Profile of Cytokines and Chemokines Triggered by Wild-Type Strains of Rabies Virus in Mice

Abstract

Abstract. Rabies is a lethal infectious disease that causes 55,000 human deaths per year and is transmitted by various mammalian species, such as dogs and bats. The host immune response is essential for avoiding viral progression and promoting viral clearance. Cytokines and chemokines are crucial in the development of an immediate antiviral response; the rabies virus (RABV) attempts to evade this immune response. The virus's capacity for evasion is correlated with its pathogenicity and the host's inflammatory response, with highly pathogenic strains being the most efficient at hijacking the host's defense mechanisms and thereby decreasing inflammation. The purpose of this study was to evaluate the expression of a set of cytokine and chemokine genes that are related to the immune response in the brains of mice inoculated intramuscularly or intracerebrally with two wild-type strains of RABV, one from dog and the other from vampire bat. The results demonstrated that the gene expression profile is intrinsic to the specific rabies variant. The prompt production of cytokines and chemokines seems to be more important than their levels of expression for surviving a rabies infection.

Gene Expression Profile Induced by Two Different Variants of Street Rabies Virus in Mice

“…They observed altered gene expression at days 2 (29 genes), 4 (109 genes) and 6 (98 genes) post-inoculation in eight major groups: immune response, metabolism, receptor and transport, growth factors, death-mediated factors, transcription and translation factors, proteases and kinases. The up-regulation of VCAM-1 in the present study demonstrates the participation of this molecule in viral penetration, in which the activation occurred immediately after entry of the virus in the brain and in the absence of clinical signs, corroborating previous works published by our group and others [9,[15][16][17].…”

“…The V2 RABV variant was more lethal thanV3, in agreement with previous studies [9][10][11][12]. Fuoco et al (2019) showed that intradermal inoculation of mice with a RABV isolate from an insectivorous bat led to 33% mortality whereas an isolate from a wild canid (Cerdocyon thous, crab-eating fox) led to 67% mortality [13].…”

“…In a previous study [9], we demonstrated that cytokine and chemokine genes associated with the immune response, measured by reverse transcription and quantitative PCR, were differentially expressed in the CNS of mice inoculated with canine or bat RABV variants. Here, we extend these studies to a microarray analysis of brain tissue from mice inoculated with the same variants at 5-and 10-days post inoculation (d.p.i.…”

“…Brain tissue RNA was extracted with the Invitek®kit (Berlin, Germany) according to the manufacturer's instructions and stored at −80 • C. Before microarray analysis was performed, the presence of RABV in the brain was confirmed by detection of the RABV N protein gene by RT-qPCR as previously described [9]. Validation of the results obtained in the microarray were made by RT-qPCR using Mouse Quantitect ® Primer Assay (Qiagen ® , Hilden, Germany) for specific cytokines and chemokines as previously described [9].…”

The Diagnosis, Clinical Course, Treatment, and Prevention of the Rabies Virus

“…The presence of these cytokines initiate a cascade reaction, upregulating proteins necessary for the inflammatory response such as the major histocompatibility complex and adhesion molecules. These proteins then interact with leukocytes to allow the blood brain barrier to become more permeable, thus causing an immune response leading to encephalitis [30]. As for the natural defense against rabies, RABV signals a series of molecular cascades that initiates type I interferon responses that have antiviral properties, decreasing the pathogenicity of rabies [31].…”