Monocytes as Contributors to Neuroinflammation During ZIKV Infection in the Immunocompetent Adult 6 views

Zika virus (ZIKV) is a neurotropic pathogen linked to neuropathogenesis in adults, causing conditions such as Guillain-Barré syndrome (GBS) and fatal encephalitis. Intracranial injection of virus in immunocompromised mice have shown neuroinflammation and subsequent brain damage. However, the mechanisms underlying ZIKV-induced neuroinflammation in immunocompetent adult mice via peripheral infection remain unclear. To investigate this, we utilized a murine model of ZIKV infection via footpad injection. Our findings reveal that acute ZIKV infection at 4 days post-infection (4 dpi) induces significant apoptosis and neuroinflammation in the adult brain, persisting up to 28 dpi. Notably, ZIKV infection triggers apoptosis in the hippocampus and cortex—key regions involved in memory—and induces early immune cell infiltration. Additionally, microglial activation occurs following infection at 7 dpi, with viral RNA detected in the brain. Bulk RNA sequencing of the hippocampus at 28 dpi further reveals the activation of inflammatory pathways, underscoring the prolonged neuroinflammatory response in the infected brain. Microglial activation is likely driven by infiltrating monocytes, as inhibiting monocyte recruitment reduced the expression of microglial activation genes. Further investigation into more mechanistic insights revealed that the mitochondrial pyruvate carrier protein if knocked out helps modulate ZIKV pathogenesis. These results suggest that targeting monocyte- induced inflammatory mediators could be potential therapeutic interventions for ZIKV. To determine the molecular mechanism for ZIKV-induced microglial activation, I investigated the impact of mitochondria function on activation of pathogenic microglia. Mitochondria have essential functions in glucose/lipid metabolism linking to the supply of energy in the body. Recent studies report that mitochondria play a role in inflammatory responses. In particular, mitochondrial pyruvate carrier (MPC) is involved in metabolism as well as inflammatory responses. We show that in pharmacological inhibition of MPC using the MSDC inhibitor, human THP-1 monocytes have increased viral RNA and a decrease in certain inflammatory cytokine gene levels and anti-viral genes like ISG15 and RIG-I. Additionally, in the MPC2 knockout BMDMs, ZIKV RNA is increased along with decreased levels in inflammatory gene induction and increased secreted inflammatory proteins. These results indicate a role for MPC in mounting inflammatory responses during ZIKV infection.

PHD (Doctor of Philosophy)

Zika virus; Monocytes; Chronic; Neuroinflammation; Microglia; Immunocompetent model; Metabolism

English

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2026-04-15