Vela, J. | bioRxiv Science

bioRxiv2026

CD40 ligand and IFN-γ induce proinflammatory activity and microglia-mediated neurodegeneration in human stem cell models

The cluster of differentiation 40 (CD40)/CD40 ligand (CD40L) co-stimulatory pathway plays a critical role in the activation and regulation of immune networks involving both adaptive and innate immune cells. Dysregulation of this pathway has been implicated in multiple autoimmune diseases, including multiple sclerosis (MS). MS is characterized by progressive neurodegeneration driven by compartmentalized neuroinflammation within the central nervous system (CNS), sustained low-grade T cell infiltration at the blood-brain barrier, and T cell reactivation at CNS border tissues. CD40L-expressing T cells can activate CD40-expressing microglia, which are a critical effector cell that contribute to neurodegeneration in MS. However, the consequence of this functional interaction in the brain remains poorly understood. Here, we demonstrate that the combination of CD40L and interferon-gamma (IFN-{gamma}), a cytokine produced by activated T cells, induces a robust inflammatory response and cell death in human induced pluripotent stem cells (hiPSC)-derived microglia. Stimulation with CD40L elicited microglial clustering, morphological transformation, and robust release of proinflammatory cytokines including interleukin-12 (IL-12), tumor necrosis factor-alpha (TNF-), and IL-6. Anti-CD40L antibody treatment reversed both cell death and inflammatory response and partially normalized the associated transcriptional changes. Furthermore, using an hiPSC-derived tri-culture system comprising neurons, astrocytes, and microglia, we demonstrated that CD40L and IFN-{gamma} trigger microglia-dependent neuronal dysregulation and death. Anti-CD40L treatment substantially attenuated neuronal injury. Finally, transcriptomic enrichment analysis identified CD40L-mediated microglial gene expression signatures that correlated with CD40 expression in primary progressive MS brain tissue but not in the normal-appearing white matter of healthy controls. Collectively, these findings support a role for the microglial CD40/T cell CD40L axis in MS pathology and suggest CD40L blockade as a potential therapeutic strategy warranting further investigation.

neuroscience↗

bioRxiv2024

Exposure to cooler temperatures during pupal development increases Aedes aegypti vector competence and the R0 for Zika virus

Temperature profoundly affects various aspects of ectotherm biology. Notably, in mosquito species that spread viral diseases, temperature influences not only vector biology, but also the dynamics of pathogen-vector interactions. However, research attempting to address the role of the thermal environment in disease transmission often employs constant temperatures, which do not reflect the natural diurnal fluctuations these organisms experience. Additionally, most studies focus on adult mosquitoes in the period following virus infection. Much less attention has been paid to evidence indicating that temperatures experienced during earlier developmental stages may also affect the ability of disease vectors to be infected with and transmit viruses. Here, we show that Aedes aegypti exposed to temperatures below 25{degrees}C, specifically during the pupal stage of development, exhibit heightened susceptibility to Zika virus (ZIKV), which increases transmission efficiency. Modeling suggests that exposing mosquitoes to cooler fluctuating diurnal temperature ranges only during the relatively short pupal stage increases the R0 or reproductive number of ZIKV. Data loggers placed near Harris County Mosquito Control trap sites consistently recorded temperatures below 25{degrees}C, indicating natural exposure to such conditions. These results highlight the significance of thermal heterogeneity in the microhabitats where container-breeding mosquitoes undergo development. Such heterogeneity may play a more important role in the transmission of mosquito-borne diseases than previously recognized. Author SummaryA paucity of information regarding how natural heterogeneity in thermal environments influences the spread of viral pathogens by mosquito species hinders our ability to decipher current and future patterns of disease transmission under changing climatic conditions. Here, we show that Ae. aegypti pupae exposed to cooler fluctuating diurnal temperature ranges, mimicking realistic field conditions, increases vector competence for ZIKV. Modeling cooler temperatures during immature life stages predicts slower development and increased mortality, counterbalancing increases in disease transmission. However, exposing mosquitoes to lower temperatures only during the relatively short pupal stage was predicted to increase the R0 value of ZIKV. These results suggest that environmental temperatures specifically experienced during the pupal stage may have an important role in disease transmission.

microbiology↗