A closer look at multiple-clone Plasmodium vivax infections: detection methods, prevalence and consequences

The naturally occurring clonal diversity among field isolates of the major human malaria parasite Plasmodium vivax remained unexplored until the early 1990s, when improved molecular methods allowed the use of blood samples obtained directly from patients, without prior in vitro culture, for genotyping purposes. Here we briefly review the molecular strategies currently used to detect genetically distinct clones in patient-derived P. vivax samples, present evidence that multiple-clone P. vivax infections are commonly detected in areas with different levels of malaria transmission and discuss possible evolutionary and epidemiological consequences of the competition between genetically distinct clones in natural human infections. We suggest that, when two or more genetically distinct clones are present in the same host, intra-host competition for limited resources may select for P. vivax traits that represent major public health challenges, such as increased virulence, increased transmissibility and antimalarial drug resistance.CNPqMount Sinai School of Medicin

Quantificando os efeitos do aquecimento global e das condições socioeconômicas locais na transmissão de malária

OBJETIVO: Apresenta-se um modelo matemático mostrando como esse instrumento pode ser importante para descrever a transmissão de malária. MÉTODOS: Baseado no modelo proposto previamente, foram quantificados os efeitos de dois fatores que podem afetar a transmissão da malaria: a temperatura ambiente e as condições socioeconômicas locais. RESULTADOS/CONCLUSÕES: A quantificação foi feita estudando o modelo proposto no estado estacionário e na sua dinâmica. Dependendo do nível de risco de malária, os principais efeitos na transmissão de malária são devidos à temperatura ambiente ou às condições socioeconômicas.OBJECTIVE: To show how a mathematical model can be used to describe and to understand the malaria transmission. METHODS: The effects on malaria transmission due to the impact of the global temperature changes and prevailing social and economic conditions in a community were assessed based on a previously presented compartmental model, which describes the overall transmission of malaria. RESULTS/CONCLUSIONS: The assessments were made from the scenarios produced by the model both in steady state and dynamic analyses. Depending on the risk level of malaria, the effects on malaria transmission can be predicted by the temperature ambient or local social and-economic conditions

A birth cohort study

Funding Information: The MINA‐Brazil Study has been funded by the Brazilian National Council for Scientific and Technological Development (CNPq, grant number 407255/2013‐3) and the São Paulo Research Foundation (FAPESP, grant number 2016/00270‐6). Dr Matijasevich, Dr Antunes and Dr Cardoso are recipients of CNPq senior research scholarships. Mrs Maruyama and Mrs Pinheiro received doctoral scholarship from FAPESP (grant 2017/22723‐5) and CAPES, respectively. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Publisher Copyright: © 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.Objectives: Previous cohort studies have found a positive association between prolonged breastfeeding (≥12 months) on dental caries, but few of them analysed the mediated effect of sugar consumption on this association. This study investigated whether prolonged breastfeeding is a risk factor for caries at 2-year follow-up assessment (21–27 months of age) and whether this effect is mediated by sugar consumption. Methods: A birth cohort study was performed in the Brazilian Amazon (n = 800). Dental caries was assessed using the dmf-t index. Prolonged breastfeeding was the main exposure. Data on baseline covariables and sugar consumption at follow-up visits were analysed. We estimated the OR for total causal effect (TCE) and natural indirect effect (NIE) of prolonged breastfeeding on dental caries using the G-formula. Results: The prevalence of caries was 22.8% (95% CI: 19.8%–25.8%). Children who were breastfed for 12–23 months (TCE = 1.13, 95% CI: 1.05–1.20) and for ≥24 months (TCE = 1.27, 95% CI: 1.14–1.40) presented a higher risk of caries at age of 2 years than those breastfed <12 months. However, this risk was slightly mediated by a decreased frequency of sugar consumption at age of 2 years only for breastfeeding from 12 to 23 months (NIE; OR = 0.95, 95% CI: 0.91–0.97). Conclusions: In this study, the effect of prolonged breastfeeding on the increased risk of dental caries was slightly mediated by sugar consumption. Early feeding practices for caries prevention and promoting breastfeeding while avoiding sugar consumption should be targeted in the first 2 years of life.publishersversioninpres

Genetic relatedness of Plasmodium falciparum isolates and the origin of allelic diversity at the merozoite surface protein-1 (MSP-1) locus in Brazil and Vietnam

BACKGROUND: Despite the extensive polymorphism at the merozoite surface protein-1 (MSP-1) locus of Plasmodium falciparum, that encodes a major repetitive malaria vaccine candidate antigen, identical and nearly identical alleles frequently occur in sympatric parasites. Here we used microsatellite haplotyping to estimate the genetic distance between isolates carrying identical and nearly identical MSP-1 alleles. METHODS: We analyzed 28 isolates from hypoendemic areas in north-western Brazil, collected between 1985 and 1998, and 23 isolates obtained in mesoendemic southern Vietnam in 1996. MSP-1 alleles were characterized by combining PCR typing with allele-specific primers and partial DNA sequencing. The following single-copy microsatellite markers were typed : Polyα, TA42 (only for Brazilian samples), TA81, TA1, TA87, TA109 (only for Brazilian samples), 2490, ARAII, PfG377, PfPK2, and TA60. RESULTS: The low pair-wise average genetic distance between microsatellite haplotypes of isolates sharing identical MSP-1 alleles indicates that epidemic propagation of discrete parasite clones originated most identical MSP-1 alleles in parasite populations from Brazil and Vietnam. At least one epidemic clone propagating in Brazil remained relatively unchanged over more than one decade. Moreover, we found no evidence that rearrangements of MSP-1 repeats, putatively created by mitotic recombination events, generated new alleles within clonal lineages of parasites in either country. CONCLUSION: Identical MSP-1 alleles originated from co-ancestry in both populations, whereas nearly identical MSP-1 alleles have probably appeared independently in unrelated parasite lineages

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

Modeling the Effects of Relapse in the Transmission Dynamics of Malaria Parasites

Often regarded as “benign,” Plasmodium vivax infections lay in the shadows of the much more virulent P. falciparum infections. However, about 1.98 billion people are at risk of both parasites worldwide, stressing the need to understand the epidemiology of Plasmodium vivax, particularly under the scope of decreasing P. falciparum prevalence and ecological interactions between both species. Two epidemiological observations put the dynamics of both species into perspective: (1) ACT campaigns have had a greater impact on P. falciparum prevalence. (2) Complete clinical immunity is attained at younger ages for P. vivax, under similar infection rates. We systematically compared two mathematical models of transmission for both Plasmodium species. Simulations suggest that an ACT therapy combined with a hypnozoite killing drug would eliminate both species. However, P. vivax elimination is predicted to be unstable. Differences in age profiles of clinical malaria can be explained solely by P. vivax's ability to relapse, which accelerates the acquisition of clinical immunity and serves as an immunity boosting mechanism. P. vivax transmission can subsist in areas of low mosquito abundance and is robust to drug administration initiatives due to relapse, making it an inconvenient and cumbersome, yet less lethal alternative to P. falciparum

Modelling the epidemiology of residual Plasmodium vivax malaria in a heterogeneous host population : a case study in the Amazon Basin

The overall malaria burden in the Americas has decreased dramatically over the past two decades, but residual transmission pockets persist across the Amazon Basin, where Plasmodium vivax is the predominant infecting species. Current elimination efforts require a better quantitative understanding of malaria transmission dynamics for planning, monitoring, and evaluating interventions at the community level. This can be achieved with mathematical models that properly account for risk heterogeneity in communities approaching elimination, where few individuals disproportionately contribute to overall malaria prevalence, morbidity, and onwards transmission. Here we analyse demographic information combined with routinely collected malaria morbidity data from the town of Mâncio Lima, the main urban transmission hotspot of Brazil. We estimate the proportion of high-risk subjects in the host population by fitting compartmental susceptible-infected-susceptible (SIS) transmission models simultaneously to age-stratified vivax malaria incidence densities and the frequency distribution of P. vivax malaria attacks experienced by each individual over 12 months. Simulations with the best-fitting SIS model indicate that 20% of the hosts contribute 86% of the overall vivax malaria burden. Despite the low overall force of infection typically found in the Amazon, about one order of magnitude lower than that in rural Africa, high-risk individuals gradually develop clinical immunity following repeated infections and eventually constitute a substantial infectious reservoir comprised of asymptomatic parasite carriers that is overlooked by routine surveillance but likely fuels onwards malaria transmission. High-risk individuals therefore represent a priority target for more intensive and effective interventions that may not be readily delivered to the entire community

Challenges for malaria elimination in Brazil

Brazil currently contributes 42 % of all malaria cases reported in the Latin America and the Caribbean, a region where major progress towards malaria elimination has been achieved in recent years. In 2014, malaria burden in Brazil (143,910 microscopically confirmed cases and 41 malaria-related deaths) has reached its lowest levels in 35 years, Plasmodium falciparum is highly focal, and the geographic boundary of transmission has considerably shrunk. Transmission in Brazil remains entrenched in the Amazon Basin, which accounts for 99.5 % of the country’s malaria burden. This paper reviews major lessons learned from past and current malaria control policies in Brazil. A comprehensive discussion of the scientific and logistic challenges that may impact malaria elimination efforts in the country is presented in light of the launching of the Plan for Elimination of Malaria in Brazil in November 2015. Challenges for malaria elimination addressed include the high prevalence of symptomless and submicroscopic infections, emerging anti-malarial drug resistance in P. falciparum and Plasmodium vivax and the lack of safe anti-relapse drugs, the largely neglected burden of malaria in pregnancy, the need for better vector control strategies where Anopheles mosquitoes present a highly variable biting behaviour, human movement, the need for effective surveillance and tools to identify foci of infection in areas with low transmission, and the effects of environmental changes and climatic variability in transmission. Control actions launched in Brazil and results to come are likely to influence control programs in other countries in the Americas

CD4 T follicular cells and B cells

© 2023 Wiley-VCH GmbH.Regulatory and effector cell responses to Plasmodium vivax, the most common human malaria parasite outside Africa, remain understudied in naturally infected populations. Here, we describe peripheral CD4 + T- and B-cell populations during and shortly after an uncomplicated P. vivax infection in 38 continuously exposed adult Amazonians. Consistent with previous observations, we found an increased frequency in CD4 + CD45RA - CD25 + FoxP3 + T regulatory cells that express the inhibitory molecule CTLA-4 during the acute infection, with a sustained expansion of CD21 - CD27 - atypical memory cells within the CD19 + B-cell compartment. Both Th1- and Th2-type subsets of CXCR5 + ICOS hi PD-1 + circulating T follicular helper (cTfh) cells, which are thought to contribute to antibody production, were induced during P. vivax infection, with a positive correlation between overall cTfh cell frequency and IgG antibody titers to the P. vivax blood-stage antigen MSP1 19 . We identified significant changes in cell populations that had not been described in human malaria, such as an increased frequency of CTLA-4 + T follicular regulatory cells that antagonize Tfh cells, and a decreased frequency of circulating CD24 hi CD27 + B regulatory cells in response to acute infection. In conclusion, we disclose a complex immunoregulatory network that is critical to understand how naturally acquired immunity develops in P. vivax malaria.publishersversionepub_ahead_of_prin