NOD2 activation reprograms infiltrating inflammatory monocytes in the Zika virus infected CNS to maintain neural correlates of learning and memory

Jeremy D Hill; Alice H W Dong; Joshua Liu; Marina Diniz Barbezani; Tallulah S Andrews; Robyn S Klein

doi:10.64898/2026.05.19.726300

NOD2 activation reprograms infiltrating inflammatory monocytes in the Zika virus infected CNS to maintain neural correlates of learning and memory

bioRxiv [Preprint]. 2026 May 21:2026.05.19.726300. doi: 10.64898/2026.05.19.726300.

Authors

Jeremy D Hill¹, Alice H W Dong¹, Joshua Liu², Marina Diniz Barbezani¹, Tallulah S Andrews^{3

4}, Robyn S Klein^{1

5

6}

Affiliations

¹ Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON.
² Department of Medicine, Washington University School of Medicine, St. Louis, MO.
³ Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, ON.
⁴ Department of Computer Science, Western Univeristy, London, ON.
⁵ Department of Internal Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON.
⁶ Western Institute of Neuroscience, Western University, London, ON.

Abstract

Zika virus (ZIKV) encephalitis induces cytokine-mediated cognitive deficits which persist long-term. Here, we determined if NOD2-mediated conversion of monocytes from Ly6C^Hi inflammatory to Ly6C^Lo anti-inflammatory phenotypes during ZIKV encephalitis preserves neural correlates of learning and memory within the hippocampus. Short-term administration of the NOD2 agonist, muramyl dipeptide (MDP), during peak ZIKV infection prevents synapse elimination and loss of adult hippocampal neurogenesis, without impacting CNS virologic control. Transcriptomic analyses of forebrain immune cells in MDP-treated mice revealed functional modulation of infiltrated monocytes and T cells, reducing their expression of proinflammatory cytokines, with limited effects on microglia, compared to controls. Notably, NOD2 activation in peripheral immune cells alone balances innate immune signals, preserving synapses, and increasing macrophage phagocytic capacities that do not target synapses. Our findings identify infiltrating Ly6C^Hi monocytes as key drivers of long-term cognitive dysfunction following ZIKV encephalitis and as potential therapeutic targets for limiting synapse loss.

Keywords: NOD2; Viral encephalitis; Zika virus; adult neurogenesis; inflammatory monocyte; microglia; muramyl dipeptide; spatial learning and memory; synapse elimination.

Publication types

Preprint