Equine herpesvirus 1 elicits a strong pro-inflammatory response in the brain of mice

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Mesquita, Leonardo P. ; Costa, Rafael C. ; Zanatto, Dennis A. ; Bruhn, Fabio R. P. ; Mesquita, Lais L. R. ; Lara, M. C. C. S. H. ; Villalobos, E. M. C. ; Massoco, Cristina O. ; Mori, Claudia M. C. ; Mori, Enio ; Maiorka, Paulo C.

• Document type: Journal article
• Source: JOURNAL OF GENERAL VIROLOGY; v. 102, n. 3, p. 12-pg., 2021-01-01.

Abstract

Equine herpesvirus type 1 (EHV-1) is an emerging pathogen that causes encephalomyelitis in horses and non-equid species. Several aspects of the immune response in the central nervous system (CNS), mainly regarding the role of inflammatory mediators during EHV-1 encephalitis, remain unknown. Moreover, understanding the mechanisms underlying extensive neuropathology induced by viruses would be helpful to establish therapeutic strategies. Therefore, we aimed to evaluate some aspects of the innate immune response during highly neurovirulent EHV-1 infection. C57BL/6 mice infected intranasally with A4/72 and A9/92 EHV-1 strains developed a fulminant neurological disease at 3 days post-inoculation with high viral titres in the brain. These mice developed severe encephalitis with infiltration of monocytes and CD8+ T cells to the brain. The inflammatory infiltrate followed the detection of the chemokines CCL2, CCL3, CCL4, CCL5, CXCL2, CXCL9 and CXCL-10 in the brain. Notably, the levels of CCL3, CCL4, CCL5 and CXCL9 were higher in A4/72-infected mice, which presented higher numbers of inflammatory cells within the CNS. Pro-inflammatory cytokines, such as interleukins (ILs) IL-1 alpha, IL-1 beta, IL-6, IL-12 beta, and tumour necrosis factor (TNF), were also detected in the CNS, and Toll-like receptor (TLR) TLR2, TLR3 and TLR9 genes were also upregulated within the brain of EHV-1-infected mice. However, no expression of interferon-gamma (IFN-gamma) and IL-12 alpha, which are important for controlling the replication of other herpesviruses, was detected in EHV-1-infected mice. The results show that the activated innate immune mechanisms could not prevent EHV-1 replication within the CNS, but most likely contributed to the extensive neuropathology. The mouse model of viral encephalitis proposed here will also be useful to study the mechanisms underlying extensive neuropathology. (AU)

• FAPESP's process: 16/24856-0 - Characterization of inflammatory response in the central nervous system in mouse models of viral and protozoan infection
• Grantee: Paulo César Maiorka
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/09396-2 - Characterization of immune response in the central nervous system of mice infected with highly neurovirulent strains of Equid Herpesvirus type 1
• Grantee: Leonardo Pereira Mesquita
• Support Opportunities: Scholarships in Brazil - Post-Doctoral