Theophilus Nang Wakai

Background: Population-level studies have linked malaria endemicity to shorter leukocyte telomere length, but the patient-level molecular basis of this association remains unknown. This study investigated the associations of microscopy-confirmed malaria with relative leukocyte telomere length (rTL), human telomerase reverse transcriptase (hTERT) expression, parasite density, and haematological parameters in an endemic Nigerian cohort. Methods: A total of 304 participants with complete microscopy and haematological data were included, comprising equal numbers of malaria-positive (n = 152) and malaria-negative (n = 152) individuals. From this cohort, an age-matched molecular subset of 40 participants (22 malaria-positive and 18 malaria-negative) was selected for rTL and hTERT analyses. Relative leukocyte telomere length was determined as the telomere-to-single-copy gene (T/S) ratio using 36B4, while hTERT expression was quantified by RT-qPCR using GAPDH as the housekeeping gene. Results: Malaria-positive participants had significantly lower haemoglobin and platelet counts than controls (both p < 0.001). In the molecular subset, malaria-positive participants had significantly shorter rTL than controls ( p < 0.001), whereas hTERT expression was significantly higher ( p = 0.004). Among malaria-positive participants, rTL differed across parasite-density categories ( p = 0.011) and was inversely associated with parasite density (r = −0.68, p < 0.001). Exploratory multivariable analyses showed that malaria positivity and higher parasite density were independently associated with shorter relative leukocyte telomere length. Discussion/conclusion: To the best of our knowledge, this study is the first to provide patient-level evidence supporting the hypothesis that active malaria may contribute to the shorter relative leukocyte telomere length observed in malaria-endemic African populations. Longitudinal studies are needed to determine whether these changes are transient, cumulative, or reversible following treatment.

Introduction: Malaria pathogenesis involves both parasite burden and host inflammatory and oxidative stress responses that contribute to haematological alterations. Full blood count (FBC)-derived indices have been explored as accessible surrogate biomarkers, reflecting systemic inflammatory changes; however, they provide limited mechanistic insight into underlying haem-driven oxidative stress pathways. Haem oxygenase-1 (HO-1) reflects cellular responses to free haem, while interleukin-6 (IL-6) mediates systemic inflammation. However, their combined role in relation to parasitaemia and haematological alterations in endemic populations remains insufficiently defined. This study evaluated plasma HO-1 and IL-6 as complementary host-response biomarkers in a hospital-based malaria-endemic population. Methods: This cross-sectional study was conducted at Covenant University Medical Centre (CUMC), Canaanland, Ota, Ogun State, Nigeria. A total of 647 individuals were screened, and 304 participants with complete microscopy and haematological data were retained in the analytical cohort (152 microscopy-positive and 152 microscopy-negative). An integrated biomarker subset of 40 participants with matched plasma samples and complete laboratory data was used for ELISA, correlation, and receiver operating characteristic (ROC) analyses. Group comparisons used Mann-Whitney U and Kruskal-Wallis tests, categorical variables were compared using chi-square or Fisher exact tests, and associations were assessed using Spearman correlation. Results: In the analytical cohort, microscopy-positive participants had lower haemoglobin, haematocrit, red-cell count, mean cell indices, and platelet counts, together with higher temperature and white-cell counts than microscopy-negative participants (all p< 0.001 for the major contrasts). Fever and anaemia were also substantially more frequent in microscopy-positive participants. In the biomarker subset, IL-6 was significantly higher in malaria-positive participants than malaria-negative participants (median 141.28 vs 106.58 pg/mL; p = 0.027), whereas HO-1 showed a non-significant upward shift (230.98 vs 193.73 ng/mL; p = 0.131). IL-6 correlated positively with HO-1 (rho = 0.702, p< 0.001), parasitaemia (rho = 0.387, p = 0.015), and temperature (rho = 0.432, p = 0.006), and negatively with haemoglobin (rho = -0.417, p = 0.008). ROC analysis showed moderate discriminatory performance for IL-6 and lower performance for HO-1. IL-6 yielded an AUC of 0.709 (95% CI 0.531–0.874), with sensitivity of 72.7% and specificity of 76.5% at the Youden-optimal threshold. HO-1 yielded an AUC of 0.641 (95% CI 0.440–0.826), while the combined IL-6 + HO-1 model yielded an AUC of 0.687 (95% CI 0.461–0.886). Conclusions: IL-6 showed better discriminatory performance than HO-1 in this cohort, while HO-1 demonstrated only modest and non-significant differences between groups. These findings suggest that IL-6 may be a more informative adjunct inflammatory marker in malaria, whereas the role of HO-1 requires further validation in larger studies.

Malaria is a life-threatening parasitic disease and remains a major cause of morbidity and mortality worldwide. The clinical course of malaria ranges from uncomplicated infection to severe disease, driven by extensive hemolysis, inflammation, and oxidative stress. Heme oxygenase-1 (HO-1), an inducible enzyme involved in heme degradation, has been demonstrated to play a crucial role in the host’s response to Plasmodium infection. Experimental and clinical studies suggest that HO-1 is strongly induced during malaria and plays a crucial role in regulating inflammation, oxidative damage, and tissue injury. In murine models, HO-1 induction confers protection against severe malaria complications, including cerebral malaria and organ dysfunction, partly by modulating pro-inflammatory cytokines and vascular permeability. Conversely, elevated HO-1 expression in specific immune cell populations has been associated with heightened inflammatory responses and disease severity in humans, highlighting its context-dependent effects. Here, we review the key roles of HO-1 in malaria pathogenesis, emphasising its dual protective and pathological functions, and discuss its potential relevance as a diagnostic and prognostic biomarker and as a therapeutic target.

Malaria remains a significant burden to public health, causing an estimated 282 million new cases in 2024 alone. Recurrent infections and increasing antimalarial resistance contribute to weakening immunity, a process that includes accelerated cellular ageing in immune cells, associated with telomere shortening. Increasing evidence suggests a link between Plasmodium infection and accelerated telomere shortening, as well as immune cell senescence. hTERT, a catalytic subunit of human telomerase enzyme is essential for maintaining telomere length (TL) and cellular replicative capacity. Although predominantly inactive in most somatic cells, hTERT appears to be partially reactivated during chronic malaria, contributing to limited restoration of telomere loss. Mechanisms that drive this unprecedented response is yet to be elucidated. Interferon-gamma (IFN-γ) is a key mediator of malaria immunity, driving immune activation, lymphocyte proliferation, and parasite clearance. Evidence from other disease contexts, like cancer, where IFN-γ signaling has been linked to hTERT regulation, it is plausible to hypothesize that sustained IFN-γ activity may influence hTERT expression during malaria infection; however, this remains hypothetical. While cytokines such as interleukin-6 (IL-6) have been suggested to modulate hTERT, the involvement of IFN-γ in regulating hTERT in its regulation during malaria has not been experimentally validated. Herein, we review emerging evidence on IFN-γ–association to immune activation and explores its potential implications for hTERT regulation and telomere dynamics in malaria, a key knowledge gap that is relevant to immune senescence and susceptibility to reinfection.

Infection with the malaria parasite Plasmodium, remains a major cause of illness and death world-wide. The development of evasion strategies by the parasite from host immunity and its adaptability to antimalarial drugs has raised the urgency for developing new strategies to combat this disease. One promising avenue is targeting telomeres – sequences found at chromosome termini– and telomerase – the enzyme that catalysis synthesis of telomeres using an intrinsic RNA template. As telomeres shorten critically, cells undergo replicative senescence or apoptosis. Plasmodium, lacking telomerase activity in its human stages, exploits alternative mechanisms, accelerating telomere shortening, aging, and immune evasion. Chemical telomerase inhibitors show promise as antimalarials. In this review, we examine the potential of targeting this system in malaria therapy, with telomerase inhibitors offering a novel approach. A systematic search on PubMed using Boolean techniques identified 246 relevant articles from 1985 to March 31, 2024. After filtering, 43 articles met inclusion criteria, supplemented by snowball sampling. The telomerase inhibitor drug strategy is widely applicable against cancer. However, given the drugability of telomerase and the absolute requirement for active telomere maintenance in the vast majority of parasites including plasmodium, telomerase and telomere maintenance could well represent the Achilles heel of the parasite