expressing TLR9. Thus, together our results indicate that the unmethylated CpG motifs found in the T. cruzi genome are likely to be main parasite targets and probably become available to TLR9 when parasites are destroyed in the lysosome-fused vacuoles during parasite invasion/uptake by phagocytes.
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Células Dendríticas/inmunología , Células Dendríticas/parasitología , Lisosomas/inmunología , FN-kappa B/metabolismo , Receptor Toll-Like 9/metabolismo , Trypanosoma cruzi/inmunología , Animales , Línea Celular , Islas de CpG/inmunología , Células Dendríticas/citología , Interacciones Huésped-Parásitos , Humanos , Lisosomas/parasitología , Ratones , Ratones Noqueados , FN-kappa B/inmunología , Oligodesoxirribonucleótidos/inmunología , Retroelementos , Receptor Toll-Like 9/inmunología , Trypanosoma cruzi/genéticaRESUMEN
We investigated the role of different TLRs and MyD88 in host resistance to infection and malaria pathogenesis. TLR2(-/-), TLR4(-/-), TLR6(-/-), TLR9(-/-) or CD14(-/-) mice showed no change in phenotypes (parasitemia, body weight and temperature) when infected with Plasmodium chabaudi chabaudi (AS). MyD88(-/-) mice displayed comparable ability to wild type animals in controlling and clearing parasitemia. Importantly, MyD88(-/-) mice exhibited impaired production of TNF-alpha and IFN-gamma as well as attenuated symptoms, as indicated by changes in body weight and temperature during parasitemia. Consistently, CD11b(+) monocytes and CD11c(+) dendritic cells from infected MyD88(-/-) mice were shown impaired for production of pro-inflammatory cytokines, and in initiating CD4(+) T cell responses. Importantly, the inhibition of T cell activation with anti-CD134L, mostly inhibited IFN-gamma, partially inhibited TNF-alpha production, and protected the animals from malaria symptoms. Our findings suggest that MyD88 and possibly its associated TLRs expressed by dendritic cells play an important role in pro-inflammatory responses, T cell activation, and pathogenesis of malaria, but are not critical for the immunological control of the erythrocytic stage of P. chabaudi.
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Linfocitos T CD4-Positivos/inmunología , Células Dendríticas/inmunología , Malaria/inmunología , Factor 88 de Diferenciación Mieloide/inmunología , Plasmodium chabaudi/inmunología , Receptores Toll-Like/inmunología , Animales , Citocinas/inmunología , Citometría de Flujo , Inmunofenotipificación , Activación de Linfocitos/inmunología , Malaria/parasitología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Parasitemia/inmunología , Bazo/inmunologíaRESUMEN
TLRs function as pattern recognition receptors in mammals and play an essential role in the recognition of microbial components. We found that the injection of glycoinositolphospholipids (GIPLs) from Trypanosoma cruzi into the peritoneal cavity of mice induced neutrophil recruitment in a TLR4-dependent manner: the injection of GIPL in the TLR4-deficient strain of mice (C57BL/10ScCr) caused no inflammatory response. In contrast, in TLR2 knockout mice, neutrophil chemoattraction did not differ significantly from that seen in wild-type controls. GIPL-induced neutrophil attraction and MIP-2 production were also severely affected in TLR4-mutant C3H/HeJ mice. The role of TLR4 was confirmed in vitro by testing genetically engineered mutants derived from TLR2-deficient Chinese hamster ovary (CHO)-K1 fibroblasts that were transfected with CD14 (CHO/CD14). Wild-type CHO/CD14 cells express the hamster TLR4 molecule and the mutant line, in addition, expresses a nonfunctional form of MD-2. In comparison to wild-type cells, mutant CHO/CD14 cells failed to respond to GIPLs, indicating a necessity for a functional TLR4/MD-2 complex in GIPL-induced NF-kappaB activation. Finally, we found that TLR4-mutant mice were hypersusceptible to T. cruzi infection, as evidenced by a higher parasitemia and earlier mortality. These results demonstrate that natural resistance to T. cruzi is TLR4 dependent, most likely due to TLR4 recognition of their GIPLs.