BoDV‐1 infection induces neuroinflammation by activating the TLR4/MyD88/IRF5 signaling pathway, leading to learning and memory impairment in rats

Abstract

Borna disease virus (BoDV-1) can infect the hippocampus and limbic lobes of newborn rodents, causing cognitive deficits and abnormal behavior. Studies have found that neuroinflammation caused by viral infection in early life can affect brain development and impair learning and memory function, revealing the important role of neuroinflammation in cognitive impairment caused by viral infection. However, there is no research to explore the pathogenic mechanism of BoDV-1 in cognition from the direction of neuroinflammation. We established a BoDV-1 infection model in rats, and tested the learning and memory impairment by Morris water maze (MWM) experiment. RNAseq was introduced to detect changes in the gene expression profile of BoDV-1 infection, focusing on inflammation factors and related signaling pathways. BoDV-1 infection impairs the learning and memory of Sprague-Dawley rats in the MWM test and increases the expression of inflammatory cytokines in the hippocampus. RNAseq analysis found 986 differentially expressed genes (DEGs), of which 845 genes were upregulated and 141 genes were downregulated, and 28 genes were found to be enriched in the toll-like receptor (TLR) pathway. The expression of TLR4, MyD88, and IRF5 in the hippocampus was significantly changed in the BoDV-1 group. Our results indicate that BoDV-1 infection stimulates TLR4/ MyD88/IRF5 pathway activation, causing the release of downstream inflammatory factors, which leads to neuroinflammation in rats. Neuroinflammation may play a significant role in learning and memory impairment caused by BoDV-1 infection.

Transcriptome Analysis of Duck and Chicken Brains Infected with Aquatic Bird Bornavirus-1 (ABBV-1)

“…Multiple pattern-recognition receptor (PRR) pathways were enriched, including the ‘toll-like receptor-signaling pathway’, ‘NOD-like receptor-signaling pathway’, ‘cytosolic DNA-sensing pathway’, and ‘RIG-I-like receptor-signaling pathway’. The ‘toll-like receptor-signaling pathway’, ‘NOD-like receptor-signaling pathway’, and ‘cytosolic DNA-sensing pathway’ were also enriched in the brains of the rats after infection with BoDV-1 [ 23 ], corroborating our findings. Some of the DEGs enriched by ABBV-1 infection in these pathways included numerous PRRs genes, such as TLR1A (binds di- and triacylated lipopeptides), TLR3 (binds dsRNA), TLR4 (binds bacterial lipopolysaccharide), TLR7 (binds ssRNA), DHX58 (also known as (aka) LGP2 and binds to dsRNA), IFIH1 (encodes MDA5 and regulated by DHX58 ), and TMEM173 (aka STING1 and binds DNA) [ 52 , 53 , 54 , 55 , 56 , 57 ].…”

“…By contrast, the neuroinflammation caused by other orthobornaviruses, such as BoDV-1, variegated squirrel bornavirus 1 (VSBV-1), and parrot bornavirus-2 (PaBV-2), can result in disease development driven by T-cell-dominated immunopathogenesis, often resulting in histological evidence of neuronal degeneration [ 2 , 14 , 43 , 44 , 45 ]. In one genome-wide RNAseq study, the BoDV-1 infection of newborn rats led to neurological signs in the animal, and the transcriptomic analysis of their brains showed the upregulation of inflammatory cytokines [ 23 ]. Additionally, KEGG pathways similar to those enriched in duck and chicken brains infected with ABBV-1, such as ‘cytokine-cytokine receptor interaction’, ‘toll-like receptor signaling pathway’, ‘NOD-like receptor signaling pathway’, and ‘intestinal immune network for IgA production’, were enriched in the rat brains [ 23 ].…”

“…In one genome-wide RNAseq study, the BoDV-1 infection of newborn rats led to neurological signs in the animal, and the transcriptomic analysis of their brains showed the upregulation of inflammatory cytokines [ 23 ]. Additionally, KEGG pathways similar to those enriched in duck and chicken brains infected with ABBV-1, such as ‘cytokine-cytokine receptor interaction’, ‘toll-like receptor signaling pathway’, ‘NOD-like receptor signaling pathway’, and ‘intestinal immune network for IgA production’, were enriched in the rat brains [ 23 ]. However, very few studies have evaluated the transcriptomic profiles of viral infection in avian brains.…”

“…Little is known about the molecular pathogenesis and cellular response to bornavirus infection. To our knowledge, only four microarray studies, two proteomic studies, and one next-generation RNA-sequencing study have been conducted on tissues or cells infected with BoDV-1 [ 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. However, no transcriptomic studies have been conducted on avian species infected with bornaviruses in general, or ABBV-1 in particular.…”

SARS-CoV-2 spike protein induces TLR-4-mediated long-term cognitive dysfunction recapitulating post-COVID syndrome

“…The pattern recognition receptor TLR4 has been implicated in the neuropathology of viral encephalitis classically associated with memory impairment, including those caused by WNV, Japanese encephalitis virus (JEV) and BDV, as well as age-related neurodegenerative diseases(Cui et al, 2020; Han et al, 2014; Sabouri et al, 2014; Tang et al, 2021). Notably, in silico simulations predicted that the S protein could be recognized by the TLR4(Bhattacharya et al, 2020; Choudhury and Mukherjee, 2020), with this interaction activating the inflammatory signaling, independently of ACE2(Frank et al, 2022; Olajide et al, 2022; Shirato and Kizaki, 2021; Zhao et al, 2021).…”