Biology subjects

Pava, Z.

Publications and source records attributed to Pava, Z..

6 recordsLinked to original sources

bioRxiv2026

Circulating T-follicular helper and type I regulatory T cells have overlapping phenotypes in P. falciparum malaria and are maintained by parasite exposure.

Immunity to P. falciparum malaria develops slowly, requiring repeated infection in areas of high transmission, and wanes rapidly in the absence of parasite exposure. Key to this immunity, is the development of antibodies which is supported by CD4 T follicular helper (Tfh) cells that drive robust germinal centre responses. However, in malaria, the malaria-specific CD4 T cell compartment in peripheral blood is dominated by Type 1 regulatory T cells (Tr1), which produce high levels of IL-10 in response to parasites. Tr1-like Tfh cells (Tfh10) have been reported in several settings of repeated antigen stimulation but have not been investigated in malaria. Here we used single-cell RNA sequencing and multiparameter flow cytometry to characterise malaria-specific Tfh and Tr1 cells in a longitudinal cohort of highly exposed individuals and assessed their persistence after transmission interruption. Malaria-specific Tfh and Tr1 cells shared overlapping profiles, and Tr1 cell-like transcriptional signatures and phenotypes were detectable within the Tfh cell compartment. Tfh10 cell subsets were the dominant phenotype of malaria-specific Tfh cells. Following disruption of malaria transmission, the frequencies of malaria-specific Tr1 and Tfh10 cells declined. These findings highlight a close relationship between Tfh and Tr1 cells and show that the Tfh cell compartment in malaria is dominated by Tfh10 cells. The rapid waning of these cells in the absence of continuous exposure is consistent with requirements of persistent antigen in maintaining regulatory CD4 T cell phenotypes.

immunology↗

bioRxiv2026

Latent cytomegalovirus disrupts NK cell responses to P. falciparum and impairs parasite control

BackgroundNK cells are major innate and adaptive responders to malaria, with multiple roles in protection. Function of NK cells is heterogeneous, underpinned by expression of a diversity of receptors. One driver of NK cell heterogeneity is latent CMV infection, which drives the expansion of memory-like NK cells. We have recently reported that latent CMV infection can negatively impact the adaptive immune response to malaria, but whether CMV-mediated changes to the NK cell compartment also impact innate responses to malaria is unknown. MethodsWe investigated the impact of latent CMV infection on NK cell response to the malaria parasite Plasmodium falciparum in vitro, and in CMV seronegative and seropositive individuals during controlled human malaria infection. We analysed NK cell activation, cytotoxicity and NK cell receptor expression. Additionally, we investigated the impact of CMV serostatus on cytokine production in response to TLR stimulation in the myeloid cell compartment. The impact of CMV and NK cell responses on parasite control and malaria symptoms was investigated. ResultsNK cells from CMV seropositive individuals had reduced responsiveness to P. falciparum parasites in vitro and had reduced activation during controlled human infection. Reduced activation was not restricted to NK subsets modulated by CMV but occurred across the entire NK cell compartment. Consistent with global NK cell attenuation, IL-12 production from myeloid cells, a response that supports NK cell activation on exposure to P. falciparum parasites, was lower in CMV infected individuals. Linking NK cell activation to clinical outcomes, NK cells expressing perforin were associated with parasite control in CMV seronegative individuals. ConclusionCMV infection modulates NK cell responses during malaria by disruption of IL-12, leading to reduced parasite control.

immunology↗

bioRxiv2025

CCR7 Expression Distinguishes Functionally Distinct pTfh1 Subsets with Roles in Malaria-Specific Immunity

Antibodies induced by infection or vaccination are essential mediators of protection. Induction of these protective responses is mediated by T-follicular CD4 T (Tfh) cells, and targeting these cells may be a strategy to boost antibody mediate protection. In humans, Tfh cells are analysed based on expression of CXCR3 and CCR6, with different subsets of Tfh (Tfh1, Tfh2, Tfh17) associated with antibody induction in a context-dependent manner. Here we dissected Tfh cells heterogeneity in healthy donors and individuals during controlled human malaria infection using scRNAseq. We identified two distinct Tfh1-like subsets with functional relevance, defined based on CCR7 expression. CCR7neg Tfh1 cells express markers of cytotoxicity, while CCR7pos Tfh1 cells produce reduced inflammatory cytokines and similar IL-21 resulting in unique cytokine milieu. In controlled human malaria infection, both CCR7pos and CCR7neg Tfh1, along with Tfh2 cells, clonally expanded and were transcriptionally and phenotypically activated. However, only CCR7pos Tfh1 and Tfh2 cells associated with antibody development, suggesting a role for both these Tfh subsets in promoting humoral immunity to malaria. Data identify specific protective Tfh subsets that can be targeted to improve antibody mediated protection to malaria induced, and provide a frame work to dissect the role of Tfh subsets in other disease contexts.

immunology↗

bioRxiv2024

Age is an intrinsic driver of inflammatory responses to malaria

Age is a critical factor influencing the host immune response to infection and disease pathogenesis. In malaria, the risk of severe disease increases with age in non-immune individuals. Malaria severity is in part driven by inflammation, but the specific cells and mechanisms contributing to age-dependent disease risk are incompletely understood. Here, we assessed inflammatory cytokines in non-immune children and adults with clinical malaria, and the phenotypic, functional and transcriptional differences of in vitro innate cell responders to malaria parasites in naive children and adults. During naturally acquired malaria, age was associated with increased plasma levels of inflammatory chemokines CCL2, CCL3, CXCL8, CXLC9, along with CRP, and IDO, which were associated with clinical symptoms. In malaria naive individuals, classical monocyte and V{delta}2+ {gamma}{delta} T cell responses from adults were characterized by higher inflammatory cytokine production, and transcriptional activation following stimulation with malaria parasites. Classical monocyte responses in adults were dominated by CCL2 production, while in children the response had increased IL10 production and enrichment in IL10 signaling pathways upon parasite stimulation. This heightened inflammatory response in adults was not mitigated by parasite induced Tregs. Taken together, these findings identify cellular mechanisms of age-dependent host responses that play crucial roles in driving inflammatory responses in malaria.

immunology↗

bioRxiv2022

Malaria drives unique regulatory responses across multiple immune cell subsets

Plasmodium falciparum malaria results in immunoregulatory responses across multiple cell subsets, which protects the individual from inflammatory mediated immunopathogenesis. However, these anti-inflammatory responses also hamper the development of effective anti-parasitic immunity. Understanding malaria induced tolerogenic responses in specific cell subsets may inform the development of strategies to boost protective immunity during drug treatment and vaccination. Here, we analysed the immune landscape with single cell RNA sequencing of peripheral blood mononuclear cells during falciparum malaria and at convalescence in children and adults from a low malaria transmission area in Malaysia. To understand malaria driven changes specific to each immune cell subset, we interrogated transcriptional changes in sub-clustered major immune cell types during infection. We found that malaria drove development of immunosuppressive monocytes, alongside NK and {gamma}{delta} T cells which regulated inflammatory function but maintained cytolytic capacity. IL10-producing CD4 T cells and IL10-producing regulatory B cells were also induced. Type I interferon responses were identified across all cell types, linking Type I interferon signalling with the induction of immunoregulatory networks during malaria. Together, these findings provide insights into cell-specific and shared immunoregulatory changes induced during malaria, and provides a data set resource for additional analysis of anti-parasitic immunity and disease pathogenesis.

immunology↗

bioRxiv2019

A molecular barcode and online tool to identify and map imported infection with Plasmodium vivax

Imported cases present a considerable challenge to the elimination of malaria. Traditionally, patient travel history has been used to identify imported cases, but the long-latency liver stages confound this approach in Plasmodium vivax. Molecular tools to identify and map imported cases offer a more robust approach, that can be combined with drug resistance and other surveillance markers in high-throughput, population-based genotyping frameworks. Using a machine learning approach incorporating hierarchical FST (HFST) and decision tree (DT) analysis applied to 831 P. vivax genomes from 20 countries, we identified a 28-Single Nucleotide Polymorphism (SNP) barcode with high capacity to predict the country of origin. The Matthews correlation coefficient (MCC), which provides a measure of the quality of the classifications, ranging from -1 (total disagreement) to 1 (perfect prediction), exceeded 0.9 in 15 countries in cross-validation evaluations. When combined with an existing 37-SNP P. vivax barcode, the 65-SNP panel exhibits MCC scores exceeding 0.9 in 17 countries with up to 30% missing data. As a secondary objective, several genes were identified with moderate MCC scores (median MCC range from 0.54-0.68), amenable as markers for rapid testing using low-throughput genotyping approaches. A likelihood-based classifier framework was established, that supports analysis of missing data and polyclonal infections. To facilitate investigator-lead analyses, the likelihood framework is provided as a web-based, open-access platform (vivaxGEN-geo) to support the analysis and interpretation of data produced either at the 28-SNP core or full 65-SNP barcode. These tools can be used by malaria control programs to identify the main reservoirs of infection so that resources can be focused to where they are needed most.

molecular biology↗