Biology subjects

Arinaitwe, E.

Publications and source records attributed to Arinaitwe, E..

8 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↗

bioRxiv2025

CXCR6⁺ CD127- Tr1 Cells Balance Immunity and Persistence in Plasmodium falciparum Infection

Plasmodium falciparum (Pf) induces the clonal expansion of antigen-specific type 1 regulatory T (Tr1) cells with a capacity for long-term memory. Tr1 cells comprise nearly 90% of the Pf blood stage antigen-specific CD4+ T cell pool in children. Though, whether Tr1 cells contribute to protection from malaria remains undetermined. To address this critical gap in knowledge, we first performed scRNAseq on gated cell populations to validate CXCR6+ CD127- as new phenotypic markers to enrich for bona-fide Tr1 cells. Importantly, these Tr1 cells potently suppressed the proliferation of other CD4+ T cells in vitro via IL-10 secretion. Among children living in malaria-endemic Uganda, CXCR6+ CD127- Tr1 cells were the dominant responding subset to Pf-infected red blood cell stimulation in vitro. They also rapidly expanded following malaria and expressed IL-10 and IFNg during infection in vivo. Tr1 abundance correlated with plasma concentrations of granzyme A, IFNg, IL-10, and LAG3, suggesting that these cells act systemically. Higher CXCR6+ CD127- Tr1 cell frequencies correlated with a lower probability of symptoms given parasitemia but were also associated with delayed parasite clearance among untreated, asymptomatic children. These data suggest that Tr1 cells help mediate clinical immunity to malaria but may also facilitate parasite persistence through mechanisms of immune regulation.

immunology↗

bioRxiv2025

Inhibitory NK receptors regulate the γδ T cell response to malaria

Gamma delta ({gamma}{delta}) T cells are important mediators of the immune response to childhood malaria infection. Human V{gamma}9+V{delta}2+ T cells possess intrinsic, HLA-independent responsiveness to Plasmodium falciparum phosphoantigens produced in the blood stage of malaria infection. Engagement of the {gamma}{delta} T cell receptor (TCR) by phosphoantigen-bound butyrophilin molecules results in V{gamma}9+V{delta}2+ T cell expansion, pro-inflammatory cytokine production, and release of cytotoxic granules that mediate parasite killing. Repeated malaria infection, however, leads to a reduction in circulating V{gamma}9+V{delta}2+ T cells and upregulation of immunomodulatory molecules, including NK receptors, that correlates with less severe symptoms upon infection. We explore phenotypic and functional differences of {gamma}{delta} T cells in Ugandan children with high versus low malaria exposure, utilizing high-parameter spectral flow cytometry analysis of PBMCs. We observed significant differences in expression of inhibitory NK receptors - KIR2DL1, KIR2DL2/3, KIR3DL1, LILRB1, and NKG2A - on {gamma}{delta} T cell subsets, with V{gamma}9+V{delta}2+ T cells exhibiting a divergent mechanism of control compared to other subsets. We found that NKG2A and KIR3DL1 expression associated with potent V{gamma}9+V{delta}2+ T cell responses to TCR- and Fc receptor (FcR)-mediated stimulation while KIR2DL1, KIR2DL2/3 and LILRB1 associated with reduced degranulation and cytokine production. These results identify a new role for inhibitory NK receptors expressed on {gamma}{delta} T cells, exerting a finely tuned balance of activating and inhibitory signals to regulate the response to malaria-related antigens. AUTHOR SUMMARYMalaria remains one of the deadliest infectious diseases, disproportionately affecting young children in sub-Saharan Africa who succumb to sequelae of Plasmodium falciparum infection. However, children living in highly endemic areas experience repeated malaria infection and develop naturally acquired-but not sterilizing-immunity which leads to an asymptomatic reinfection pattern. The immune factors that determine the balance of inflammatory and tolerogenic functions seen in non-sterilizing malaria immunity are yet to be fully understood. Here, we focus on the phenotypic and functional differences in one cell type between children with a history of low versus high malaria exposure. We identified a group of inhibitory surface receptors that improved the antimalarial function of this cell, and another group that worsened their function. Our study clarifies the immune landscape in highly malaria-exposed individuals and illuminates one potential system of regulating the cellular response to repeat infection.

immunology↗

bioRxiv2025

Significant variations in tolerance to clothianidin and pirimiphos-methyl in Anopheles gambiae and Anopheles funestus populations during a dramatic malaria resurgence despite sustained indoor residual spraying in Uganda

A dramatic malaria resurgence occurred in areas of Uganda between 2020 and 2022 coincident with the switch to clothianidin-based formulations for indoor residual spraying. During the resurgence, Anopheles funestus numbers increased but when an alternative insecticide, pirimiphos methyl, was reintroduced in 2023, both malaria cases and An. funestus mosquito density fell. In this study, we investigated possible causes of the resurgence by assessing; 1) whether sufficient quantities of insecticide were sprayed; 2) the residual insecticide bioefficacy against wild mosquitoes and; 3) the insecticide susceptibility of vector populations using standard test tube assays and wall cone assays. In 2023, after adjusting for extraction efficiency, 70-80% of the houses had optimal residual concentrations of insecticides (clothianidin >0.3g/m2; pirimiphos methyl >0.5g/m2) with significant variations between sampling rounds and wall types. Mud walls had the lowest residual concentration of insecticides, and the lowest observed mortality in wall cone assays, compared to fired bricks with plaster/cement/paint. In the studies of residual bio efficacy, by World Health Organization (WHO) definitions, An. funestus showed resistance to clothianidin (<80% mortality) up to 11 months and susceptibility to pirimiphos methyl (>90% mortality) when exposed to wall surfaces up to 7 months post-spray. In WHO tube tests, variations were observed in susceptibility to clothianidin in An. funestus populations using dose- and time-response assays (80-98% mortality). In 2022, An. gambiae was largely susceptible to the clothianidin-based formulation Sumishield (85-90% mortality) although the levels dropped slightly in 2023 (60-85% mortality) mainly in mud and pole houses. In contrast, An. gambiae was mildly susceptible to the pirimiphos methyl-based formulation Actellic ([~]80% mortality) and time response assays showed An. gambiae populations had very low knockdown and mortality at lower exposure time compared to An. funestus. Regression models showed a positive association between residual insecticide concentration (RIC) and mortality in houses sprayed with Sumishield but not Actellic houses. Despite the possible variations observed in spray operations, the study revealed that An. funestus exhibited a higher tolerance to clothianidin-based formulations compared to An. gambiae, and this might have driven the malaria resurgence observed in Uganda. However, there are signals of An. gambiae resistance to pirimiphos-methyl which will require further investigation and monitoring.

zoology↗

bioRxiv2024

Pfs230 Domain 12 is a potent malaria transmission-blocking vaccine candidate

Malaria transmission-blocking vaccines (TBV) target sexual stage parasites that are transmitted to mosquitoes and critical for spread of the pathogen. The clinically most advanced TBV candidate contains part of the Pro-domain (Pro) and Domain 1 (D1) of Plasmodium falciparum surface protein Pfs230. Subunit vaccines that contain other domains of Pfs230 have so far failed to induce functional antibodies. Here, we produced eight single domain fragments of Pfs230 in Drosophila melanogaster S2 cells and assessed their immunogenicity in mouse immunizations. In addition to D1-specific antibodies, antibodies raised against Domain 12 (D12) showed strong recognition of Pfs230 on the surface of female parasites. Importantly, D12-specific antibodies showed strong functional transmission-reducing activity in membrane feeding assays with cultured parasites, an activity that was complement-dependent. Murine D12-specific antibodies further reduced mosquito transmission of parasites acquired from naturally infected parasite carriers. The D12 antigen was recognized by sera from an all-age cohort of individuals who had been naturally exposed to Plasmodium falciparum with antibody levels increasing with age. In conclusion, we identified Pfs230D12 as a promising new TBV candidate. Impact statementPfs230 Domain 12 induces antibodies in mice that strongly reduce transmission of lab-cultured and naturally circulating malaria parasites to mosquitoes.

immunology↗

bioRxiv2021

Age dependent changes in circulating Tfh cells influence the development of functional antibodies to malaria in children.

T-follicular helper (Tfh) cells are key drivers of antibodies that protect from malaria. However, little is known regarding the host and parasite factors that influence Tfh and functional antibody development. Here, we use samples from a large cross-sectional study of children residing in an area of high malaria transmission in Uganda to characterize Tfh cells and functional antibodies to multiple parasites stages. We identify a dramatic re-distribution of the Tfh cell compartment with age that is independent of malaria exposure, with Th2-Tfh cells predominating in early childhood, while Th1-Tfh cell gradually increase to adult levels over the first decade of life. Functional antibody acquisition is age-dependent and hierarchical acquired based on parasite stage, with merozoite responses followed by sporozoite and gametocyte antibodies. Antibodies were boosted in children with current infection, and were higher in females. The children with the very highest antibody levels had increased Tfh cell activation and proliferation, consistent with a key role of Tfh cells in antibody development. Together, these data reveal a complex relationship between the circulating Tfh compartment, antibody development and protection from malaria.

immunology↗

bioRxiv2020

Impact of a rapid decline in malaria transmission on antimalarial IgG subclasses and avidity

Understanding how immunity to malaria is affected by declining transmission is important to aid vaccine design and understand disease resurgence. Both IgG subclasses and avidity of antigen-specific responses are important components of an effective immune response.Using a multiplex bead array assay, we measured the total IgG, IgG subclasses, and avidity profiles of responses to 18 P. falciparum blood stage antigens in samples from 160 Ugandans collected at 2 time points during high malaria transmission and 2 time points following a dramatic reduction in transmission.Results demonstrated that, for the antigens tested, (i) the rate of decay of total IgG following infection declined with age and was driven consistently by the decrease in IgG3 and occasionally the decrease in IgG1; (ii) the proportion of IgG3 relative to IgG1 in the absence of infection increased with age; (iii) the increase in avidity index (the strength of association between the antibody and antigen) following infection was largely due to a rapid loss of non-avid compared to avid total IgG; and (iv) both avid and non-avid total IgG in the absence of infection increased with age.Further studies are required to understand the functional differences between IgG1 and IgG3 in order to determine their contribution to the longevity of protective immunity to malaria. Measuring changes in antibody avidity may be a better approach of detecting affinity maturation compared to avidity index due to the differential expansion and contraction of high and low avidity total IgG.Competing Interest StatementThe authors have declared no competing interest.View Full Text

immunology↗

bioRxiv2017

Quantification of anti-parasite and anti-disease immunity to malaria as a function of age and exposure

Malaria immunity is complex and multi-faceted, and fundamental gaps remain in our understanding of how it develops. Here, we use detailed clinical and entomological data from three parallel cohort studies conducted across the malaria transmission spectrum in Uganda to quantify the development of immunity against symptomatic Plasmodium falciparum as a function of age and transmission intensity. We focus on: anti-parasite immunity (i.e; ability to control parasite densities) and anti-disease immunity (i.e; ability to tolerate higher parasite densities without fever). Our findings suggest a strong effect of age on both types of immunity, that remains significant after adjusting for cumulative exposure. They also show a non-linear effect of transmission intensity, where children experiencing the lowest transmission appear to develop immunity faster than those experiencing higher transmission. These findings illustrate how anti-parasite and anti-disease immunity develop in parallel, reducing the probability of experiencing symptomatic malaria upon each subsequent P. falciparum infection.

epidemiology↗