TGF-β signaling pathways are present in diverse animal species, which indicates their evolutionary importance in modulating several conserved biological processes and maintaining host homeostasis by adjusting the activity of innate immune mechanisms. Drosophila melanogaster utilizes two related but separable cascades of the canonical TGF-β signaling pathway: The Bone Morphogenetic Protein and Activin branches. Recent studies have produced significant information on the immune role of TGF-β signaling in the fruit fly model during response against certain bacterial pathogens. Results from further investigations have generated novel insights into the role of Drosophila TGF-β signaling molecules as immune regulators opposing infection against nematode parasites and their mutualistic bacterial partners. This knowledge has revealed a previously unknown layer of the host innate immune system. Here we summarize these recent breakthroughs focusing on the participation of TGF-β signaling factors in various Drosophila immune processes in relation to infection with potent bacteria and nematode parasites. The presented information provides important clues indicating directions for future research into the design of novel strategies for the effective control of infectious diseases caused by bacterial pathogens and parasitic nematodes.

Trained immunity (TRIM) enhances innate immune responses through epigenetic and metabolic reprogramming but may become maladaptive, contributing to chronic inflammation. In people living with HIV (PLWH), maladaptive TRIM has been proposed but remains insufficiently characterized. We examined inflammatory cytokine production in monocyte-derived macrophages (MDMs) obtained from PLWH and age-matched individuals without HIV infection. Baseline cytokine output and responses to stimulation of Toll-like receptors (TLR) were measured. We further examined whether TRIM influenced susceptibility to HIV infection in MDMs derived from monocytes exposed to extracellular vesicles carrying the HIV-1 Nef protein (Nef EVs). Baseline IL-6 production did not differ between unstimulated MDMs from PLWH and uninfected controls. Although sex-associated differences were initially observed, these effects were no longer significant after adjustment for infection duration. IL-6 responses following TLR2 and TLR7 stimulation, but not TLR4 stimulation, were significantly amplified in PLWH-derived MDMs, consistent with a trained phenotype. Similar trends were observed in sex-stratified analyses but did not reach statistical significance. The magnitude of unstimulated IL-6 production positively correlated with duration of HIV infection, suggesting cumulative TRIM imprinting over time. Despite heightened inflammatory responsiveness, TRIM did not reduce susceptibility to HIV infection in Nef EV-exposed MDMs, indicating functional maladaptation rather than protective priming. These findings provide evidence of maladaptive TRIM in PLWH, characterized by preserved basal cytokine output but exaggerated inflammatory responses to innate immune stimulation without antiviral benefit. The association with infection duration supports progressive innate immune reprogramming as a contributor to HIV-associated inflammation. No statistically significant differences in trained immune responses were observed between male and female PLWH after accounting for duration of infection. Further studies are needed to define the mechanisms underlying this maladaptation and its clinical consequences.

Background: Trained immunity (TRIM) enhances innate immune responses through epigenetic and metabolic reprogramming but can become maladaptive, contributing to chronic inflammation. In people living with HIV (PLWH), maladaptive TRIM has been proposed but remains insufficiently defined. Methods: We examined inflammatory cytokine production in monocyte-derived macrophages (MDMs) obtained from PLWH and age-matched individuals without HIV infection. Baseline cytokine output and responses to Toll-like receptor (TLR) stimulation were measured. We also assessed whether TRIM influenced susceptibility of MDMs to HIV infection. Results: Unstimulated MDMs from male, but not female, PLWH produced significantly higher levels of IL-6 compared with uninfected controls. IL-6 production positively correlated with duration of HIV infection, suggesting cumulative TRIM imprinting. TLR engagement markedly amplified cytokine responses in PLWH-derived MDMs, consistent with a trained phenotype. Despite enhanced inflammatory responsiveness, TRIM did not confer protection from HIV infection of MDMs, indicating functional maladaptation rather than beneficial priming. Conclusions: These findings provide evidence of maladaptive TRIM in PLWH, characterized by persistent inflammation and heightened cytokine responsiveness. The observed sex-specific differences suggest distinct TRIM programming in male and female PLWH. Further studies are needed to elucidate mechanisms driving these disparities and to determine their impact on HIV-associated inflammation and clinical outcomes.