Correction: Variation in Human Cytochrome P-450 Drug-Metabolism Genes: A Gateway to the Understanding of Plasmodium vivax Relapses.

[This corrects the article DOI: 10.1371/journal.pone.0160172.]

Prospective assessment of malaria infection in a semi-isolated Amazonian indigenous Yanomami community: Transmission heterogeneity and predominance of submicroscopic infection.

In the Amazon basin, indigenous forest-dwelling communities typically suffer from a high burden of infectious diseases, including malaria. Difficulties in accessing these isolated ethnic groups, such as the semi-nomadic Yanomami, make official malaria data largely underestimated. In the current study, we longitudinally surveyed microscopic and submicroscopic malaria infection in four Yanomami villages of the Marari community in the northern-most region of the Brazilian Amazon. Malaria parasite species-specific PCR-based detection of ribosomal and non-ribosomal targets showed that approximately 75% to 80% of all malaria infections were submicroscopic, with the ratio of submicroscopic to microscopic infection remaining stable over the 4-month follow-up period. Although the prevalence of malaria infection fluctuated over time, microscopically-detectable parasitemia was only found in children and adolescents, presumably reflecting their higher susceptibility to malaria infection. As well as temporal variation, the prevalence of malaria infection differed significantly between villages (from 1% to 19%), demonstrating a marked heterogeneity at micro-scales. Over the study period, Plasmodium vivax was the most commonly detected malaria parasite species, followed by P. malariae, and much less frequently P. falciparum. Consecutive blood samples from 859 out of the 981 studied Yanomami showed that malaria parasites were detected in only 8% of the previously malaria-positive individuals, with most of them young children (median age 3 yrs). Overall, our results show that molecular tools are more sensitive for the identification of malaria infection among the Yanomami, which is characterized by heterogeneous transmission, a predominance of low-density infections, circulation of multiple malaria parasite species, and a higher susceptibility in young children. Our findings are important for the design and implementation of the new strategic interventions that will be required for the elimination of malaria from isolated indigenous populations in Latin America

Susceptibility to Plasmodium vivax malaria associated with DARC (Duffy antigen) polymorphisms is influenced by the time of exposure to malaria

Submitted by Nuzia Santos ([email protected]) on 2019-06-24T16:13:41Z No. of bitstreams: 1 Susceptibility to Plasmodium vivax malaria.pdf: 1166943 bytes, checksum: 8c68739c4ccbf3121183fed31318881b (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2019-06-24T16:24:09Z (GMT) No. of bitstreams: 1 Susceptibility to Plasmodium vivax malaria.pdf: 1166943 bytes, checksum: 8c68739c4ccbf3121183fed31318881b (MD5)Made available in DSpace on 2019-06-24T16:24:09Z (GMT). No. of bitstreams: 1 Susceptibility to Plasmodium vivax malaria.pdf: 1166943 bytes, checksum: 8c68739c4ccbf3121183fed31318881b (MD5) Previous issue date: 2018Fundação Oswaldo Cruz. Instituto Rene Rachou. Biologia Molecular e Imunologia da Malária. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto Rene Rachou. Biologia Molecular e Imunologia da Malária. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto Rene Rachou. Biologia Molecular e Imunologia da Malária. Belo Horizonte, MG, Brasil.Universidade Federal de Minas Gerais. Departamento de Engenharia de Produção. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto Rene Rachou. Biologia Molecular e Imunologia da Malária. Belo Horizonte, MG, Brasil.Universidade Federal de Mato Grosso. Cuiabá, MT, Brasil.Universidade Federal de Mato Grosso. Hospital Julio Muller. Cuiabá, MT, Brazil.Universidade de São Paulo. Faculdade de Ciências Farmacêuticas. Departamento de Análises Clínicas e Toxicológicas. São Paulo, SP, Brazil.Fundação Oswaldo Cruz. Instituto Rene Rachou. Biologia Molecular e Imunologia da Malária. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto Rene Rachou. Biologia Molecular e Imunologia da Malária. Belo Horizonte, MG, Brasil.Fundação Oswaldo Cruz. Instituto Rene Rachou. Biologia Molecular e Imunologia da Malária. Belo Horizonte, MG, Brasil.Malaria has provided a major selective pressure and has modulated the genetic diversity of the human genome. The variants of the Duffy Antigen/Receptor for Chemokines (DARC) gene have probably been selected by malaria parasites, particularly the FY*O allele, which is fixed in sub-Saharan Africa and confers resistance to Plasmodium vivax infection. Here, we showed the influence of genomic ancestry on the distribution of DARC genotypes in a highly admixed Brazilian population and confirmed the decreased susceptibility of the FY*A/FY*O genotype to clinical P. vivax malaria. FY*B/FY*O individuals were associated with a greater risk of developing clinical malaria. A remarkable difference among DARC variants concerning the susceptibility to clinical malaria was more evident for individuals who were less exposed to malaria, as measured by the time of residence in the endemic area. Additionally, we found that DARC-negative and FY*A/FY*O individuals had a greater chance of acquiring high levels of antibodies against the 19-kDa C-terminal region of the P. vivax merozoite surface protein-1. Altogether, our results provide evidence that DARC polymorphisms modulate the susceptibility to clinical P. vivax malaria and influence the naturally-acquired humoral immune response to malaria blood antigens, which may interfere with the efficacy of a future vaccine against malaria

Analysis of the parasite haplotype and time to relapse in days for carriers of CYP2C8 polymorphisms.

<p>Frequency of parasite haplotype between patients without or with CYP2C8 mutation. Parasites were classified according to the number of identical markers: <i>identical</i> in black (10 identical markers); <i>related</i> in gray (8 to 9 identical markers); and <i>heterologous</i> in light gray (less than 8 identical markers).</p

Analysis of the molecular interactions of polymorphic residues of CYP2D6 and their effects on the metabolism of primaquine.

<p>(A) The residue P34 has a buried side chain that is inserted into a predominantly hydrophobic environment (the hydrophobic interactions are depicted as gray dots) and is performing a main-chain to side-chain polar interaction with a neighboring beta strand (red dashes). The mutation P34S is predicted to destabilize the protein because it disrupts the local hydrophobic interaction network and affects the backbone rigidity. (B) The interactions for docked PQ (dark gray) and residue T107 (green). Threonine 107 is located in the vicinity of the PQ binding pocket (6.1 Å from PQ) and also nearby important catalytic residues (depicted in blue). (C) The mutation T107I results in the formation of increased local interactions, reducing CYP2D6 flexibility. Residues are colored based on their predicted effect on flexibility, ranging from more flexible (red) to less flexible (blue).</p

Demographic and epidemiological data of individuals who were enrolled in this study.

<p>Demographic and epidemiological data of individuals who were enrolled in this study.</p

Variation in Human Cytochrome P-450 Drug-Metabolism Genes: A Gateway to the Understanding of <i>Plasmodium vivax</i> Relapses

<div><p>Although <i>Plasmodium vivax</i> relapses are classically associated with hypnozoite activation, it has been proposed that a proportion of these cases are due to primaquine (PQ) treatment failure caused by polymorphisms in cytochrome P-450 2D6 (CYP2D6). Here, we present evidence that CYP2D6 polymorphisms are implicated in PQ failure, which was reinforced by findings in genetically similar parasites, and may explain a number of <i>vivax</i> relapses. Using a computational approach, these polymorphisms were predicted to affect the activity of CYP2D6 through changes in the structural stability that could lead to disruption of the PQ-enzyme interactions. Furthermore, because PQ is co-administered with chloroquine (CQ), we investigated whether CQ-impaired metabolism by cytochrome P-450 2C8 (CYP2C8) could also contribute to <i>vivax</i> recurrences. Our results show that CYP2C8-mutated patients frequently relapsed early (<42 days) and had a higher proportion of genetically similar parasites, suggesting the possibility of recrudescence due to CQ therapeutic failure. These results highlight the importance of pharmacogenetic studies as a tool to monitor the efficacy of antimalarial therapy.</p></div

Genotypes and allele frequencies of the <i>CYP2D6</i> gene in <i>P</i>. <i>vivax</i>-infected patients who had single or multiple episodes of relapse.

<p>Genotypes and allele frequencies of the <i>CYP2D6</i> gene in <i>P</i>. <i>vivax</i>-infected patients who had single or multiple episodes of relapse.</p

Frequency of CYP2D6 polymorphisms and parasite haplotype among <i>P</i>. <i>vivax-</i>infected patients who had single (n = 28) or multiple (n = 18) episodes of relapse.

<p>(A) The number of CYP2D6 polymorphisms is represented by the different intensity of color as specified in the legend. A simple logistic regression model shows a significant relationship between the mutant status for CYP2D6 and the increased number of relapses (OR, 12.4; 95% CI, 2.80–88.57; <i>P</i> = .003). (B) Frequency of parasite haplotype in patients without or with CYP2D6 mutation. Parasites were classified according to the number of markers containing identical alleles: <i>identical</i> in black (parasites showing all 10 identical markers); <i>related</i> in gray (8 to 9 identical markers); and <i>heterologous</i> in light gray (less than 8 identical markers).</p