Inflammatory response and MAPK and NF-\u03baB pathway activation induced by natural street rabies virus infection in the brain tissues of dogs and humans

Qian Wang,Wu Yang Zhu,Shu Qing Liu,Yuan Xie,Xin Gao

doi:10.1186/s12985-020-01429-4

Abstract

BackgroundStreet rabies virus (RABV) usually infects hosts at peripheral sites and migrates from motor or sensory nerves to the central nervous system. Several studies have found that inflammation is mild in a mouse model of street RABV infection. However, the pathogenetic mechanisms of street RABV in naturally infected dogs or humans are not well understood.MethodsBrain tissues collected from 3 dogs and 3 humans were used; these tissue samples were collected under the natural condition of rabies-induced death. The inflammatory response and pathway activation in the brain tissue samples of dogs and humans were evaluated by HE, IHC, ARY006, WB and ELISA. The clinical isolate street RABV strains CGS-17 and CXZ-15 from 30 six-week-old ICR mice were used to construct the mouse infection model presented here.ResultsNeuronal degeneration and increased lymphocyte infiltration in the cerebral cortex, especially marked activation of microglia, formation of glial nodules, and neuronophagy, were observed in the dogs and humans infected with the street RABV strains. The various levels of proinflammatory chemokines, particularly CXCL1, CXCL12, CCL2, and CCL5, were increased significantly in the context of infection with street RABV strains in dogs and humans in relation to healthy controls, and the levels of MAPK and NF-κB phosphorylation were also increased in dogs and humans with natural infection. We also found that the degrees of pathological change, inflammatory response, MAPK and NF-κB signaling pathway activation were obviously increased during natural infection in dogs and humans compared with artificial model infection in mice.ConclusionThe data obtained here provide direct evidence for the RABV-induced activation of the inflammatory response in a dog infection model, which is a relatively accurate reflection of the pathogenic mechanism of human street RABV infection. These observations provide insight into the precise roles of underlying mechanisms in fatal natural RABV infection.

Highlights

Street rabies virus (RABV) usually infects hosts at peripheral sites and migrates from motor or sensory nerves to the central nervous system
We found that the expression of CXCL1, CXCL12, CCL2, CCL5 and TIMP-1 was significantly increased upon CGS-17 and CXZ-15 infection
The expression of CXCL1, CXCL12, CCL2, and CCL5 in dog brain tissue infected by CGS-17 and CXZ-15 was quantified using canine ELISA kits, as described previously [25], and we found that the levels of CXCL1, CXCL12, CCL5, and CCL2 were obviously increased in street RABVinfected dog brain tissues in relation to healthy tissues (Additional file 2: Figure S2)

Summary

Introduction

Street rabies virus (RABV) usually infects hosts at peripheral sites and migrates from motor or sensory nerves to the central nervous system. Street RABV usually infects hosts at peripheral sites and migrates from motor or sensory nerves to the central nervous system (CNS), Liu et al Virol J (2020) 17:157 and it employs a series of strategies to evade host immune responses [2]. Most street RABV strains evade the host innate immune system, and neuronal pathology or damage to the CNS is limited in street rabies patients with only mild inflammation [6]. Increasing evidence suggests that excessive immune responses may be associated with pathological processes and that some chemokines (such as CXCL10 and CCL5) are associated with excessive inflammation in the CNS, contributing to the increased pathogenicity observed in neurological diseases in mice infected with attenuated RABV [9]

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