The potential of interferon-gamma in the regulation of hTERT expression: insights into telomere dynamics and immune activation in malaria

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.