Individual variation in Plasmodium vivax malaria risk - Are repeatedly infected people just unlucky?

Copyright: © 2023 Corder et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Extensive research has examined why some people have frequent Plasmodium falciparum malaria episodes in sub-Saharan Africa while others remain free of disease most of the time. In contrast, malaria risk heterogeneity remains little studied in regions where P. vivax is the dominant species. Are repeatedly infected people in vivax malaria settings such as the Amazon just unlucky? Here, we briefly review evidence that human genetic polymorphism and acquired immunity after repeated exposure to parasites can modulate the risk of P. vivax infection and disease in predictable ways. One-fifth of the hosts account for 80% or more of the community-wide vivax malaria burden and contribute disproportionally to onward transmission, representing a priority target of more intensive interventions to achieve malaria elimination. Importantly, high-risk individuals eventually develop clinical immunity, even in areas with very low or residual malaria transmission, and may constitute a large but silent parasite reservoir.publishersversionpublishe

Genetic Modulators of Hemolytic Anemia in Angolan Children with Sickle Cell Anemia

Sickle Cell Anemia (SCA) is a recessive genetic disease caused by the c.20A>T variant in HBB gene. It is characterised by sickled erythrocytes, chronic hemolytic anemia and vaso-occlusive events. However, these manifestations are heterogeneous due to environmental and genetic modifying factors. The aim of this study was to investigate genetic modifiers of hemolytic anemia in pediatric SCA patients living in Africa, where the disease is a severe public health problem. The study was conducted on 200 Angolan SCA 3-12 year-old children. Thirteen polymorphic regions in genes previously associated with vascular cell adhesion (VCAM1 and CD36), vascular tonus (NOS3) or erythrocyte hemoglobinisation (HBA), were genotyped using PCR, RFLP, Gap-PCR and Sanger sequencing. Hematological and biochemical phenotypes were obtained at steady state and clinical adverse events were collected from patients’ medical records. Results revealed a high level (67.5%) of α-thalassemia co-inheritance (del. 3.7kb in HBA), which improve patients’ health by delaying the onset of the disease, decreasing anemia and the number of blood transfusions. Two SNPs in CD36 (rs1984112 and rs1413661) showed impact on anemia severity. Particularly, genotypes containing the rs1413661_allele C revealed to be risk factors for severe anemia, as they were associated with lower hemoglobin levels, increased number of hospitalizations and transfusions. This is the first report associating this SNP with SCA pathology. Moreover, the rs1041163_allele C in VCAM1 was associated with lower LDH levels, inversely the rs2070744_allele C in NOS3 was associated with higher LDH levels and a higher number of hospitalizations, being a possible risk factor for increased hemolytic rate. This study contributed to the understanding of SCA complex pathophysiology. It confirmed the positive role of α-thal., both in SCA related anemia and in its clinical manifestations. In addition, it reinforced the importance of vascular cell adhesion in hemolytic anemia variability. In this context, we propose the SNP rs1413661 in CD36 as an important novel genetic modulator of SCA in Africa.Partially funding by FCT/Aga Khan Dev. Network, #330842553N/

Analysis of genetic mutations associated with anti-malarial drug resistance in Plasmodium falciparum from the Democratic Republic of East Timor

<p>Abstract</p> <p>Background</p> <p>In response to chloroquine (CQ) resistance, the policy for the first-line treatment of uncomplicated malaria in the Democratic Republic of East Timor (DRET) was changed in early 2000. The combination of sulphadoxine-pyrimethamine (SP) was then introduced for the treatment of uncomplicated falciparum malaria.</p> <p>Methods</p> <p>Blood samples were collected in two different periods (2003–2004 and 2004–2005) from individuals attending hospitals or clinics in six districts of the DRET and checked for <it>Plasmodium falciparum </it>infection. 112 PCR-positive samples were inspected for genetic polymorphisms in the <it>pfcrt</it>, <it>pfmdr1</it>, <it>pfdhfr </it>and <it>pfdhps </it>genes. Different alleles were interrogated for potential associations that could be indicative of non-random linkage.</p> <p>Results</p> <p>Overall prevalence of mutations associated with resistance to CQ and SP was extremely high. The mutant form of <it>Pfcrt </it>(76T) was found to be fixed even after five years of alleged CQ removal. There was a significant increase in the prevalence of the <it>pfdhps </it>437G mutation (X²= 31.1; p = 0.001) from the first to second survey periods. A non-random association was observed between <it>pfdhfr</it>51/<it>pfdhps</it>437 (p = 0.001) and <it>pfdhfr </it>59/<it>pfdhps </it>437 (p = 0.013) alleles.</p> <p>Conclusion</p> <p>Persistence of CQ-resistant mutants even after supposed drug withdrawal suggests one or all of the following: local <it>P. falciparum </it>may still be inadvertently exposed to the drug, that mutant parasites are being "imported" into the country, and/or reduced genetic diversity and low parasite transmission help maintain mutant haplotypes. The association between <it>pfdhfr</it>51/<it>pfdhps</it>437 and <it>pfdhfr </it>59/<it>pfdhps </it>437 alleles indicates that these are undergoing concomitant positive selection in the DRET.</p

Genetic modulation of anemia severity, hemolysis level, and hospitalization rate in Angolan children with Sickle Cell Anemia

Background Sickle Cell Anemia (SCA) is a genetic disease caused by the c.20 A > T mutation in HBB gene, generally characterized by sickle erythrocytes, chronic hemolytic anemia, and vaso-occlusive events. This study aimed to investigate genetic modulators of anemia severity, chronic hemolytic rate, and clinical manifestations in pediatric SCA patients from Angola, where the disease is a severe public health problem. Methods and Results The study was conducted on 200 SCA children living in Luanda or Caxito province. Their clinical phenotype was collected from patients’ hospital records. Hematological and biochemical phenotypes were characterized in steady state condition. Twelve polymorphic regions in VCAM1, CD36 and NOS3 genes were genotyped using PCR, RFLP, and Sanger sequencing. CD36 gene promoter variants showed a significant impact on anemia severity. Particularly, the rs1413661_C allele was associated with lower hemoglobin levels, and increased number of hospitalizations and transfusions. This is the first report associating this SNP with SCA phenotypic heterogeneity. Moreover, the rs1041163_C allele in VCAM1 was associated with lower LDH levels; inversely the rs2070744_C allele in NOS3 was related with higher LDH levels and number of hospitalizations, being a risk factor for increased hemolytic rate. Conclusion This study highlights, for the first time in the Angolan population, the importance of the genetic modifiers of vascular cell adhesion and nitric oxide metabolism in SCA pediatric phenotypic variability.publishersversionpublishe

Sickle cell disease and gut health: the influence of intestinal parasites and the microbiome on Angolan children

This work was funded by the following grants: IPL/IDI&CA2022/ParasitSCD, FCT/Aga Khan (project no. 330842553), and FCT/MCTES (https://doi.org/10.54499/UIDB/05608/2020 and https://doi.org/10.54499/UIDP/05608/2020)-H&TRC. Author M.D. has received financial support from an FCT research fellowship UI/BD/150705/2020 (https://doi.org/10.54499/UI/BD/150705/2020).Parasitic infections are a common problem in developing countries and can intensify morbidity in patients with sickle cell disease (SCD), increasing the severity of anemia and the need for transfusions. It has been demonstrated that both helminths and protozoa can affect gut microbiome composition. On the other hand, the presence of specific bacterial communities can also influence parasite establishment. Considering this, our aim was to associate the presence of intestinal parasites with the results of hematological analyses and microbiome composition evaluations in a population of Angolan children with and without SCD. A total of 113 stool samples were collected, and gut microbiome analysis was performed using 16S sequencing and real-time PCR to detect eight different intestinal parasites. In our population, more than half of children (55%) had at least one parasitic infection, and of these, 43% were co-infected. Giardia intestinalis and Ascaris lumbricoides were more frequently found in children from the rural area of Bengo. Moreover, SCD children with ascariasis exhibited higher values of leukocytes and neutrophils, whereas the total hemoglobin levels were lower. In regards to the gut microbiome, the presence of intestinal parasites lowered the prevalence of some beneficial bacteria, namely: Lactobacillus, Bifidobacterium, Cuneatibacter, Bacteroides uniformis, Roseburia, and Shuttleworthia. This study presents the prevalence of several intestinal parasites in a high-risk transmission area with scarce information and opens new perspectives for understanding the interaction between parasites, the microbiome, and SCD.info:eu-repo/semantics/publishedVersio

Sickle cell disease: current drug treatments and functional foods with therapeutic potential

Miguel Brito gratefully acknowledges the FCT/MCTES national support through the projects H&TRC UIDB/05608/2020, UIDP/05608/2020, and IPL/IDI&CA2023/Ipasthma_ESTeSL. J.M. Oliveira acknowledges the financial support of CICECO–Aveiro Institute of Materials, UIDB/50011/2020, UIDP/50011/2020 & LA/P/0006/2020, financed by national funds through the FCT/MCTES (PIDDAC). Ana Paula Arez would like to acknowledge Fundação para a Ciência e a Tecnologia for funds to GHTM—UID/04413/2020 and LA-REAL LA/P/0117/2020.Sickle cell anemia (SCA), the most common form of sickle cell disease (SCD), is a genetic blood disorder. Red blood cells break down prematurely, causing anemia and often blocking blood vessels, leading to chronic pain, organ damage, and increased infection risk. SCD arises from a single-nucleotide mutation in the β-globin gene, substituting glutamic acid with valine in the β-globin chain. This review examines treatments evaluated through randomized controlled trials for managing SCD, analyzes the potential of functional foods (dietary components with health benefits) as a complementary strategy, and explores the use of bioactive compounds as functional food ingredients. While randomized trials show promise for certain drugs, functional foods enriched with bioactive compounds also hold therapeutic potential. Further research is needed to confirm clinical efficacy, optimal dosages, and specific effects of these compounds on SCD, potentially offering a cost-effective and accessible approach to managing the disease.info:eu-repo/semantics/publishedVersio

Characterization of a cohort of Angolan children with sickle cell anemia treated with hydroxyurea

Background: Sickle Cell Anemia (SCA) is a monogenic disease, although its severity and response to treatment are very heterogeneous. Objectives: This study aims to characterize a cohort of Angolan children with SCA and evaluate their response to hydroxyurea (HU) treatment and the potential side effects and toxicity. Methods: The study enrolled 215 patients between 3 and 12 years old before and after the administration of HU, at a fix dose of 20 mg/kg/day for 12 months. Results: A total of 157 patients started HU medication and 141 of them completed the 12-month treatment. After initiating HU treatment, the frequency of clinical events decreased (transfusions 53.4 %, hospitalizations 47.1 %). The response to HU medication varied among patients, with some experiencing an increase in fetal hemoglobin (HbF) of <5 %. The mean increase in HbF was 11.9 %, ranging from 1.8 % to 31 %. Responders to HU treatment were 57 %, inadequate responders 38.7 % and non-adherent 4.2 %. No clinical side effects related to HU were reported. Hematological toxicities were transient and reversible. Children naïve to HU and with lower HbF reported higher number of hospitalizations caused by malaria infection. During HU treatment, the frequency of malaria episodes did not appear to be affected by HbF levels. Conclusions: the present study provided a valuable contribution to the understanding of the clinical and laboratory profiles of Angolan children with SCA. These findings support the evidence that the implementation of prophylactic measures and treatment with HU is associated with increased survival in children with SCA.This research was funded by Fundação para a Ciência e Tecnologia Ministério da Ciência, Tecnologia e Ensino Superior (FCT-MCTES) and Aga Khan Foundation (FCT/MCTES/Aga Khan, project n◦ 330842553), by FCT/MCTES funding to H&TRC (UIDB/05608/2020, UIDP/05608/2020) and to GHTM IHMT NOVA (UIBD/04413/2020) and LA-REAL –LA/P/0117/2020.info:eu-repo/semantics/publishedVersio

Epidemiological characterization of Plasmodium falciparum in the Republic of Cabo Verde: implications for potential large-scale re-emergence of malaria

BACKGROUND: Malaria has come near eradication at archipelago of Cabo Verde in 1970. Infections are now only observed in Santiago, where outbreaks occur. In these islands, malaria is considered by the international community as being of limited risk and, therefore, no prophylaxis is recommended. Since the understanding of factors that determine malaria outbreaks are crucial for controlling the disease, the present study aimed to investigate if the malaria infections observed in Santiago Island are maintained in isolated foci and in asymptomatic individuals. METHODS: The occurrence of asymptomatic carriers in villages with history of malaria as well as the level of exposure of these populations were investigated using PCR and serological analyses. RESULTS: Results indicate that malaria is maintained as asymptomatic and sub-patent infections and that the majority of the circulating parasite populations harbour chloroquine-resistant mutations. CONCLUSION: These observations highlight the alarming prospect of malaria to become a serious public health problem and underscore the need for a tighter surveillance

Mosquito fauna on the Cape Verde Islands (West Africa): an update on species distribution and a new finding

To evaluate the risk of transmission of vector-borne diseases, regular updates of the geographic distribution of insect vectors are required. In the archipelago of Cape Verde, nine mosquito species have been reported. Of these, four are major vectors of diseases that have been present in the archipelago: yellow fever, lymphatic filariasis, malaria and, currently, an outbreak of dengue. In order to assess variation in mosquito biodiversity, we have carried out an update on the distribution of the mosquito species in Cape Verde, based on an enquiry of 26 unpublished technical reports (1983-2006) and on the results of an entomological survey carried out in 2007. Overall, there seems to be a general trend for an expansion of biological diversity in the islands. Mosquito species richness was negatively correlated with the distance of the islands from the mainland but not with the size of the islands. Human- and/or sporadic climatic-mediated events of dispersal may have contributed to a homogenization of species richness regardless of island size but other ecological factors may also have affected the mosquito biogeography in the archipelago. An additional species, Culex perexiguus, was collected for the first time in the archipelago during the 2007 survey

Avaliação clínica da resposta ao tratamento com Hidroxiureia em crianças com Anemia de Células Falciformes em Angola

Resumo publicado em: XII Jornadas Científicas do IHMT: livro de resumos, p. 13. http://ihmtweb.ihmt.unl.pt/Download/JornadasCientificas/XII/Livro-de-resumos_v4.pdfIntrodução: A Anemia de Células Falciformes (ACF) é uma doença genética causada por uma mutação na cadeia beta globina da hemoglobina, dando origem à hemoglobina S. É caracterizada por fenómenos vaso-oclusivos e hemólise crónica. A hemoglobina fetal (HbF) é o modificador central da doença e é passível de manipulação terapêutica. A Hidroxiureia (HU) é o único fármaco aprovado para indução de HbF em pacientes com ACF. Contudo, alguns estudos mostraram que as respostas individuais ao tratamento com HU são muito variáveis. O objectivo deste estudo é a avaliação da eficácia do tratamento com HU em crianças angolanas com ACF. Será feita a apresentação preliminar de dadosde 6 meses de tratamento com HU.Métodos: O estudo incluiu143 crianças dos 3 aos 12 anos de idade, com o diagnóstico de ACF medicadas com HU na dose de 20mg/kg/dia. O seguimento clínico foi feito mensalmente e incluiu o registo de intercorrências, exame físico, avaliação hematológica e dos parâmetros bioquímicos para estudo da hemólise e da toxicidade atribuída à HU. A HbF foi quantificada em estado basal e ao 6⁰ mês de tratamento. Resultados: Comparativamente à fase antes do tratamento e a avaliação feita ao 6⁰ mês de tratamento houve redução de: (1) frequência de episódios de crises dolorosas (59 vs 25), (2) número de transfusões (16 vs 4), (3) número de internamentos (12 vs 3). Uma criança teve recorrência de AVC no 2⁰mês e outra teve necrose asséptica da cabeça do fémur ao 5⁰mês de tratamento. O valor médio da hemoglobina (g/dl) variou de 7,5 para 8,1 (valor mínimo 5,2 e máximo 10,1 vs valor mínimo 5,8 e máximo 10,7). Em 56,1% dos pacientes houve aumento da HbF com valores médios de 5,7% emestado basal e 12,4% ao 6⁰mês de tratamento. Contudo em 12,9% dos pacientes não houve variação da % da HbF e em 30,9% das crianças o aumento da HbF foi inferior a 3% do valor da HbF basal.Na análise dos parâmetros de hemólise o valor percentual médiodos reticulócitosdecresceu de 10,1 para 6,57%, a bilirrubina indirecta (mg/dl) variou de 1,19 para 0,52. A desidrogenase láctea (U/L) não teve variação nos valores médios embora o valor máximo tenha decrescidode 1230 para 1067 e o valor mínimo de 115,1 para 106,3U/L. Não foram registados efeitos secundários importantes relacionados à HU.Conclusão: A HU teve eficácia clínica na maioria dos pacientes evidenciada pelos parâmetros clínicos e laboratoriais. Para além disso, foi demonstrada variabilidade na resposta à terapêutica pelo que está em curso a identificação de polimorfismos associados a essa variabilidade.Parcialmente financiado por FCT/Aga Khan Dev. Network, #330842553info:eu-repo/semantics/publishedVersio