Jamille Gregório Dombrowski

Malaria, caused by Plasmodium parasites, kills 610,000 people annually. The increasing availability of large-scale whole-genome sequencing (WGS) datasets enables investigation of parasite genetic diversity, population structure, and the spread of drug resistance. To investigate Plasmodium falciparum evolution, we analyse 17,565 isolates (17,489 previously published; 76 newly sequenced) from 39 countries, using identity-by-descent (IBD) networks, population structure inference, and selection scans. Analyses reveal distinct patterns of selection, transmission, and drug resistance. Selection analyses identify genomic regions across multiple metrics, encompassing established and emerging drug-resistance loci. These patterns highlight region-specific adaptive processes within Southeast Asia. IBD analyses reveal recent haplotype sharing that shows strong local selection. New WGS from Brazil show increased IBD around pfcrt , consistent with local drug-selection pressures. Similarly, isolates from Vietnam exhibit high relatedness and elevated IBD around pfKIC3 , with all isolates carrying the pfkelch13 C580Y artemisinin resistance mutation. Elevated IBD in pfKIC7 and pfKIC9 in South America and the Horn of Africa suggests alternative pathways for future artemisinin resistance. Together, these findings highlight the genomic basis of P. falciparum adaptation and offer improved resolution for genomic surveillance of evolving parasite populations.

Placental malaria (PM) causes mortality and severe morbidity in areas with stable Plasmodium falciparum transmission. The selective placental accumulation of P. falciparum -infected erythrocytes (IEs) is mediated by VAR2CSA, a PfEMP1-type parasite ligand that binds exclusively to placenta-restricted CSA. VAR2CSA-specific IgG is therefore generally restricted to women exposed to P. falciparum infection during pregnancy. However, widespread acquisition of VAR2CSA-reactive IgG outside pregnancy among Colombian and Brazilian individuals has been reported, supposedly due to cross-reactivity between VAR2CSA and the P. vivax -specific antigen PvDBP. Here, we measured levels and Fc-afucosylation of VAR2CSA-reactive IgG in plasma from pregnant Brazilian women at delivery, using full-length VAR2CSA (FV2) expressed in baculovirus-transfected insect cells (FV2 _BIC ) or Chinese hamster ovary cells (FV2 _CHO ) as well as the corresponding native antigen (IT4VAR04) on the IE surface. We also measured levels of IgG specific for GLURP ( P. falciparum- specific) and PvDBP ( P. vivax -specific). FV2 _CHO -specific IgG levels were lower than FV2 _BIC -reactive IgG levels. Furthermore, only FV2 _CHO -specific IgG was restricted to women exposed to P. falciparum during pregnancy. Levels of PvDBP-specific IgG were significantly higher among P. vivax -exposed pregnant women but did not correlate with FV2-specific IgG levels. Finally, FV2 _CHO -specific IgG was markedly Fc-afucosylated in contrast to FV2 _BIC -reactive IgG. Our findings caution against using levels of IgG reacting with recombinant proteins expressed in insect cells as a measure of exposure to VAR2CSA during pregnancy, at least in South America. Furthermore, our data do not support the hypothesis that exposure to PvDBP induces IgG that cross-reacts with VAR2CSA and contributes to protection against PM.

Alterations in angiogenic proteins play a role in newborn growth potential, and they have been widely studied, but not further explored in malaria research. We aimed to identify maternal peripheral proteins that are associated with newborn growth parameters in the context of malaria in pregnancy. We analysed data and biological samples collected from 386 pregnant women with and without malaria selected from previous cohort study in the Amazon region, Brazil, between 2013 and 2015. ELISAs were used to quantify Ang-1, Ang-2, Tie2, VEGF, sFlt1, VEGFR2, PlGF, sENG, and leptin in peripheral plasma at time of delivery. We generated receiver operating characteristic curves and multivariable logistic regression models to assess the associations of maternal peripheral protein levels with the anthropometric profiles of newborns. Tie2, sFlt1, sENG and leptin were associated to growth parameters in newborns of mothers who had malaria during pregnancy. sFlt1 levels were associated with newborn weight and length, and sENG was associated with newborn length in Plasmodium vivax -infected women. Tie2, sFlt1 and leptin levels were associated with newborn length in Plasmodium falciparum -infected women. Identifying maternal peripheral proteins associated with newborn outcomes might help in understanding biological dynamics of malaria in pregnancy in areas of low transmission, improving future health interventions, and encourage further studies with angiogenic proteins.

This study updates data on the distribution of CCR5Δ32 allele frequency in populations from Brazilian states. CCR5Δ32 is a variant allele of the CCR5 gene, which prevents (in homozygosity) or reduces (in heterozygosity) the expression of the CCR5 protein on the surface of leukocytes, being an important factor in infectious diseases. Also, this study reports the frequency of CCR5Δ32 in women from the state of Acre, located in the Brazilian Amazon, a region where the Δ32 allele and malaria are observed concurrently. We found allele frequencies of 2.88% in Plasmodium-infected women and of 1.04% among uninfected women. The low Δ32 allele frequencies observed in Acre, compared to other Brazilian regions, could be a reflection of the particular ancestry patterns in current Amazonian populations influenced by past European colonization.

Background: Plasmodium vivax infection, when it occurs during pregnancy, has often been associated with serious adverse pregnancy outcomes. However, immunological alterations in pregnancy and their consequences have been little explored. We characterized the humoral immune response in pregnant women exposed to malaria by P. vivax antigens and its association with the maternal inflammatory profile and poor pregnancy outcomes. Methods: An observational cohort study in the Brazilian Amazon was conducted between 2013 and 2015. After applying exclusion criteria, 242 mother-child pairs were included in the analysis. Data on maternal infection, gestational outcomes, and inflammatory factors were evaluated in the maternal peripheral plasma. In samples from the first infection, the presence of total IgG and its subclasses in plasma against PvMSP1₁₉ protein were also quantified. Results: Previous exposure to malaria, observed by anti-total IgG antibodies to the PvMSP1₁₉ antigen, increased the inflammatory response to infection when the pregnant woman had malaria during pregnancy. IL-6 and IL-10 levels were positively correlated with parasitemia and with total IgG levels; but they were negatively correlated with the gestational age at delivery from Pv-infected woman. In multivariate linear regression analyses, IgG 1, 2 and 4 was negatively and positively associated with cytokines IL-6 and IL-10, respectively, in P. vivax-infection. Conclusions: An association between the humoral immune response and the peripheral inflammatory cytokine profile with the adverse outcomes in malaria in pregnancy by P. vivax was observed. Previous exposure to the parasite can influence the IL-6 and IL-10 response, which is associated with increased parasitemia, reduced maternal weight gain and premature delivery.

Malaria in pregnancy (MiP) is a public health problem in malaria-endemic areas, contributing to detrimental outcomes for both mother and fetus. Primigravida and second-time mothers are most affected by severe anemia complications and babies with low birth weight compared to multigravida women. Infected erythrocytes (IE) reach the placenta, activating the immune response by placental monocyte infiltration and inflammation. However, specific markers of MiP result in poor outcomes, such as low birth weight, and intrauterine growth restriction for babies and maternal anemia in women infected with Plasmodium falciparum are limited. In this study, we identified the plasma proteome signature of a mouse model infected with Plasmodium berghei ANKA and pregnant women infected with Plasmodium falciparum infection using quantitative mass spectrometry-based proteomics. A total of 279 and 249 proteins were quantified in murine and human plasma samples, of which 28% and 30% were regulated proteins, respectively. Most of the regulated proteins in both organisms are involved in complement system activation during malaria in pregnancy. CBA anaphylatoxin assay confirmed the complement system activation by the increase in C3a and C4a anaphylatoxins in the infected plasma compared to non-infected plasma. Moreover, correlation analysis showed the association between complement system activation and reduced head circumference in newborns from Pf-infected mothers. The data obtained in this study highlight the correlation between the complement system and immune and newborn outcomes resulting from malaria in pregnancy.

Since December 2019, the world has been experiencing the COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and we now face the emergence of several variants. We aimed to assess the differences between the wild-type (Wt) (Wuhan) strain and the P.1 (Gamma) and Delta variants using infected K18-hACE2 mice. The clinical manifestations, behavior, virus load, pulmonary capacity, and histopathological alterations were analyzed. The P.1-infected mice showed weight loss and more severe clinical manifestations of COVID-19 than the Wt and Delta-infected mice. The respiratory capacity was reduced in the P.1-infected mice compared to the other groups. Pulmonary histological findings demonstrated that a more aggressive disease was generated by the P.1 and Delta variants compared to the Wt strain of the virus. The quantification of the SARS-CoV-2 viral copies varied greatly among the infected mice although it was higher in P.1-infected mice on the day of death. Our data revealed that K18-hACE2 mice infected with the P.1 variant develop a more severe infectious disease than those infected with the other variants, despite the significant heterogeneity among the mice.