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Monocytes as Contributors to Neuroinflammation During ZIKV Infection in the Immunocompetent Adult6 views
Author
Garcia Diaz, Josefina, Microbiology - School of Medicine, University of Virginia0000-0002-0116-2752
Advisors
Hahn, Young
Abstract
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.
Garcia Diaz, Josefina. Monocytes as Contributors to Neuroinflammation During ZIKV Infection in the Immunocompetent Adult. University of Virginia, Microbiology - School of Medicine, PHD (Doctor of Philosophy), 2026-04-15, https://doi.org/10.18130/5gg7-dd29.