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1.
Function (Oxf) ; 5(3): zqae009, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38706961

RESUMO

Global prevalence of hypertension is on the rise, burdening healthcare, especially in developing countries where infectious diseases, such as malaria, are also rampant. Whether hypertension could predispose or increase susceptibility to malaria, however, has not been extensively explored. Previously, we reported that hypertension is associated with abnormal red blood cell (RBC) physiology and anemia. Since RBC are target host cells for malarial parasite, Plasmodium, we hypothesized that hypertensive patients with abnormal RBC physiology are at greater risk or susceptibility to Plasmodium infection. To test this hypothesis, normotensive (BPN/3J) and hypertensive (BPH/2J) mice were characterized for their RBC physiology and subsequently infected with Plasmodium yoelii (P. yoelii), a murine-specific non-lethal strain. When compared to BPN mice, BPH mice displayed microcytic anemia with RBC highly resistant to osmotic hemolysis. Further, BPH RBC exhibited greater membrane rigidity and an altered lipid composition, as evidenced by higher levels of phospholipids and saturated fatty acid, such as stearate (C18:0), along with lower levels of polyunsaturated fatty acid like arachidonate (C20:4). Moreover, BPH mice had significantly greater circulating Ter119+ CD71+ reticulocytes, or immature RBC, prone to P. yoelii infection. Upon infection with P. yoelii, BPH mice experienced significant body weight loss accompanied by sustained parasitemia, indices of anemia, and substantial increase in systemic pro-inflammatory mediators, compared to BPN mice, indicating that BPH mice were incompetent to clear P. yoelii infection. Collectively, these data demonstrate that aberrant RBC physiology observed in hypertensive BPH mice contributes to an increased susceptibility to P. yoelii infection and malaria-associated pathology.


Assuntos
Eritrócitos , Hipertensão , Malária , Plasmodium yoelii , Animais , Malária/imunologia , Malária/parasitologia , Malária/complicações , Malária/sangue , Malária/fisiopatologia , Camundongos , Eritrócitos/parasitologia , Eritrócitos/metabolismo , Suscetibilidade a Doenças , Masculino , Anemia/parasitologia , Modelos Animais de Doenças , Hemólise
2.
Am J Cardiol ; 165: 116-123, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-34906368

RESUMO

Studies have proposed that malaria may lead to electrocardiographic (ECG) changes and pericardial inflammation. We aimed to investigate the frequency of ECG alterations, determined by ECG and Holter monitoring, and pericardial effusion in patients with malaria infection. We performed a prospective observational study of adult patients with uncomplicated malaria in Amazonas, Brazil. Peripheral blood smears, ECG, and bedside echocardiography were conducted before antimalarial treatment and repeated at follow-up after completed treatment. We evaluated the diagnostic value of PR-segment depression, PR-segment elevation, and Spodick's sign for detecting pericardial effusion. A subset of patients underwent Holter monitoring at baseline. Among 98 cases of uncomplicated malaria (55% men; mean age 40 years; median parasite density 1,774/µl), 75 had Plasmodium vivax, 22 Plasmodium falciparum, and 1 had mixed infection. At baseline, 17% (n = 17) had PR-segment depression, 12% (n = 12) PR-segment elevation, 3% (n = 2) Spodick's sign, and the prevalence of pericardial effusion was 9% (n = 9). ECG alterations had sensitivities of 22% to 89% and specificities of 88% to 100% for detecting pericardial effusion at baseline. PR-segment depression had the best accuracy (sensitivity 89%, specificity 90%). Of the 25 patients, 4 patients who did not have pericardial effusion, displayed nonsustained ventricular tachycardia, determined by Holter monitoring (median duration 43 hours). Follow-up examination data were obtained for 71 patients (median 31 days), for whom PR-segment depression, elevation, and pericardial effusion had reduced significantly (p <0.05). In conclusion, our findings suggest that ECG alterations may be useful to detect pericardial effusion in malaria and that these findings decrease after completed antimalarial treatment.


Assuntos
Eletrocardiografia , Malária/fisiopatologia , Derrame Pericárdico/epidemiologia , Taquicardia Ventricular/epidemiologia , Adulto , Antimaláricos/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Brasil/epidemiologia , Estudos de Casos e Controles , Cloroquina/uso terapêutico , Eletrocardiografia Ambulatorial , Feminino , Humanos , Malária/complicações , Malária/tratamento farmacológico , Malária Falciparum/complicações , Malária Falciparum/tratamento farmacológico , Malária Falciparum/fisiopatologia , Malária Vivax/complicações , Malária Vivax/tratamento farmacológico , Malária Vivax/fisiopatologia , Masculino , Pessoa de Meia-Idade , Derrame Pericárdico/diagnóstico , Derrame Pericárdico/etiologia , Derrame Pericárdico/fisiopatologia , Primaquina/uso terapêutico , Estudos Prospectivos , Sensibilidade e Especificidade , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/fisiopatologia
3.
PLoS One ; 16(10): e0258491, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34644348

RESUMO

Mastitis is an inflammation of the mammary gland in the breast and is typically due to bacterial infection. In malaria-endemic areas, mastitis with accompanying fever can be challenging to differentiate from malaria. At the same time, it is unclear whether malaria infection is directly involved in the development of mastitis. In the present study, whether mastitis develops during infection with malaria parasites was investigated using a rodent malaria model with Plasmodium berghei (P. berghei; Pb) ANKA. The course of parasitemia in postpartum mice infected with Pb ANKA was similar to the course in infected virgin mice. However, infected postpartum mice died earlier than did infected virgin mice. In addition, the weight of pups from mice infected with Pb ANKA was significantly reduced compared with pups from uninfected mice. The macroscopic and histological analyses showed apparent changes, such as destruction of the alveolus wall and extensive presence of leukocytes, in mammary gland tissue in mice infected during the postpartum period. The findings suggest that women during the postpartum period are more vulnerable to complications when infected with malaria parasites, particularly women who do not acquire protective immunity against malaria parasites. Based on the proteomic analysis, IFN-γ signaling pathway-related proteins in mammary gland tissue of the infected postpartum mice were increased. Our results indicate that inflammation induced by IFN-γ, a proinflammatory cytokine, may contribute to negative histological changes in mammary gland tissue of postpartum mice infected with Pb ANKA. In IFN-γ receptor 1-deficient (IFNGR1-KO) mice, the histological changes in mammary gland tissue of the infected postpartum wild-type mice were improved to almost normal mammary gland structure. Furthermore, weight loss in pups delivered by infected IFNGR1-KO postpartum mice was not observed. Taken together, these findings indicate that inflammation induced by IFN-γ is associated with development of mastitis in postpartum mice infected with Pb ANKA. The present study results may increase our understanding of how disease aggravation occurs during postpartum malaria.


Assuntos
Malária/patologia , Glândulas Mamárias Animais/metabolismo , Animais , Modelos Animais de Doenças , Eritrócitos/parasitologia , Eritrócitos/patologia , Feminino , Interferon gama/metabolismo , Malária/fisiopatologia , Glândulas Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptídeos/análise , Plasmodium berghei/patogenicidade , Período Pós-Parto , Gravidez , Proteômica , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Transdução de Sinais/genética , Regulação para Cima , Receptor de Interferon gama
4.
PLoS Med ; 18(9): e1003701, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34582452

RESUMO

BACKGROUND: Annually 125 million pregnancies are at risk of malaria infection. However, the impact of exposure to malaria in pregnancy on neurodevelopment in children is not well understood. We hypothesized that malaria in pregnancy and associated maternal immune activation result in neurodevelopmental delay in exposed offspring. METHODS AND FINDINGS: Between April 2014 and April 2015, we followed 421 Malawian mother-baby dyads (median [IQR] maternal age: 21 [19, 28] years) who were previously enrolled (median [IQR] gestational age at enrollment: 19.7 [17.9, 22.1] weeks) in a randomized controlled malaria prevention trial with 5 or 6 scheduled assessments of antenatal malaria infection by PCR. Children were evaluated at 12, 18, and/or 24 months of age with cognitive tests previously validated in Malawi: the Malawi Developmental Assessment Tool (MDAT) and the MacArthur-Bates Communicative Development Inventories (MCAB-CDI). We assessed the impact of antenatal malaria (n [%] positive: 240 [57.3]), placental malaria (n [%] positive: 112 [29.6]), and maternal immune activation on neurocognitive development in children. Linear mixed-effects analysis showed that children exposed to antenatal malaria between 33 and 37 weeks gestation had delayed language development across the 2-year follow-up, as measured by MCAB-CDI (adjusted beta estimate [95% CI], -7.53 [-13.04, -2.02], p = 0.008). Maternal immune activation, characterized by increased maternal sTNFRII concentration, between 33 and 37 weeks was associated with lower MCAB-CDI language score (adjusted beta estimate [95% CI], -8.57 [-13.09, -4.06], p < 0.001). Main limitations of this study include a relatively short length of follow-up and a potential for residual confounding that is characteristic of observational studies. CONCLUSIONS: This mother-baby cohort presents evidence of a relationship between malaria in pregnancy and neurodevelopmental delay in offspring. Malaria in pregnancy may be a modifiable risk factor for neurodevelopmental injury independent of birth weight or prematurity. Successful interventions to prevent malaria during pregnancy may reduce the risk of neurocognitive delay in children.


Assuntos
Transtornos do Desenvolvimento da Linguagem/etiologia , Malária/fisiopatologia , Transtornos Neurocognitivos/etiologia , Complicações Infecciosas na Gravidez , Estudos de Coortes , Feminino , Humanos , Lactente , Transmissão Vertical de Doenças Infecciosas , Malária/embriologia , Malária/imunologia , Malaui , Masculino , Transtornos Neurocognitivos/prevenção & controle , Testes Neuropsicológicos , Gravidez , Complicações Infecciosas na Gravidez/imunologia
5.
PLoS Negl Trop Dis ; 15(6): e0009509, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34161336

RESUMO

Iron and copper chelation restricts Plasmodium growth in vitro and in mammalian hosts. The parasite alters metal homeostasis in red blood cells to its favor, for example metabolizing hemoglobin to hemozoin. Metal interactions with the mosquito have not, however, been studied. Here, we describe the metallomes of Anopheles albimanus and Aedes aegypti throughout their life cycle and following a blood meal. Consistent with previous reports, we found evidence of maternal iron deposition in embryos of Ae. aegypti, but less so in An. albimanus. Sodium, potassium, iron, and copper are present at higher concentrations during larval developmental stages. Two An. albimanus phenotypes that differ in their susceptibility to Plasmodium berghei infection were studied. The susceptible white stripe (ws) phenotype was named after a dorsal white stripe apparent during larval stages 3, 4, and pupae. During larval stage 3, ws larvae accumulate more iron and copper than the resistant brown stripe (bs) phenotype counterparts. A similar increase in copper and iron accumulation was also observed in the susceptible ws, but not in the resistant bs phenotype following P. berghei infection. Feeding ws mosquitoes with extracellular iron and copper chelators before and after receiving Plasmodium-infected blood protected from infection and simultaneously affected follicular development in the case of iron chelation. Unexpectedly, the application of the iron chelator to the bs strain reverted resistance to infection. Besides a drop in iron, iron-chelated bs mosquitoes experienced a concomitant loss of copper. Thus, the effect of metal chelation on P. berghei infectivity was strain-specific.


Assuntos
Anopheles/metabolismo , Anopheles/parasitologia , Cobre/metabolismo , Ferro/metabolismo , Animais , Anopheles/crescimento & desenvolvimento , Sangue/metabolismo , Quelantes/farmacologia , Feminino , Interações Hospedeiro-Parasita , Malária/fisiopatologia , Masculino , Fenantrolinas/farmacologia , Plasmodium berghei/fisiologia
6.
Molecules ; 26(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33921170

RESUMO

Malaria is one of the most life-threatening infectious diseases and constitutes a major health problem, especially in Africa. Although artemisinin combination therapies remain efficacious to treat malaria, the emergence of resistant parasites emphasizes the urgent need of new alternative chemotherapies. One strategy is the repurposing of existing drugs. Herein, we reviewed the antimalarial effects of marketed antibiotics, and described in detail the fast-acting antibiotics that showed activity in nanomolar concentrations. Antibiotics have been used for prophylaxis and treatment of malaria for many years and are of particular interest because they might exert a different mode of action than current antimalarials, and can be used simultaneously to treat concomitant bacterial infections.


Assuntos
Antimaláricos/uso terapêutico , Reposicionamento de Medicamentos/métodos , Animais , Antibacterianos/uso terapêutico , Resistência a Medicamentos/genética , Humanos , Malária/fisiopatologia , Plasmodium falciparum/genética , Plasmodium falciparum/patogenicidade
7.
Biomolecules ; 11(3)2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804076

RESUMO

Galectin-9 (Gal-9) is a ß-galactoside-binding lectin capable of promoting or suppressing the progression of infectious diseases. This protein is susceptible to cleavage of its linker-peptides by several proteases, and the resulting cleaved forms, N-terminal carbohydrate recognition domain (CRD) and C-terminal CRD, bind to various glycans. It has been suggested that full-length (FL)-Gal-9 and the truncated (Tr)-Gal-9s could exert different functions from one another via their different glycan-binding activities. We propose that FL-Gal-9 regulates the pathogenesis of infectious diseases, including human immunodeficiency virus (HIV) infection, HIV co-infected with opportunistic infection (HIV/OI), dengue, malaria, leptospirosis, and tuberculosis (TB). We also suggest that the blood levels of FL-Gal-9 reflect the severity of dengue, malaria, and HIV/OI, and those of Tr-Gal-9 markedly reflect the severity of HIV/OI. Recently, matrix metallopeptidase-9 (MMP-9) was suggested to be an indicator of respiratory failure from coronavirus disease 2019 (COVID-19) as well as useful for differentiating pulmonary from extrapulmonary TB. The protease cleavage of FL-Gal-9 may lead to uncontrolled hyper-immune activation, including a cytokine storm. In summary, Gal-9 has potential to reflect the disease severity for the acute and chronic infectious diseases.


Assuntos
Doenças Transmissíveis/sangue , Galectinas/sangue , Doença Aguda , Sequência de Aminoácidos , COVID-19/sangue , COVID-19/fisiopatologia , Doença Crônica , Doenças Transmissíveis/imunologia , Doenças Transmissíveis/fisiopatologia , Dengue/sangue , Dengue/fisiopatologia , Galectinas/genética , Galectinas/metabolismo , Infecções por HIV/sangue , Infecções por HIV/fisiopatologia , Humanos , Fatores Imunológicos/metabolismo , Leptospirose/sangue , Leptospirose/fisiopatologia , Malária/sangue , Malária/fisiopatologia , Tuberculose/sangue , Tuberculose/fisiopatologia
8.
Malar J ; 19(1): 424, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33228734

RESUMO

BACKGROUND: Well-defined promoters are essential elements for genetic studies in all organisms, and enable controlled expression of endogenous genes, transgene expression, and gene editing. Despite this, there is a paucity of defined promoters for the rodent-infectious malaria parasites. This is especially true for Plasmodium yoelii, which is often used to study the mosquito and liver stages of malarial infection, as well as host immune responses to infection. METHODS: Here six promoters were selected from across the parasite's life cycle (clag-a, dynein heavy chain delta, lap4, trap, uis4, lisp2) that have been invoked in the literature as controlling their genes in a stage-specific manner. A minimal promoter length for the constitutive pybip promoter that confers strong expression levels was also determined, which is useful for expression of reporters and gene editing enzymes. RESULTS: Instead, it was observed that these promoters confer stage-enriched gene control, as some parasites also effectively use these promoters in other stages. Thus, when used alone, these promoters could complicate the interpretation of results obtained from promoter swaps, stage-targeted recombination, or gene editing experiments. CONCLUSIONS: Together these data indicate that achieving stage-specific effects, such as gene editing, is likely best done using a two-component system with independent promoter activities overlapping only in the intended life cycle stage.


Assuntos
Genes de Protozoários , Malária/fisiopatologia , Plasmodium yoelii/genética , Regiões Promotoras Genéticas , Animais , Feminino , Camundongos
9.
Nat Cell Biol ; 22(12): 1399-1410, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33230302

RESUMO

Severe infections are a major stress on haematopoiesis, where the consequences for haematopoietic stem cells (HSCs) have only recently started to emerge. HSC function critically depends on the integrity of complex bone marrow (BM) niches; however, what role the BM microenvironment plays in mediating the effects of infection on HSCs remains an open question. Here, using a murine model of malaria and combining single-cell RNA sequencing, mathematical modelling, transplantation assays and intravital microscopy, we show that haematopoiesis is reprogrammed upon infection, whereby the HSC compartment turns over substantially faster than at steady-state and HSC function is drastically affected. Interferon is found to affect both haematopoietic and mesenchymal BM cells and we specifically identify a dramatic loss of osteoblasts and alterations in endothelial cell function. Osteo-active parathyroid hormone treatment abolishes infection-triggered HSC proliferation and-coupled with reactive oxygen species quenching-enables partial rescuing of HSC function.


Assuntos
Hematopoese/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Malária/fisiopatologia , Nicho de Células-Tronco/fisiologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/fisiologia , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Perfilação da Expressão Gênica/métodos , Hematopoese/efeitos dos fármacos , Hematopoese/genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Malária/parasitologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoblastos/citologia , Osteoblastos/metabolismo , Osteoblastos/fisiologia , Hormônio Paratireóideo/farmacologia , Plasmodium berghei/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Nicho de Células-Tronco/genética
10.
PLoS Pathog ; 16(10): e1009007, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33104759

RESUMO

All symptoms of malaria disease are associated with the asexual blood stages of development, involving cycles of red blood cell (RBC) invasion and egress by the Plasmodium spp. merozoite. Merozoite invasion is rapid and is actively powered by a parasite actomyosin motor. The current accepted model for actomyosin force generation envisages arrays of parasite myosins, pushing against short actin filaments connected to the external milieu that drive the merozoite forwards into the RBC. In Plasmodium falciparum, the most virulent human malaria species, Myosin A (PfMyoA) is critical for parasite replication. However, the precise function of PfMyoA in invasion, its regulation, the role of other myosins and overall energetics of invasion remain unclear. Here, we developed a conditional mutagenesis strategy combined with live video microscopy to probe PfMyoA function and that of the auxiliary motor PfMyoB in invasion. By imaging conditional mutants with increasing defects in force production, based on disruption to a key PfMyoA phospho-regulation site, the absence of the PfMyoA essential light chain, or complete motor absence, we define three distinct stages of incomplete RBC invasion. These three defects reveal three energetic barriers to successful entry: RBC deformation (pre-entry), mid-invasion initiation, and completion of internalisation, each requiring an active parasite motor. In defining distinct energetic barriers to invasion, these data illuminate the mechanical challenges faced in this remarkable process of protozoan parasitism, highlighting distinct myosin functions and identifying potential targets for preventing malaria pathogenesis.


Assuntos
Actomiosina/metabolismo , Eritrócitos/fisiologia , Plasmodium falciparum/metabolismo , Citoesqueleto de Actina/metabolismo , Actomiosina/fisiologia , Animais , Eritrócitos/metabolismo , Eritrócitos/parasitologia , Humanos , Malária/metabolismo , Malária/fisiopatologia , Malária Falciparum/parasitologia , Merozoítos/metabolismo , Miosinas/metabolismo , Miosina não Muscular Tipo IIA/metabolismo , Miosina não Muscular Tipo IIA/fisiologia , Parasitos/metabolismo , Plasmodium falciparum/patogenicidade , Proteínas de Protozoários/metabolismo
11.
PLoS Comput Biol ; 16(10): e1008211, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33031367

RESUMO

To understand why some hosts get sicker than others from the same type of infection, it is essential to explain how key processes, such as host responses to infection and parasite growth, are influenced by various biotic and abiotic factors. In many disease systems, the initial infection dose impacts host morbidity and mortality. To explore drivers of dose-dependence and individual variation in infection outcomes, we devised a mathematical model of malaria infection that allowed host and parasite traits to be linear functions (reaction norms) of the initial dose. We fitted the model, using a hierarchical Bayesian approach, to experimental time-series data of acute Plasmodium chabaudi infection across doses spanning seven orders of magnitude. We found evidence for both dose-dependent facilitation and debilitation of host responses. Most importantly, increasing dose reduced the strength of activation of indiscriminate host clearance of red blood cells while increasing the half-life of that response, leading to the maximal response at an intermediate dose. We also explored the causes of diverse infection outcomes across replicate mice receiving the same dose. Besides random noise in the injected dose, we found variation in peak parasite load was due to unobserved individual variation in host responses to clear infected cells. Individual variation in anaemia was likely driven by random variation in parasite burst size, which is linked to the rate of host cells lost to malaria infection. General host vigour in the absence of infection was also correlated with host health during malaria infection. Our work demonstrates that the reaction norm approach provides a useful quantitative framework for examining the impact of a continuous external factor on within-host infection processes.


Assuntos
Interações Hospedeiro-Parasita , Malária , Anemia/complicações , Animais , Teorema de Bayes , Biologia Computacional , Feminino , Malária/complicações , Malária/imunologia , Malária/parasitologia , Malária/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Carga Parasitária , Plasmodium chabaudi/patogenicidade , Plasmodium chabaudi/fisiologia
12.
Malar J ; 19(1): 280, 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32758231

RESUMO

BACKGROUND: Maternal malarial infection leads to poor perinatal outcomes, including low birth weight from preterm delivery and/or fetal growth restriction, particularly in primigravidas. In placental malaria, Plasmodium falciparum-infected red blood cells cause an inflammatory response that can interfere with maternal-fetal exchange, leading to poor growth. The type I interferon (IFN-I) pathway plays an immunomodulatory role in viral and bacterial infections, usually by suppressing inflammatory responses. However, its role in placental malaria is unknown. This study examines the cytokine responses in placental tissue from subsets of malaria-infected and uninfected women, and attempts to correlate them with particular birth outcomes. METHODS: 40 whole placental biopsy samples were obtained from pregnant women at least 16 years of age recruited to a larger prospective chemoprevention trial against malaria. These were patients at Tororo District Hospital in Uganda, an area of high malaria endemicity where approximately 40% of women have evidence of malaria infection at delivery. They were regularly followed at a local clinic and monitored for fever, with blood smears performed then and at time of delivery to diagnose malaria infection. Placenta biopsies were taken for histological diagnosis of placental malaria, as well as quantitative PCR analysis of genes in the IFN-I pathway (IFN-ß, IL-10 and MX-1). Parameters such as infant birth weight and gestational age were also recorded. RESULTS: Histological analysis revealed placental malaria in 18 samples, while 22 were found to be uninfected. RT-PCR analysis showed a four-fold increase in IFN-ß and IL-10 expression in multigravidas with placental malaria when compared to gravidity-matched, uninfected controls. This effect was not observed in primigravidas. Interestingly, linear regression analysis showed a positive association between IFN-ß levels and higher birth weights (ß = 101.2 g per log2-fold increase in IFN-ß expression, p = 0.042). This association was strongest in primigravidas with placental malaria (ß = 339.0, p = 0.006). CONCLUSIONS: These results demonstrate differential regulation of the IFN-I pathway in placental malaria according to gravidity, with the greatest anti-inflammatory response seen in multigravidas. The association between IFN-ß levels and higher birth weight also suggests a protective role for IFN-I against fetal growth restriction in placental malaria.


Assuntos
Peso ao Nascer/fisiologia , Número de Gestações , Interferons/metabolismo , Malária/metabolismo , Placenta/parasitologia , Complicações Parasitárias na Gravidez/metabolismo , Adolescente , Adulto , Feminino , Humanos , Malária/parasitologia , Malária/fisiopatologia , Gravidez , Complicações Parasitárias na Gravidez/parasitologia , Complicações Parasitárias na Gravidez/fisiopatologia , Uganda , Adulto Jovem
13.
Malar J ; 19(1): 254, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32664933

RESUMO

BACKGROUND: Malaria is one of the most prevalent infectious disease in the world with 3.2 billion humans at risk. Malaria causes splenomegaly and damage in other organs including skeletal muscles. Skeletal muscles comprise nearly 50% of the human body and are largely responsible for the regulation and modulation of overall metabolism. It is essential to understand how malaria damages muscles in order to develop effective preventive measures and/or treatments. Using a pre-clinical animal model, the potential molecular mechanisms of Plasmodium infection affecting skeletal muscles of mice were investigated. METHODS: Mouse Signal Transduction Pathway Finder PCR Array was used to monitor gene expression changes of 10 essential signalling pathways in skeletal muscles from mice infected with Plasmodium berghei and Plasmodium chabaudi. Then, a new targeted-lipidomic approach using liquid chromatography with tandem mass spectrometry (LC-MS/MS) to profile 158 lipid signalling mediators (LMs), mostly eicosanoids derived from arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), was applied. Finally, 16 key LMs directly associated with inflammation, oxidative stress, and tissue healing in skeletal muscles, were quantified. RESULTS: The results showed that the expression of key genes altered by Plasmodium infection is associated with inflammation, oxidative stress, and atrophy. In support to gene profiling results, lipidomics revealed higher concentrations of LMs in skeletal muscles directly related to inflammatory responses, while on the levels of LMs crucial in resolving inflammation and tissue repair reduced significantly. CONCLUSION: The results provide new insights into the molecular mechanisms of malaria-induced muscle damage and revealed a potential mechanism modulating inflammation in malarial muscles. These pre-clinical studies should help with future clinical studies in humans aimed at monitoring of disease progression and development of specific interventions for the prevention and mitigation of long-term chronic effects on skeletal muscle function.


Assuntos
Malária/fisiopatologia , Músculo Esquelético/fisiopatologia , Plasmodium berghei/fisiologia , Plasmodium chabaudi/fisiologia , Animais , Masculino , Camundongos
14.
PLoS Comput Biol ; 16(7): e1008069, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32716940

RESUMO

Nitric oxide (NO) is a gaseous signaling molecule that plays an important role in neurovascular coupling. NO produced by neurons diffuses into the smooth muscle surrounding cerebral arterioles, driving vasodilation. However, the rate of NO degradation in hemoglobin is orders of magnitude higher than in brain tissue, though how this might impact NO signaling dynamics is not completely understood. We used simulations to investigate how the spatial and temporal patterns of NO generation and degradation impacted dilation of a penetrating arteriole in cortex. We found that the spatial location of NO production and the size of the vessel both played an important role in determining its responsiveness to NO. The much higher rate of NO degradation and scavenging of NO in the blood relative to the tissue drove emergent vascular dynamics. Large vasodilation events could be followed by post-stimulus constrictions driven by the increased degradation of NO by the blood, and vasomotion-like 0.1-0.3 Hz oscillations could also be generated. We found that these dynamics could be enhanced by elevation of free hemoglobin in the plasma, which occurs in diseases such as malaria and sickle cell anemia, or following blood transfusions. Finally, we show that changes in blood flow during hypoxia or hyperoxia could be explained by altered NO degradation in the parenchyma. Our simulations suggest that many common vascular dynamics may be emergent phenomena generated by NO degradation by the blood or parenchyma.


Assuntos
Encéfalo/fisiologia , Circulação Cerebrovascular , Óxido Nítrico/metabolismo , Anemia Falciforme/fisiopatologia , Arteríolas , Transfusão de Sangue , Sistema Livre de Células , Simulação por Computador , Difusão , Células Endoteliais/metabolismo , Eritrócitos/metabolismo , Hemodinâmica , Humanos , Processamento de Imagem Assistida por Computador , Imageamento Tridimensional , Malária/fisiopatologia , Mitocôndrias/metabolismo , Músculo Liso/metabolismo , Oscilometria , Distribuição de Poisson , Transdução de Sinais , Vasodilatação
15.
BMC Biol ; 18(1): 83, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620114

RESUMO

BACKGROUND: Experimental reproducibility in mouse models is impacted by both genetics and environment. The generation of reproducible data is critical for the biomedical enterprise and has become a major concern for the scientific community and funding agencies alike. Among the factors that impact reproducibility in experimental mouse models is the variable composition of the microbiota in mice supplied by different commercial vendors. Less attention has been paid to how the microbiota of mice supplied by a particular vendor might change over time. RESULTS: In the course of conducting a series of experiments in a mouse model of malaria, we observed a profound and lasting change in the severity of malaria in mice infected with Plasmodium yoelii; while for several years mice obtained from a specific production suite of a specific commercial vendor were able to clear the parasites effectively in a relatively short time, mice subsequently shipped from the same unit suffered much more severe disease. Gut microbiota analysis of frozen cecal samples identified a distinct and lasting shift in bacteria populations that coincided with the altered response of the later shipments of mice to infection with malaria parasites. Germ-free mice colonized with cecal microbiota from mice within the same production suite before and after this change followed by Plasmodium infection provided a direct demonstration that the change in gut microbiota profoundly impacted the severity of malaria. Moreover, spatial changes in gut microbiota composition were also shown to alter the acute bacterial burden following Salmonella infection, and tumor burden in a lung tumorigenesis model. CONCLUSION: These changes in gut bacteria may have impacted the experimental reproducibility of diverse research groups and highlight the need for both laboratory animal providers and researchers to collaborate in determining the methods and criteria needed to stabilize the gut microbiota of animal breeding colonies and research cohorts, and to develop a microbiota solution to increase experimental rigor and reproducibility.


Assuntos
Modelos Animais de Doenças , Microbioma Gastrointestinal , Malária/fisiopatologia , Plasmodium yoelii/fisiologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Análise Espaço-Temporal
16.
Cent Nerv Syst Agents Med Chem ; 20(2): 110-121, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32496991

RESUMO

BACKGROUND: Drug repositioning is becoming popular due to the development of resistance to almost all the recommended antimalarials. Pregabalin and gabapentin are chemical analogs of gamma- aminobutyric acid (GABA) approved for the treatment of epilepsy and neuropathic pain. OBJECTIVE: This study investigates acute toxicities and antimalarial activities of pregabalin and gabapentin in the murine malarial model. METHODS: Acute toxicities were assessed using the method of Lorke, while curative activities were assessed by the administration of serial doses of pregabalin and gabapentin to Plasmodium berghei infected mice. Pregabalin was further investigated for its prophylactic activity, and curative potential when combined with either artesunate or amodiaquine. All drugs were freshly prepared and administered orally. Thin films were collected, stained, and observed under the microscope for the estimation of parasitemia and calculation of percentage chemoinhibition or chemoprevention. In pregabalin -artesunate or -amodiaquine combination aspect of this study, survival day post-infection (SDPI) was recorded, while parasitemia was re-estimated for animals that survived till day 28. RESULTS: The oral LD50 of gabapentin, as well as pregabalin, was >5,000 mg/kg. Gabapentin at 100 and 200 mg/Kg demonstrated 35.64% and -12.78% chemoinhibition, respectively, while pregabalin demonstrated 75.60% and 100.00% chemoinhibition at doses of 12.5 and 25 mg/Kg, respectively. Moreover, pregabalin at individual doses of 25, 50 mg/Kg, and in combination with either artesunate or amodiaquine demonstrated 100.00% chemoinhibition. In its prophylactic study, pregabalin was found to be 100% chemopreventive at individual doses of 12.5 and 25 mg/Kg. CONCLUSION: Both GABA analogs have antimalarial properties, but pregabalin proved to be more efficacious.


Assuntos
Antimaláricos/uso terapêutico , Reposicionamento de Medicamentos/métodos , Malária/tratamento farmacológico , Plasmodium berghei/efeitos dos fármacos , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/uso terapêutico , Animais , Antimaláricos/farmacologia , Feminino , Gabapentina/farmacologia , Gabapentina/uso terapêutico , Malária/fisiopatologia , Masculino , Camundongos , Plasmodium berghei/fisiologia , Pregabalina/farmacologia , Pregabalina/uso terapêutico , Ácido gama-Aminobutírico/farmacologia
17.
J Neuroimaging ; 30(4): 463-467, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32449973

RESUMO

BACKGROUND AND PURPOSE: Hemoglobin (Hbg) is often thought to impact cerebral blood flow velocity (CBFV). This study was performed to investigate the relationship between Hbg value and CBFV in African children with malaria. METHODS: In this prospective, observational study, children aged 3 months to 18 years with malaria and a normal Blantyre coma score underwent a single transcranial Doppler ultrasound (TCD) examination with a concurrent Hbg check. RESULTS: One hundred fifty-six children with a mean age of 43 months were enrolled. Thirty-three children (21%) had severe anemia (Hbg <5g/dL), 46 (29%) had moderate anemia (Hbg 5-6.9 g/dL), 63 children (41%) had mild anemia (7-9.9 g/dL), and 14 children (9%) had no anemia (Hbg >10 g/dL) at the time of TCD examination. Mean averaged CBFV in the middle cerebral artery (MCA) for the cohort was 99% of predicted based on normative values standardized for age. There was no significant correlation between Hbg levels and measured CBFV in the MCA (r = -.09; 95% CI, -.24-.07; P = .29). CONCLUSION: In a large sample of African children with malaria, Hbg did not correlate with CBFVs as measured by TCD. Future work that includes baseline TCD measurements and Hbg values as well as other physiological parameters known to influence CBFVs is necessary to confirm these findings.


Assuntos
Anemia/fisiopatologia , Velocidade do Fluxo Sanguíneo/fisiologia , Circulação Cerebrovascular/fisiologia , Hemoglobinas/análise , Malária/fisiopatologia , Ultrassonografia Doppler Transcraniana , Anemia/sangue , Anemia/diagnóstico por imagem , Anemia/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Malária/sangue , Malária/complicações , Malária/diagnóstico por imagem , Masculino , Artéria Cerebral Média/diagnóstico por imagem , Estudos Prospectivos
18.
Science ; 368(6492): 746-753, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32409471

RESUMO

Malarial rhythmic fevers are the consequence of the synchronous bursting of red blood cells (RBCs) on completion of the malaria parasite asexual cell cycle. Here, we hypothesized that an intrinsic clock in the parasite Plasmodium chabaudi underlies the 24-hour-based rhythms of RBC bursting in mice. We show that parasite rhythms are flexible and lengthen to match the rhythms of hosts with long circadian periods. We also show that malaria rhythms persist even when host food intake is evenly spread across 24 hours, suggesting that host feeding cues are not required for synchrony. Moreover, we find that the parasite population remains synchronous and rhythmic even in an arrhythmic clock mutant host. Thus, we propose that parasite rhythms are generated by the parasite, possibly to anticipate its circadian environment.


Assuntos
Ritmo Circadiano/fisiologia , Febre/fisiopatologia , Febre/parasitologia , Interações Hospedeiro-Parasita/fisiologia , Malária/fisiopatologia , Malária/parasitologia , Plasmodium chabaudi/fisiologia , Animais , Proteínas CLOCK/genética , Ritmo Circadiano/genética , Sinais (Psicologia) , Escuridão , Ingestão de Alimentos , Eritrócitos/parasitologia , Comportamento Alimentar , Regulação da Expressão Gênica , Interações Hospedeiro-Parasita/genética , Camundongos , Camundongos Mutantes , Plasmodium chabaudi/genética , Transcrição Gênica
19.
Med J Malaysia ; 75(2): 171-172, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32281602

RESUMO

We report a rare case of severe Plasmodium knowlesi malaria and dengue co-infection in a 36-year-old lady with hyperparasitaemia, metabolic acidosis, haemolysis and acute kidney injury. She was in shock requiring inotropic support and elective intubation. She had pericardial tamponade which necessitate pericardiocentesis to allow for haemodynamic stability during haemodialysis. She underwent haemodialysis, was ventilated for six days and stayed in hospital for 29 days. She was discharged home well with almost complete renal recovery. Physicians must have a high degree of suspicion for dengue co-infection in malaria patients with plasma leakage such as pericardial effusion to allow for prompt management.


Assuntos
Coinfecção , Dengue/fisiopatologia , Malária/fisiopatologia , Plasmodium knowlesi/isolamento & purificação , Injúria Renal Aguda/terapia , Adulto , Feminino , Humanos , Malásia , Diálise Renal , Resultado do Tratamento
20.
Am J Hypertens ; 33(8): 695-702, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32211753

RESUMO

Malaria etiologies with pathophysiological similarities to hypertension currently constitute a major subject of research. The malaria-high blood pressure hypothesis is strongly supported by observations of the increasing incidence of hypertension in malaria-endemic, low- and middle-income countries with poor socioeconomic conditions, particularly in sub-Saharan African countries. Malnutrition and low birth weight with persistent symptomatic malaria presentations in pregnancy correlate strongly with the development of preeclampsia, gestational hypertension and subsequent hypertension in adult life. Evidence suggest that the link between malaria infection and high blood pressure involves interactions between malaria parasites and erythrocytes, the inflammatory process, effects of the infection during pregnancy; effects on renal and vascular functions as well as effects in sickle cell disease. Possible mechanisms which provide justification for the malaria-high blood pressure hypothesis include the following: endothelial dysfunction (reduced nitric oxide (NO) levels), impaired release of local neurotransmitters and cytokines, decrease in vascular smooth muscle cell viability and/or alterations in cellular calcium signaling leading to enhanced vascular reactivity, remodeling, and cardiomyopathies, deranged homeostasis through dehydration, elevated intracellular mediators and proinflammatory cytokine responses, possible genetic regulations, activation of the renin-angiotensin-aldosterone system mechanisms and renal derangements, severe anemia and hemolysis, renal failure, and end organ damage. Two key mediators of the malaria-high blood pressure association are: endothelial dysfunction (reduced NO) and increased angiotensin-converting enzyme activity/angiotensin II levels. Sickle cell disease is associated with protection against malaria infection and reduced blood pressure. In this review, we present the state of knowledge about the malaria-blood pressure hypothesis and suggest insights for future studies.


Assuntos
Endotélio/fisiopatologia , Hipertensão/fisiopatologia , Malária/fisiopatologia , Sistema Renina-Angiotensina/fisiologia , Angiotensina II/metabolismo , Sinalização do Cálcio , Sobrevivência Celular , Citocinas/metabolismo , Países em Desenvolvimento , Endotélio/metabolismo , Feminino , Humanos , Hipertensão/epidemiologia , Hipertensão/imunologia , Hipertensão/metabolismo , Hipertensão Induzida pela Gravidez/epidemiologia , Inflamação/imunologia , Inflamação/metabolismo , Malária/epidemiologia , Malária/imunologia , Malária/metabolismo , Músculo Liso Vascular , Miócitos de Músculo Liso/metabolismo , Neurotransmissores/metabolismo , Óxido Nítrico/metabolismo , Peptidil Dipeptidase A/metabolismo , Pré-Eclâmpsia/epidemiologia , Gravidez
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