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The CXCL10/CXCR3 Axis Promotes Disease Pathogenesis in Mice upon CVA2 Infection.

Publication ,  Journal Article
Liang, R; Chen, S; Jin, Y; Tao, L; Ji, W; Zhu, P; Li, D; Zhang, Y; Zhang, W; Duan, G
Published in: Microbiol Spectr
June 29, 2022

Coxsackievirus A2 (CVA2) is an emerging pathogen that results in hand-foot-and-mouth disease (HFMD) outbreaks. Systemic inflammatory response and central nervous system inflammation are the main pathological features of fatal HFMD. However, the immunopathogenesis of CVA2 infection is poorly understood. We first detected the transcriptional levels of 81 inflammation-related genes in neonatal mice with CVA2 infection. Remarkably, CVA2 induced higher expression of chemokine (C-X-C motif) ligand 10 (CXCL10) in multiple organs and tissues. CXCL10 acts through its cognate receptor chemokine (C-X-C motif) receptor 3 (CXCR3) and regulates immune responses. CXCL10/CXCR3 activation contributes to the pathogenesis of many inflammatory diseases. Next, we found CXCL10 and CXCR3 expression to be significantly elevated in the organs and tissues from CVA2-infected mice at 5 days postinfection (dpi) using immunohistochemistry (IHC). To further explore the role of CXCL10/CXCR3 in CVA2 pathogenesis, an anti-CXCR3 neutralizing antibody (αCXCR3) or IgG isotype control antibody was used to treat CVA2-infected mice on the same day as infection and every 24 h until 5 dpi. Our results showed that αCXCR3 therapy relieved the clinical manifestations and pathological damage and improved the survival rate of CVA2-infected mice. Additionally, αCXCR3 treatment reduced viral loads and reversed the proinflammatory cytokine (interleukin 6 [IL-6], tumor necrosis factor alpha [TNF-α], and IL-1β) expression, apoptosis, and inflammatory cell infiltration induced by CVA2. Collectively, our study presents evidence for the involvement of the CXCL10/CXCR3 axis in CVA2 pathogenesis. The activation of CXCL10/CXCR3 contributes to CVA2 pathogenesis by inducing apoptosis, proinflammatory cytokine expression, and inflammatory cell infiltration, which can be reversed by αCXCR3 therapy. This study provides new insight into the pathogenesis of HFMD, which has an important guiding significance for the treatment of HFMD. IMPORTANCE Systemic inflammatory response and central nervous system inflammation are the main pathological features of fatal HFMD cases. We detected the expression of 81 inflammation-related genes and found higher expression of CXCL10 in CVA2-infected mice. Next, we confirmed CXCL10/CXCR3 activation using immunohistochemistry and found that anti-CXCR3 neutralizing antibody (αCXCR3) therapy could relieve the clinical manifestations and pathological damage and improve the survival rate of CVA2-infected mice. Additionally, αCXCR3 treatment reduced viral loads and reversed the proinflammatory cytokine (IL-6, TNF-α, and IL-1β) expression, apoptosis, and inflammatory cell infiltration induced by CVA2. Collectively, our study presents the first evidence for the involvement of the CXCL10/CXCR3 axis in CVA2 pathogenesis. The activation of CXCL10/CXCR3 contributes to CVA2 pathogenesis via inducing apoptosis, proinflammatory cytokine expression, and inflammatory cell infiltration, which can be reversed by αCXCR3 therapy. This study provides new insight into the pathogenesis of HFMD, which has an important guiding significance for the treatment of HFMD.

Duke Scholars

Published In

Microbiol Spectr

DOI

EISSN

2165-0497

Publication Date

June 29, 2022

Volume

10

Issue

3

Start / End Page

e0230721

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Systemic Inflammatory Response Syndrome
  • Receptors, CXCR3
  • Mice
  • Interleukin-6
  • Inflammation
  • Coxsackievirus Infections
  • Chemokine CXCL10
  • Antibodies, Neutralizing
  • Animals
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Liang, R., Chen, S., Jin, Y., Tao, L., Ji, W., Zhu, P., … Duan, G. (2022). The CXCL10/CXCR3 Axis Promotes Disease Pathogenesis in Mice upon CVA2 Infection. Microbiol Spectr, 10(3), e0230721. https://doi.org/10.1128/spectrum.02307-21
Liang, Ruonan, Shuaiyin Chen, Yuefei Jin, Ling Tao, Wangquan Ji, Peiyu Zhu, Dong Li, Yu Zhang, Weiguo Zhang, and Guangcai Duan. “The CXCL10/CXCR3 Axis Promotes Disease Pathogenesis in Mice upon CVA2 Infection.Microbiol Spectr 10, no. 3 (June 29, 2022): e0230721. https://doi.org/10.1128/spectrum.02307-21.
Liang R, Chen S, Jin Y, Tao L, Ji W, Zhu P, et al. The CXCL10/CXCR3 Axis Promotes Disease Pathogenesis in Mice upon CVA2 Infection. Microbiol Spectr. 2022 Jun 29;10(3):e0230721.
Liang, Ruonan, et al. “The CXCL10/CXCR3 Axis Promotes Disease Pathogenesis in Mice upon CVA2 Infection.Microbiol Spectr, vol. 10, no. 3, June 2022, p. e0230721. Pubmed, doi:10.1128/spectrum.02307-21.
Liang R, Chen S, Jin Y, Tao L, Ji W, Zhu P, Li D, Zhang Y, Zhang W, Duan G. The CXCL10/CXCR3 Axis Promotes Disease Pathogenesis in Mice upon CVA2 Infection. Microbiol Spectr. 2022 Jun 29;10(3):e0230721.

Published In

Microbiol Spectr

DOI

EISSN

2165-0497

Publication Date

June 29, 2022

Volume

10

Issue

3

Start / End Page

e0230721

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Systemic Inflammatory Response Syndrome
  • Receptors, CXCR3
  • Mice
  • Interleukin-6
  • Inflammation
  • Coxsackievirus Infections
  • Chemokine CXCL10
  • Antibodies, Neutralizing
  • Animals