Zika virus-induced TNF-α signaling dysregulates expression of neurologic genes associated with psychiatric disorders

Abstract

Background Zika virus (ZIKV) is an emerging flavivirus of global concern. ZIKV infection of the central nervous system has been linked to a variety of clinical syndromes, including microcephaly in fetuses and rare but serious neurologic disease in adults. However, the potential for ZIKV to influence brain physiology and host behavior following apparently mild or subclinical infection is less well understood. Furthermore, though deficits in cognitive function are well-documented after recovery from neuroinvasive viral infection, the potential impact of ZIKV on other host behavioral domains has not been thoroughly explored. Methods We used transcriptomic profiling, including unbiased gene ontology enrichment analysis, to assess the impact of ZIKV infection on gene expression in primary cortical neuron cultures. These studies were extended with molecular biological analysis of gene expression and inflammatory cytokine signaling. In vitro observations were further confirmed using established in vivo models of ZIKV infection in immunocompetent hosts. Results Transcriptomic profiling of primary neuron cultures following ZIKV infection revealed altered expression of key genes associated with major psychiatric disorders, such as bipolar disorder and schizophrenia. Gene ontology enrichment analysis also revealed significant changes in gene expression associated with fundamental neurobiological processes, including neuronal development, neurotransmission, and others. These alterations to neurologic gene expression were also observed in the brain in vivo using several immunocompetent mouse models of ZIKV infection. Mechanistic studies identified TNF-α signaling via TNFR1 as a major regulatory mechanism controlling ZIKV-induced changes to neurologic gene expression. Conclusions Our studies reveal that cell-intrinsic innate immune responses to ZIKV infection profoundly shape neuronal transcriptional profiles, highlighting the need to further explore associations between ZIKV infection and disordered host behavioral states.

The role of glial cells in Zika virus‐induced neurodegeneration

“…Although the expressions of these inflammatory genes can elicit an antiviral response, several of these molecules represent senescence markers, and chronic neuroinflammation is a common feature of neuropsychiatric and neurodegenerative diseases, such as AD, ASD, ALS, PD, epilepsy, multiple sclerosis, and schizophrenia. Accordingly, in vitro mechanistic studies have identified TNF‐α signaling via TNFR1 as a crucial regulatory mechanism controlling ZIKV‐induced changes in neurologic gene expression (Kung et al, 2022). Several genes associated with cell functionality have been identified, particularly in astrocytes, including GFAP , BDNF , SOD2 , SLC1A3 , MAOA , ACHE , APOE , LDLR , which encode astrocyte markers and proteins associated with trophic signaling, antioxidant defenses, neurotransmitter homeostasis and cholesterol metabolism.…”

The relationship between chronic immune response and neurodegenerative damage in long COVID-19

“…West Nile virus is also known to cause a neuroinvasive disease manifesting meningitis, meningoencephalitis, encephalitis, or acute flaccid paralysis, commonly associated with diarrhea/vomiting, weakness, impaired vision, confusion, or drowsiness, and shows elevated levels of proinflammatory cytokines IL4, IL6, and IL10 in serum samples (138). Finally, Zika virus can infect the CNS and induce microcephaly in fetuses and rare but serious neurological diseases in adults, which are associated with excessive production of IFNa, IFN-b, IL-6, and TNF-a (139).…”

Assessing the role of Ndel1 oligopeptidase activity in congenital Zika syndrome: Potential predictor of congenital syndrome endophenotype and treatment response

“…Interestingly, ZIKV targets various cells in the brain, including radial glial cells, neural progenitor cells (NPCs), astrocytes, microglial and glioblastoma stem cells, affecting these brain cells by different mechanisms, such as apoptosis and cell cycle dysregulation, which may induce neurological complications and neuroimmunopathogenesis (Komarasamy et al, 2022), possibly causing the depletion of neural progenitors in the cortical layer of the brain (Ihunwo et al, 2022). Indeed, cell‐intrinsic innate immune responses to ZIKV infection profoundly shape neuronal transcriptional profiles by inducing changes to neurologic gene expression associated with psychiatric disorders (Kung et al, 2022). Noteworthy, we have previously observed a correlation between a lower Ndel1 activity and inflammatory marker interleukin‐4 (IL‐4) levels in patients with chronic schizophrenia (Nani et al, 2022).…”