Biology subjects

Nankabirwa, J.

Publications and source records attributed to Nankabirwa, J..

4 recordsLinked to original sources

bioRxiv2026

Repeated malaria exposure reprograms Vδ2+ γδT cell chromatin accessibility and immune function toward a reversible hyporesponsive state

V{delta}2+ {gamma}{delta} T cells contribute to antimalarial immunity via pro-inflammatory and cytotoxic mechanisms. Among children who have experienced repeated episodes of malaria, V{delta}2+ T cells develop reduced pro-inflammatory function through mechanisms that remain unknown. We hypothesized that recurrent malaria drives coordinated epigenetic and transcriptional remodeling of these semi-innate cells. Using PBMC from Ugandan children in cohorts spanning high and low transmission (10 children) and longitudinally across a marked decline in transmission (20 children, 3 timepoints), we profiled the epigenome and transcriptome of V{delta}2+ T cells by paired bulk ATAC-seq and RNA-seq and by CITE-seq. Higher malaria exposure was associated with reduced V{delta}2+ T cell TNF and IFN{gamma} production and with thousands of differentially accessible chromatin regions. Immunoregulatory genes including LYN, PLCG2, and HAVCR2 (Tim-3) showed increased chromatin accessibility and/or expression at high exposure, whereas pro-inflammatory gene (IFNG, GZMK, IL7R) and AP-1 (JUN/FOS) motif accessibility were increased at low exposure; linkage of regulatory elements with target genes corroborated these associations. Single-cell transcriptional analysis identified a cytotoxic CD8+CD16+CD57+ V{delta}2+ T cell subset. In our in vitro model, repeated stimulation with malaria-infected red blood cells or the phosphoantigen HMBPP was similarly associated with reduced V{delta}2+ T cell degranulation and cytokine production. Diminished responsiveness was predominantly TCR-dependent, accompanied by heightened p38 signaling, and was partially reversed by rest induced by the tyrosine kinase inhibitor dasatinib. Together these data reveal how repeated malaria may reshape cellular immunity by reprogramming V{delta}2+ T cells toward a reversible, hyporesponsive state and highlight targets for therapeutically restoring their function.

immunology↗

bioRxiv2025

Signatures of selection and mechanisms of insecticide resistance in Ugandan Anopheles funestus: Insights from embedding translational genomics into the LLINEUP cluster randomised trial.

In response to the emerging threat of insecticide resistance in malaria vectors, insecticides are being repurposed for vector control or developed de novo. Good stewardship of these finite new resources is essential if disease control programmes are to remain effective. This is dependent on timely data to help guide evidence-based decision-making for National Malaria Control programmes (NMCPs). By embedding genomics into cluster randomized control trials (cRCTs), we can perform surveillance and early detection of insecticide resistance variants to new and repurposed chemicals in natural field conditions, supporting effective stewardship. The LLIN Evaluation Uganda Project (LLINEUP) trial evaluated the efficacy of pyrethroid-piperonyl butoxide (PBO) and pyrethroids-only long-lasting insecticidal nets (LLINs). It was conducted in Uganda between 2017-2020 and was the largest cRCT to date, covering 40% of the country in 104 health sub-districts. We embedded genomic surveillance within LLINEUP to detect and track insecticide resistance variants. At baseline and throughout the trial, we sampled Anopheles mosquitoes with Prokopack aspirators and performed Illumina whole-genome sequencing. We show that An. funestus populations were relatively unaffected by the interventions, compared to An. gambiae s.l., which were markedly reduced six months following LLIN deployment. Standard approaches for describing genetic diversity and population structure e.g. fixation index (FST), Principal Component Analysis (PCA) and Neighbour-Joining (NJ) trees, were consistent with the density observations and suggestive of a single large An. funestus population in Uganda with little genetic differentiation. Genome-wide selection scans revealed strong signals of selection at the Resistance to pyrethroid-1 (RP1) locus and Cyp9k1, both loci previously implicated in pyrethroid resistance. We report two additional loci, eye diacylglycerol kinase (Dgk) ({cong}13.5Mb on the X chromosome) and O-mannosyl-transferase (TMC-like) ({cong}67.9Mb on 3RL) that showed signals of selection. Known DDT and permethrin resistance-associated variants at the Gste2 locus, L119F and L119V, were also identified. Over the trial period, changes in haplotype frequencies were observed in regions under selection, with more pronounced shifts in the PBO arm. Notably, there were significant reductions in the frequencies of swept haplotypes (measured by delta ({Delta}) H12) in the Dgk and Cyp6p9a regions, while significant increases in haplotype frequency were observed at Gste2 and Cyp9k1 loci. Our findings reveal the differential impact of the trial on An. gambiae s.l. and An. funestus densities and the differing responses of An. funestus populations to pyrethroid and pyrethroid-PBO selection pressure. These insights underscore the potential value of tailored, species- and region-specific vector control strategies, supported by regional genetic surveillance, to better control insecticide resistance evolution and spread. By embedding genomic surveillance in cRCTs we can facilitate the discovery of putative resistance variants and can provide evidence of their impact on vector control tool efficacy; both of crucial importance to evidence-based deployment of vector control tools by NMCPs.

genomics↗

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↗