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1.
Med Sci Monit Basic Res ; 27: e929207, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33397841

RESUMO

As of November 25, 2020, over 60 million people have been infected worldwide by COVID-19, causing almost 1.43 million deaths. Puzzling low incidence numbers and milder, non-fatal disease have been observed in Thailand and its Southeast (SE) Asian neighbors. Elusive genetic mechanisms might be operative, as a multitude of genetic factors are widely shared between the SE Asian populations, such as the more than 60 different thalassemia syndromes (principally dominated by the HbE trait). In this study, we have plotted COVID-19 infection and death rates in SE Asian (SEA) countries against heterozygote HbE and thalassemia carrier prevalence. COVID-19 infection and death incidence numbers appear inversely correlated with the prevalence of HbE and thalassemia heterozygote populations. We posit that the evolutionary protective effect of the HbE and other thalassemic variants against malaria and the dengue virus may extend its advantage to resistance to COVID-19 infection, as HbE heterozygote population prevalence appears to be positively correlated with immunity to COVID-19. Host immune system modulations induce antiviral interferon responses and alter structural protein integrity, thereby inhibiting cellular access and viral replication. These changes are possibly engendered by HbE carrier miRNAs. Proving this hypothesis is important, as it may shed light on the mechanism of viral resistance and lead to novel antiviral treatments. This development can thus guide decision-making and action to prevent COVID-19 infection.


Assuntos
/genética , Resistência à Doença/genética , Suscetibilidade a Doenças , Hemoglobina E/genética , Antivirais/uso terapêutico , Grupo com Ancestrais do Continente Asiático , /imunologia , Dengue/genética , Heterozigoto , Humanos , Sistema Imunitário , Interferons , Malária/genética , Pandemias , Prevalência , Tailândia/epidemiologia , Talassemia/epidemiologia , Talassemia/genética
2.
Pestic Biochem Physiol ; 171: 104746, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33357539

RESUMO

Anopheles sacharovi, a primer malaria vector species of Turkey, have a significant public health importance. It is aimed to determine the insecticide resistance status in Anopheles sacharovi populations in the Aegean and Mediterranean regions of Turkey. A total of 1638 individuals were analysed from 15 populations. Bioassay results indicated all An. sacharovi populations were resistant to DDT, malathion, fenitrothion, bendiocarb, propoxur. Many populations have begun to have resistance against permethrin and deltamethrin. Biochemical analyses results revealed that glutathione-S-transferases and P450 monooxygenases might be responsible from the mechanisms of DDT resistance; esterases and acetylcholinesterase might be responsible for organophosphate and carbamate resistance; P450 monooxygenases and esterases might be responsible for pyrethroid resistance into populations sampled from the study area. Allele-specific primers detected L1014F and L1014S mutations that provide kdr resistance against pyrethroids and DDT. Increased acetylcholinesterase insensitivity was detected while Ace-1 G119S mutations were not detected in An. sacharovi populations by using allele-specific primers. Overall results indicate the presence of multiple resistance mechanisms in Turkish An. sacharovi field populations suggesting that populations might gain resistance against all possible insecticide in the future. Therefore, insecticide resistance management strategies are urgently needed for effective vector control implementation.


Assuntos
Anopheles , Inseticidas , Malária , Piretrinas , Acetilcolinesterase/genética , Alelos , Animais , Anopheles/genética , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Malária/genética , Mosquitos Vetores , Mutação
3.
PLoS One ; 15(10): e0236616, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33044964

RESUMO

Asexual blood stages of the malaria parasite are readily amenable to genetic modification via homologous recombination, allowing functional studies of parasite genes that are not essential in this part of the life cycle. However, conventional reverse genetics cannot be applied for the functional analysis of genes that are essential during asexual blood-stage replication. Various strategies have been developed for conditional mutagenesis of Plasmodium, including recombinase-based gene deletion, regulatable promoters, and mRNA or protein destabilization systems. Among these, the dimerisable Cre (DiCre) recombinase system has emerged as a powerful approach for conditional gene deletion in P. falciparum. In this system, the bacteriophage Cre is expressed in the form of two separate, enzymatically inactive polypeptides, each fused to a different rapamycin-binding protein. Rapamycin-induced heterodimerization of the two components restores recombinase activity. We have implemented the DiCre system in the rodent malaria parasite P. berghei, and show that rapamycin-induced excision of floxed DNA sequences can be achieved with very high efficiency in both mammalian and mosquito parasite stages. This tool can be used to investigate the function of essential genes not only in asexual blood stages, but also in other parts of the malaria parasite life cycle.


Assuntos
Deleção de Genes , Edição de Genes , Genes de Protozoários/genética , Integrases/metabolismo , Malária/parasitologia , Mutagênese , Plasmodium berghei/genética , Animais , Feminino , Integrases/química , Integrases/genética , Estágios do Ciclo de Vida , Malária/genética , Malária/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
4.
PLoS Pathog ; 16(9): e1008891, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32956401

RESUMO

The transitions between developmental stages are critical points in the Plasmodium life cycle. The development of Plasmodium in the livers of their mammalian hosts bridges malaria transmission and the onset of clinical symptoms elicited by red blood cell infection. The egress of Plasmodium parasites from the liver must be a carefully orchestrated process to ensure a successful switch to the blood stage of infection. Cysteine protease activity is known to be required for liver-stage Plasmodium egress, but the crucial cysteine protease(s) remained unidentified. Here, we characterize a member of the papain-like cysteine protease family, Plasmodium berghei serine repeat antigen 4 (PbSERA4), that is required for efficient initiation of blood-stage infection. Through the generation PbSERA4-specific antisera and the creation of transgenic parasites expressing fluorescently tagged protein, we show that PbSERA4 is expressed and proteolytically processed in the liver and blood stages of infection. Targeted disruption of PbSERA4 results in viable and virulent blood-stage parasites. However, upon transmission from mosquitoes to mice, Pbsera4(-) parasites displayed a reduced capacity to initiate a new round of asexual blood-stage replication. Our results from cultured cells indicate that this defect results from an inability of the PbSERA4-deficient parasites to egress efficiently from infected cells at the culmination of liver-stage development. Protection against infection with wildtype P. berghei could be generated in animals in which Pbsera4(-) parasites failed to establish infection. Our findings confirm that liver-stage merozoite release is an active process and demonstrate that this parasite-encoded cysteine protease contributes to parasite escape from the liver.


Assuntos
Cisteína Proteases/metabolismo , Fígado/parasitologia , Malária/enzimologia , Plasmodium berghei/enzimologia , Proteínas de Protozoários/metabolismo , Animais , Cisteína Proteases/genética , Fígado/metabolismo , Malária/genética , Camundongos , Plasmodium berghei/genética , Proteínas de Protozoários/genética , Ratos , Ratos Sprague-Dawley
5.
PLoS Pathog ; 16(9): e1008840, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32913355

RESUMO

P. vivax-infected Retics (iRetics) express human leukocyte antigen class I (HLA-I), are recognized by CD8+ T cells and killed by granulysin (GNLY) and granzymes. However, how Plasmodium infection induces MHC-I expression on Retics is unknown. In addition, whether GNLY helps control Plasmodium infection in vivo has not been studied. Here, we examine these questions using rodent infection with the P. yoelii 17XNL strain, which has tropism for Retics. Infection with P. yoelii caused extramedullary erythropoiesis, reticulocytosis and expansion of CD8+CD44+CD62L- IFN-γ-producing T cells that form immune synapses with iRetics. We now provide evidence that MHC-I expression by iRetic is dependent on IFN-γ-induced transcription of IRF-1, MHC-I and ß2-microglobulin (ß2-m) in erythroblasts. Consistently, CTLs from infected wild type (WT) mice formed immune synapses with iRetics in an IFN-γ- and MHC-I-dependent manner. When challenged with P. yoelii 17XNL, WT mice cleared parasitemia and survived, while IFN-γ KO mice remained parasitemic and all died. ß2-m KO mice that do not express MHC-I and have virtually no CD8+ T cells had prolonged parasitemia, and 80% survived. Because mice do not express GNLY, GNLY-transgenic mice can be used to assess the in vivo importance of GNLY. Parasite clearance was accelerated in GNLY-transgenic mice and depletion of CD8+ T cells ablated the GNLY-mediated resistance to P. yoelii. Altogether, our results indicate that in addition to previously described mechanisms, IFN-γ promotes host resistance to the Retic-tropic P. yoelii 17XNL strain by promoting MHC-I expression on iRetics that become targets for CD8+ cytotoxic T lymphocytes and GNLY.


Assuntos
Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD8-Positivos/imunologia , Interferon gama/imunologia , Malária/imunologia , Plasmodium yoelii/imunologia , Animais , Antígenos de Diferenciação de Linfócitos T/genética , Linfócitos T CD8-Positivos/patologia , Interferon gama/genética , Malária/genética , Malária/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout
6.
PLoS Genet ; 16(7): e1008917, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32628663

RESUMO

Mechanisms of transcriptional control in malaria parasites are still not fully understood. The positioning patterns of G-quadruplex (G4) DNA motifs in the parasite's AT-rich genome, especially within the var gene family which encodes virulence factors, and in the vicinity of recombination hotspots, points towards a possible regulatory role of G4 in gene expression and genome stability. Here, we carried out the most comprehensive genome-wide survey, to date, of G4s in the Plasmodium falciparum genome using G4Hunter, which identifies G4 forming sequences (G4FS) considering their G-richness and G-skewness. We show an enrichment of G4FS in nucleosome-depleted regions and in the first exon of var genes, a pattern that is conserved within the closely related Laverania Plasmodium parasites. Under G4-stabilizing conditions, i.e., following treatment with pyridostatin (a high affinity G4 ligand), we show that a bona fide G4 found in the non-coding strand of var promoters modulates reporter gene expression. Furthermore, transcriptional profiling of pyridostatin-treated parasites, shows large scale perturbations, with deregulation affecting for instance the ApiAP2 family of transcription factors and genes involved in ribosome biogenesis. Overall, our study highlights G4s as important DNA secondary structures with a role in Plasmodium gene expression regulation, sub-telomeric recombination and var gene biology.


Assuntos
Quadruplex G , Malária/genética , Motivos de Nucleotídeos/genética , Plasmodium falciparum/genética , Aminoquinolinas/farmacologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Genoma/efeitos dos fármacos , Humanos , Malária/tratamento farmacológico , Malária/parasitologia , Ácidos Picolínicos/farmacologia , Plasmodium falciparum/patogenicidade , Regiões Promotoras Genéticas/genética , Ribossomos/efeitos dos fármacos , Ribossomos/genética
7.
Proc Natl Acad Sci U S A ; 117(28): 16567-16578, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32606244

RESUMO

Malaria infection induces complex and diverse immune responses. To elucidate the mechanisms underlying host-parasite interaction, we performed a genetic screen during early (24 h) Plasmodium yoelii infection in mice and identified a large number of interacting host and parasite genes/loci after transspecies expression quantitative trait locus (Ts-eQTL) analysis. We next investigated a host E3 ubiquitin ligase gene (March1) that was clustered with interferon (IFN)-stimulated genes (ISGs) based on the similarity of the genome-wide pattern of logarithm of the odds (LOD) scores (GPLS). March1 inhibits MAVS/STING/TRIF-induced type I IFN (IFN-I) signaling in vitro and in vivo. However, in malaria-infected hosts, deficiency of March1 reduces IFN-I production by activating inhibitors such as SOCS1, USP18, and TRIM24 and by altering immune cell populations. March1 deficiency increases CD86+DC (dendritic cell) populations and levels of IFN-γ and interleukin 10 (IL-10) at day 4 post infection, leading to improved host survival. T cell depletion reduces IFN-γ level and reverse the protective effects of March1 deficiency, which can also be achieved by antibody neutralization of IFN-γ. This study reveals functions of MARCH1 (membrane-associated ring-CH-type finger 1) in innate immune responses and provides potential avenues for activating antimalaria immunity and enhancing vaccine efficacy.


Assuntos
Malária/imunologia , Plasmodium yoelii/fisiologia , Linfócitos T/imunologia , Ubiquitina-Proteína Ligases/imunologia , Animais , Modelos Animais de Doenças , Feminino , Interações Hospedeiro-Parasita , Humanos , Imunidade Inata , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Malária/enzimologia , Malária/genética , Malária/parasitologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmodium yoelii/imunologia , Ubiquitina-Proteína Ligases/genética
8.
Hum Genet ; 139(6-7): 801-811, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32130487

RESUMO

Malaria has been the pre-eminent cause of early mortality in many parts of the world throughout much of the last five thousand years and, as a result, it is the strongest force for selective pressure on the human genome yet described. Around one third of the variability in the risk of severe and complicated malaria is now explained by additive host genetic effects. Many individual variants have been identified that are associated with malaria protection, but the most important all relate to the structure or function of red blood cells. They include the classical polymorphisms that cause sickle cell trait, α-thalassaemia, G6PD deficiency, and the major red cell blood group variants. More recently however, with improving technology and experimental design, others have been identified that include the Dantu blood group variant, polymorphisms in the red cell membrane protein ATP2B4, and several variants related to the immune response. Characterising how these genes confer their effects could eventually inform novel therapeutic approaches to combat malaria. Nevertheless, all together, only a small proportion of the heritable component of malaria resistance can be explained by the variants described so far, underscoring its complex genetic architecture and the need for continued research.


Assuntos
Resistência à Doença/genética , Eritrócitos/parasitologia , Genética Populacional , Interações Hospedeiro-Parasita/genética , Malária/genética , Plasmodium/patogenicidade , Polimorfismo Genético , Genoma Humano , Genética Humana , Humanos , Malária/imunologia , Malária/parasitologia
9.
Sci Adv ; 6(10): eaax6346, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32181339

RESUMO

Placental malaria (PM) is associated with severe inflammation leading to abortion, preterm delivery, and intrauterine growth restriction. Innate immunity responses play critical roles, but the mechanisms underlying placental immunopathology are still unclear. Here, we investigated the role of inflammasome activation in PM by scrutinizing human placenta samples from an endemic area and ablating inflammasome components in a PM mouse model. The reduction in birth weight in babies from infected mothers is paralleled by increased placental expression of AIM2 and NLRP3 inflammasomes. Using genetic dissection, we reveal that inflammasome activation pathways are involved in the production and detrimental action of interleukin-1ß (IL-1ß) in the infected placenta. The IL-1R pharmacological antagonist Anakinra improved pregnancy outcomes by restoring fetal growth and reducing resorption in an experimental model. These findings unveil that IL-1ß-mediated signaling is a determinant of PM pathogenesis, suggesting that IL-1R antagonists can improve clinical outcomes of malaria infection in pregnancy.


Assuntos
Inflamassomos/efeitos dos fármacos , Interleucina-1beta/imunologia , Malária Falciparum/imunologia , Malária/imunologia , Plasmodium falciparum/patogenicidade , Complicações Parasitárias na Gravidez/imunologia , Transdução de Sinais/efeitos dos fármacos , Animais , Caspase 1/genética , Caspase 1/imunologia , Linhagem Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Feminino , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Fatores Imunológicos/farmacologia , Inflamassomos/genética , Inflamassomos/imunologia , Interferon gama/genética , Interferon gama/imunologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Malária/tratamento farmacológico , Malária/genética , Malária/parasitologia , Malária Falciparum/genética , Malária Falciparum/parasitologia , Malária Falciparum/patologia , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Plasmodium berghei/imunologia , Plasmodium berghei/patogenicidade , Plasmodium falciparum/imunologia , Gravidez , Complicações Parasitárias na Gravidez/genética , Complicações Parasitárias na Gravidez/parasitologia , Complicações Parasitárias na Gravidez/prevenção & controle , Receptores de Interleucina-1/genética , Receptores de Interleucina-1/imunologia , Transdução de Sinais/imunologia , Células THP-1 , Trofoblastos/efeitos dos fármacos , Trofoblastos/imunologia , Trofoblastos/parasitologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
10.
Int J Mol Sci ; 21(4)2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32075230

RESUMO

Integration of multiple sources and data levels provides a great insight into the complex associations between human and malaria systems. In this study, a meta-analysis framework was developed based on a heterogeneous network model for integrating human-malaria protein similarities, a human protein interaction network, and a Plasmodium vivax protein interaction network. An iterative network propagation was performed on the heterogeneous network until we obtained stabilized weights. The association scores were calculated for qualifying a novel potential human-malaria protein association. This method provided a better performance compared to random experiments. After that, the stabilized network was clustered into association modules. The potential association candidates were then thoroughly analyzed by statistical enrichment analysis with protein complexes and known drug targets. The most promising target proteins were the succinate dehydrogenase protein complex in the human citrate (TCA) cycle pathway and the nicotinic acetylcholine receptor in the human central nervous system. Promising associations and potential drug targets were also provided for further studies and designs in therapeutic approaches for malaria at a systematic level. In conclusion, this method is efficient to identify new human-malaria protein associations and can be generalized to infer other types of association studies to further advance biomedical science.


Assuntos
Interações Hospedeiro-Patógeno/genética , Malária/genética , Plasmodium vivax/genética , Mapas de Interação de Proteínas/genética , Algoritmos , Animais , Humanos , Malária/parasitologia , Complexos Multiproteicos/genética , Plasmodium vivax/patogenicidade , Proteínas de Protozoários/genética , Succinato Desidrogenase/genética
11.
Malar J ; 19(1): 21, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941490

RESUMO

BACKGROUND: Multiple red blood cell (RBC) variants appear to offer protection against the most severe forms of Plasmodium falciparum malaria. Associations between these variants and uncomplicated malaria are less clear. METHODS: Data from a longitudinal cohort study conducted in 3 sub-counties in Uganda was used to quantify associations between three red blood cell variants Hb [AA, AS, S (rs334)], alpha thalassaemia 3.7 kb deletion, and glucose-6-phosphate dehydrogenase deficiency A-(G6PD 202A genotype) and malaria incidence, parasite prevalence, parasite density (a measure of anti-parasite immunity) and body temperature adjusted for parasite density (a measure of anti-disease immunity). All analyses were adjusted for age, average household entomological inoculation rate, and study site. Results for all variants were compared to those for wild type genotypes. RESULTS: In children, HbAS was associated, compared to wild type, with a lower incidence of malaria (IRR = 0.78, 95% CI 0.66-0.92, p = 0.003), lower parasite density upon infection (PR = 0.66, 95% CI 0.51-0.85, p = 0.001), and lower body temperature for any given parasite density (- 0.13 â„ƒ, 95% CI - 0.21, - 0.05, p = 0.002). In children, HbSS was associated with a lower incidence of malaria (IRR = 0.17, 95% CI 0.04-0.71, p = 0.02) and lower parasite density upon infection (PR = 0.31, 95% CI 0.18-0.54, p < 0.001). α-/αα thalassaemia, was associated with higher parasite prevalence in both children and adults (RR = 1.23, 95% CI 1.06-1.43, p = 0.008 and RR = 1.52, 95% CI 1.04-2.23, p = 0.03, respectively). G6PD deficiency was associated with lower body temperature for any given parasite density only among male hemizygote children (- 0.19 â„ƒ, 95% CI - 0.31, - 0.06, p = 0.003). CONCLUSION: RBC variants were associated with non-severe malaria outcomes. Elucidation of the mechanisms by which they confer protection will improve understanding of genetic protection against malaria.


Assuntos
Eritrócitos/citologia , Malária/sangue , Adulto , Fatores Etários , Distribuição Binomial , Cuidadores , Criança , Pré-Escolar , Estudos de Coortes , Eritrócitos/química , Eritrócitos/classificação , Feminino , Humanos , Incidência , Lactente , Estudos Longitudinais , Malária/epidemiologia , Malária/genética , Malária/parasitologia , Masculino , Parasitemia/sangue , Parasitemia/epidemiologia , Parasitemia/genética , Parasitemia/parasitologia , Prevalência , Estudos Prospectivos , Fatores Sexuais , Uganda/epidemiologia , Adulto Jovem
12.
Nat Commun ; 11(1): 473, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980600

RESUMO

A variant at amino acid 47 in human TP53 exists predominantly in individuals of African descent. P47S human and mouse cells show increased cancer risk due to defective ferroptosis. Here, we show that this ferroptotic defect causes iron accumulation in P47S macrophages. This high iron content alters macrophage cytokine profiles, leads to higher arginase level and activity, and decreased nitric oxide synthase activity. This leads to more productive intracellular bacterial infections but is protective against malarial toxin hemozoin. Proteomics of macrophages reveal decreased liver X receptor (LXR) activation, inflammation and antibacterial defense in P47S macrophages. Both iron chelators and LXR agonists improve the response of P47S mice to bacterial infection. African Americans with elevated saturated transferrin and serum ferritin show higher prevalence of the P47S variant (OR = 1.68 (95%CI 1.07-2.65) p = 0.023), suggestive of its role in iron accumulation in humans. This altered macrophage phenotype may confer an advantage in malaria-endemic sub-Saharan Africa.


Assuntos
Ferro/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , África ao Sul do Saara , Afro-Americanos/genética , Animais , Infecções Bacterianas/etiologia , Infecções Bacterianas/genética , Infecções Bacterianas/metabolismo , Ferritinas/sangue , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Ferroptose/fisiologia , Variação Genética , Hemeproteínas/toxicidade , Humanos , Listeriose/etiologia , Receptores X do Fígado/agonistas , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Malária/genética , Malária/metabolismo , Camundongos , Camundongos Transgênicos , Transferrina/metabolismo
13.
Immunol Rev ; 293(1): 115-143, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31608461

RESUMO

A century of conceptual and technological advances in infectious disease research has changed the face of medicine. However, there remains a lack of effective interventions and a poor understanding of host immunity to the most significant and complex pathogens, including malaria. The development of successful interventions against such intractable diseases requires a comprehensive understanding of host-pathogen immune responses. A major advance of the past decade has been a paradigm switch in thinking from the contemporary reductionist (gene-by-gene or protein-by-protein) view to a more holistic (whole organism) view. Also, a recognition that host-pathogen immunity is composed of complex, dynamic interactions of cellular and molecular components and networks that cannot be represented by any individual component in isolation. Systems immunology integrates the field of immunology with omics technologies and computational sciences to comprehensively interrogate the immune response at a systems level. Herein, we describe the system immunology toolkit and report recent studies deploying systems-level approaches in the context of natural exposure to malaria or controlled human malaria infection. We contribute our perspective on the potential of systems immunity for the rational design and development of effective interventions to improve global public health.


Assuntos
Interações Hospedeiro-Parasita/imunologia , Imunidade , Malária/imunologia , Plasmodium/imunologia , Animais , Biologia Computacional/métodos , Bases de Dados Factuais , Interações Hospedeiro-Parasita/genética , Humanos , Sistema Imunitário , Malária/genética , Malária/metabolismo , Malária/parasitologia , Proteogenômica/métodos , Projetos de Pesquisa , Biologia de Sistemas/métodos
14.
Immunol Rev ; 293(1): 144-162, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31680289

RESUMO

The complexity of the Plasmodium parasite and its life cycle poses a challenge to our understanding of the host immune response against malaria. Studying human immune responses during natural and experimental Plasmodium infections can enhance our understanding of malaria-protective immunity and inform the design of disease-modifying adjunctive therapies and next-generation malaria vaccines. Systems immunology can complement conventional approaches to facilitate our understanding of the complex immune response to the highly dynamic malaria parasite. In this review, recent studies that used systems-based approaches to evaluate human immune responses during natural and experimental Plasmodium falciparum and Plasmodium vivax infections as well as during immunization with candidate malaria vaccines are summarized and related to each other. The potential for next-generation technologies to address the current limitations of systems-based studies of human malaria are discussed.


Assuntos
Interações Hospedeiro-Parasita/imunologia , Malária/imunologia , Malária/parasitologia , Plasmodium/imunologia , Biologia de Sistemas , Biomarcadores , Perfilação da Expressão Gênica , Genômica/métodos , Interações Hospedeiro-Parasita/genética , Humanos , Imunidade , Malária/genética , Malária/metabolismo , Vacinas Antimaláricas/imunologia , Biologia de Sistemas/métodos
15.
J Hum Genet ; 65(2): 99-113, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31664161

RESUMO

Cyclooxygenase-2 [(COX-2) or prostaglandin endoperoxide H2 synthase-2 (PTGS-2)] induces the production of prostaglandins as part of the host-immune response to infections. Although a number of studies have demonstrated the effects of COX-2 promoter variants on autoimmune and inflammatory diseases, their role in malaria remains undefined. As such, we investigated the relationship between four COX-2 promoter variants (COX-2 -512 C > T, -608 T > C, -765 G > C, and -1195 A > G) and susceptibility to malaria and severe malarial anemia (SMA) upon enrollment and longitudinally over a 36-month follow-up period. All-cause mortality was also explored. The investigation was carried out in children (n = 1081, age; 2-70 months) residing in a holoendemic Plasmodium falciparum transmission region of western Kenya. At enrollment, genotypes/haplotypes (controlling for anemia-promoting covariates) did not reveal any strong effects on susceptibility to either malaria or SMA. Longitudinal analyses showed decreased malaria episodes in children who inherited the -608 CC mutant allele (RR = 0.746, P = 1.811 × 10-4) and -512C/-608T/-765G/-1195G (CTGG) haplotype (RR = 0.856, P = 0.011), and increased risk in TTCA haplotype carriers (RR = 1.115, P = 0.026). Over the follow-up period, inheritance of the rare TTCG haplotype was associated with enhanced susceptibility to both malaria (RR = 1.608, P = 0.016) and SMA (RR = 5.714, P = 0.004), while carriage of the rare TTGG haplotype increased the risk of malaria (RR = 1.755, P = 0.007), SMA (RR = 8.706, P = 3.97 × 10-4), and all-cause mortality (HR = 110.000, P = 0.001). Collectively, these results show that SNP variations in the COX-2 promoter, and their inherited combinations, are associated with the longitudinal risk of malaria, SMA, and all-cause mortality among children living in a high transmission area for P. falciparum.


Assuntos
Anemia/genética , Ciclo-Oxigenase 2/genética , Malária Falciparum/genética , Malária/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Anemia/mortalidade , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Lactente , Quênia , Estudos Longitudinais , Malária/imunologia , Malária/mortalidade , Malária/transmissão , Malária Falciparum/imunologia , Malária Falciparum/mortalidade , Malária Falciparum/transmissão , Masculino , Risco
16.
Immunol Rev ; 293(1): 25-37, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31762040

RESUMO

Natural killer cells employ a diverse arsenal of effector mechanisms to target intracellular pathogens. Differentiation of natural killer (NK) cell activation pathways occurs along a continuum from reliance on innate pro-inflammatory cytokines and stress-induced host ligands through to interaction with signals derived from acquired immune responses. Importantly, the degree of functional differentiation of the NK cell lineage influences the magnitude and specificity of interactions with host cells infected with viruses, bacteria, fungi, and parasites. Individual humans possess a vast diversity of distinct NK cell clones, each with the capacity to vary along this functional differentiation pathway, which - when combined - results in unique individual responses to different infections. Here we summarize these NK cell differentiation events, review evidence for direct interaction of malaria-infected host cells with NK cells and assess how innate inflammatory signals induced by malaria parasite-associated molecular patterns influence the indirect activation and function of NK cells. Finally, we discuss evidence that anti-malarial immunity develops in parallel with advancing NK differentiation, coincident with a loss of reliance on inflammatory signals, and a refined capacity of NK cells to target malaria parasites more precisely, particularly through antibody-dependent mechanisms.


Assuntos
Adaptação Fisiológica/imunologia , Diferenciação Celular/imunologia , Interações Hospedeiro-Parasita/imunologia , Células Matadoras Naturais/imunologia , Malária/imunologia , Malária/parasitologia , Plasmodium/imunologia , Imunidade Adaptativa , Animais , Biomarcadores , Diferenciação Celular/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Interação Gene-Ambiente , Interações Hospedeiro-Parasita/genética , Humanos , Imunidade Inata , Mediadores da Inflamação/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Malária/genética , Malária/metabolismo , Plasmodium falciparum/imunologia
17.
Immunol Rev ; 293(1): 8-24, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31840836

RESUMO

Monocytes are innate immune cells essential for host protection against malaria. Upon activation, monocytes function to help reduce parasite burden through phagocytosis, cytokine production, and antigen presentation. However, monocytes have also been implicated in the pathogenesis of severe disease through production of damaging inflammatory cytokines, resulting in systemic inflammation and vascular dysfunction. Understanding the molecular pathways influencing the balance between protection and pathology is critical. In this review, we discuss recent data regarding the role of monocytes in human malaria, including studies of innate sensing of the parasite, immunometabolism, and innate immune training. Knowledge gained from these studies may guide rational development of novel antimalarial therapies and inform vaccine development.


Assuntos
Interações Hospedeiro-Parasita/imunologia , Imunidade Inata , Malária/imunologia , Malária/parasitologia , Monócitos/imunologia , Plasmodium/imunologia , Biomarcadores , Citocinas/metabolismo , Metabolismo Energético , Epigênese Genética , Feminino , Interações Hospedeiro-Parasita/genética , Humanos , Tolerância Imunológica , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Contagem de Leucócitos , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/parasitologia , Malária/genética , Malária/metabolismo , Monócitos/metabolismo , Especificidade de Órgãos , Fagocitose/imunologia , Gravidez , Complicações Parasitárias na Gravidez
18.
Genet Epidemiol ; 44(2): 197-207, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31820489

RESUMO

Genetic association studies are popular for identifying genetic variants, such as single nucleotide polymorphisms (SNPs), that are associated with complex traits. Statistical tests are commonly performed one SNP at a time with an assumed mode of inheritance such as recessive, additive, or dominant genetic model. Such analysis can result in inadequate power when the employed model deviates from the underlying true genetic model. We propose an integrative association test procedure under a generalized linear model framework to flexibly model the data from the above three common genetic models and beyond. A computationally efficient resampling procedure is adopted to estimate the null distribution of the proposed test statistic. Simulation results show that our methods maintain the Type I error rate irrespective of the existence of confounding covariates and achieve adequate power compared to the methods with the true genetic model. The new methods are applied to two genetic studies on the resistance of severe malaria and sarcoidosis.


Assuntos
Estudos de Associação Genética , Testes Genéticos , Característica Quantitativa Herdável , Estudos de Casos e Controles , Simulação por Computador , Intervalos de Confiança , Predisposição Genética para Doença , Humanos , Padrões de Herança/genética , Malária/genética , Modelos Genéticos , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único/genética
19.
PLoS Genet ; 15(12): e1008440, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31856182

RESUMO

Small laboratory cage trials of non-drive and gene-drive strains of the Asian malaria vector mosquito, Anopheles stephensi, were used to investigate release ratios and other strain properties for their impact on transgene spread during simulated population modification. We evaluated the effects of transgenes on survival, male contributions to next-generation populations, female reproductive success and the impact of accumulation of gene drive-resistant genomic target sites resulting from nonhomologous end-joining (NHEJ) mutagenesis during Cas9, guide RNA-mediated cleavage. Experiments with a non-drive, autosomally-linked malaria-resistance gene cassette showed 'full introduction' (100% of the insects have at least one copy of the transgene) within 8 weeks (≤ 3 generations) following weekly releases of 10:1 transgenic:wild-type males in an overlapping generation trial design. Male release ratios of 1:1 resulted in cages where mosquitoes with at least one copy of the transgene fluctuated around 50%. In comparison, two of three cages in which the malaria-resistance genes were linked to a gene-drive system in an overlapping generation, single 1:1 release reached full introduction in 6-8 generations with a third cage at ~80% within the same time. Release ratios of 0.1:1 failed to establish the transgenes. A non-overlapping generation, single-release trial of the same gene-drive strain resulted in two of three cages reaching 100% introduction within 6-12 generations following a 1:1 transgenic:wild-type male release. Two of three cages with 0.33:1 transgenic:wild-type male single releases achieved full introduction in 13-16 generations. All populations exhibiting full introduction went extinct within three generations due to a significant load on females having disruptions of both copies of the target gene, kynurenine hydroxylase. While repeated releases of high-ratio (10:1) non-drive constructs could achieve full introduction, results from the 1:1 release ratios across all experimental designs favor the use of gene drive, both for efficiency and anticipated cost of the control programs.


Assuntos
Anopheles/fisiologia , Malária/prevenção & controle , Transgenes , Animais , Animais Geneticamente Modificados , Anopheles/genética , Feminino , Genética Populacional , Abrigo para Animais , Malária/genética , Masculino , Mosquitos Vetores/genética , Mosquitos Vetores/fisiologia , Fenótipo , Comportamento Sexual Animal
20.
PLoS One ; 14(12): e0224610, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31869339

RESUMO

Malaria is an infectious disease of major worldwide clinical importance that causes a variety of severe, or complicated, syndromes including cerebral malaria, which is often fatal. Leukocyte integrins are essential for host defense but also mediate physiologic responses of the innate and adaptive immune systems. We previously showed that targeted deletion of the αD subunit (αD-/-) of the αDß2 integrin, which is expressed on key leukocyte subsets in mice and humans, leads to absent expression of the integrin heterodimer on murine macrophages and reduces mortality in mice infected with Plasmodium berghei ANKA (P. berghei ANKA). To further identify mechanisms involved in the protective effect of αD deletion in this model of severe malaria we examined wild type C57BL/6 (WT) and αD-/- mice after P. berghei ANKA infection and found that vessel plugging and leukocyte infiltration were significantly decreased in the brains of αD-/- animals. Intravital microscopy demonstrated decreased rolling and adhesion of leukocytes in cerebral vessels of αD-/- mice. Flow cytometry analysis showed decreased T-lymphocyte accumulation in the brains of infected αD-/- animals. Evans blue dye exclusion assays demonstrated significantly less dye extravasation in the brains of αD-/- mice, indicating preserved blood-brain barrier integrity. WT mice that were salvaged from P. berghei ANKA infection by treatment with chloroquine had impaired aversive memory, which was not observed in αD-/- mice. We conclude that deletion of integrin αDß2 alters the natural course of experimental severe malaria, demonstrating previously unrecognized activities of a key leukocyte integrin in immune-inflammatory responses that mediate cerebral involvement.


Assuntos
Antígenos CD11/metabolismo , Cadeias alfa de Integrinas/metabolismo , Malária/fisiopatologia , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Edema Encefálico/metabolismo , Edema Encefálico/fisiopatologia , Antígenos CD11/fisiologia , Cloroquina/metabolismo , Modelos Animais de Doenças , Inflamação/metabolismo , Cadeias alfa de Integrinas/fisiologia , Integrinas/imunologia , Integrinas/metabolismo , Contagem de Leucócitos , Leucócitos/metabolismo , Leucócitos/fisiologia , Macrófagos/metabolismo , Malária/genética , Malária Cerebral/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasmodium berghei/metabolismo
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