The immune mechanism of intestinal tract Toll-like receptor in mediating EV71 virus type severe hand-foot-and-mouth disease and the MAPK pathway

Zhu,Lei; Li,Weihua; Qi,Gongjian; Liu,Na; Sheng,Liping; Shang,Lei; Qi,Boxiang

doi:10.3892/etm.2017.4245

The immune mechanism of intestinal tract Toll-like receptor in mediating EV71 virus type severe hand-foot-and-mouth disease and the MAPK pathway

Authors:
- Lei Zhu
- Weihua Li
- Gongjian Qi
- Na Liu
- Liping Sheng
- Lei Shang
- Boxiang Qi
View Affiliations

Affiliations: Department of Intensive Care Unit, Xuzhou Children's Hospital, Xuzhou, Jiangsu 221006, P.R. China
Published online on: March 20, 2017 https://doi.org/10.3892/etm.2017.4245
Pages: 2263-2266
Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Immunological response is thought to play a crucial role in the development of a severe hand-foot-and-mouth disease (HFMD) infection in children, but the mechanisms remain largely unknown. This study was designed to help in elucidating the immunopathological pathways involved in the disease by quantifying Toll-like receptor (TLR) mRNAs, MAPK factors and cytokine levels in children experiencing the disease. A total of 86 enterovirus 71 (EV71)‑infected HFMD children (49 with mild and 27 with severe disease), along with 30 healthy children were involved in the study. Peripheral vein blood samples were collected from each individual, and used to isolate peripheral blood mononuclear cells (PBMCs) for mRNA extraction and sera for measuring levels of tumor necrosis factor (TNF)‑α, interferon (IFN)‑γ, interleukin (IL)‑6 and IL‑10. The average expression levels of TLR3, TLR4, TLR7 and TLR8 mRNA in PBMCs of children with severe HFMD were significantly higher than those in the other children, the lowest values were found in the healthy control group (P<0.05). The expression levels of TLR2 and TLR9 mRNA were not significantly different (P>0.05) among the groups. Additionally, the expression levels of TNF‑α, IFN‑γ, IL‑6 and IL‑10 in the serum of the children in the severe group were significantly higher than those in the other two groups, and the lowest values were again found in the control group (P<0.05). Pearson correlation analysis showed that the TLR3, TLR4, TLR7 and TLR8 mRNA levels in PBMCs were positively correlated with the TNF-α, IFN-γ, IL‑6 and IL‑10 levels in the serum (P<0.05). Furthermore, the expression levels of the ERK, JNK and p38 mRNA in PBMCs of children in the severe group were significantly higher than those in the other two groups, with the lowest values being in the control group (P<0.05). Pearson correlation analysis showed that the TLR3, TLR4, TLR7 and TLR8 mRNA levels in PBMCs were positively correlated with ERK, JNK and p38 mRNA levels (P<0.05). The results of our study seem to indicate that the high expression levels of TLR3, TLR4, TLR7 and TLR8 induced in severe EV71 HFMD regulate the expression of cytokines by MAPK signaling pathway and negatively affect the ability of the organism to resolve the infection. Further studies are needed to test the hypothesis that immuno-modulation would be an effective treatment approach in pediatric cases of severe HFMD.

View Figures

View References

1	Long DL, Zhu SY, Li CZ, Chen CY, Du WT and Wang X: Late-onset nail changes associated with hand, foot, and mouth disease: A clinical analysis of 56 cases. Pediatr Dermatol. 33:424–428. 2016. View Article : Google Scholar : PubMed/NCBI
2	Kim C, Kang H, Kim DE, Song JH, Choi M, Kang M, Lee K, Kim HS, Shin JS, Jeong H, et al: Antiviral activity of micafungin against enterovirus 71. Virol J. 13:992016. View Article : Google Scholar : PubMed/NCBI
3	Li S, Cai C, Feng J, Li X, Wang Y, Yang J and Chen Z: Peripheral T lymphocyte subset imbalances in children with enterovirus 71-induced hand, foot and mouth disease. Virus Res. 180:84–91. 2014. View Article : Google Scholar : PubMed/NCBI
4	Yang J, Yang C, Guo N, Zhu K, Luo K, Zhang N, Zhao H, Cui Y, Chen L, Wang H, et al: Type I interferons triggered through the Toll-like receptor 3-TRIF pathway control coxsackievirus A16 infection in young mice. J Virol. 89:10860–10867. 2015. View Article : Google Scholar : PubMed/NCBI
5	Hsiao HB, Chou AH, Lin SI, Chen IH, Lien SP, Liu CC, Chong P and Liu SJ: Toll-like receptor 9-mediated protection of enterovirus 71 infection in mice is due to the release of danger-associated molecular patterns. J Virol. 88:11658–11670. 2014. View Article : Google Scholar : PubMed/NCBI
6	Chi J, He Y, Yu G and Lei L: Role of Toll-like receptor 7 in the production of inflammatory cytokines in EV-A71-infected human Jurkat T cells. Zhonghua Yu Fang Yi Xue Za Zhi. 50:266–269. 2016.(In Chinese). PubMed/NCBI
7	Dang S, Gao N, Li Y, Li M, Wang X, Jia X, Zhai S, Zhang X, Liu J, Deng H, et al: Dominant CD4-dependent RNA-dependent RNA polymerase-specific T-cell responses in children acutely infected with human enterovirus 71 and healthy adult controls. Immunology. 142:89–100. 2014. View Article : Google Scholar : PubMed/NCBI
8	Wei R, Xu L, Zhang N, Zhu K, Yang J, Yang C, Deng C, Zhu Z, de Groot AS, Altmeyer R, et al: Elevated antigen-specific Th2 type response is associated with the poor prognosis of hand, foot and mouth disease. Virus Res. 177:62–65. 2013. View Article : Google Scholar : PubMed/NCBI
9	Tan S, Tan X, Sun X, Lu G, Chen CC, Yan J, Liu J, Xu W and Gao GF: VP2 dominated CD4⁺ T cell responses against enterovirus 71 and cross-reactivity against coxsackievirus A16 and polioviruses in a healthy population. J Immunol. 191:1637–1647. 2013. View Article : Google Scholar : PubMed/NCBI
10	Liu L, Zhang Y, Wang J, Zhao H, Jiang L, Che Y, Shi H, Li R, Mo Z, Huang T, et al: Study of the integrated immune response induced by an inactivated EV71 vaccine. PLoS One. 8:e544512013. View Article : Google Scholar : PubMed/NCBI
11	Wei R, Yang C, Zeng M, Terry F, Zhu K, Yang C, Altmeyer R, Martin W, De Groot AS and Leng Q: A dominant EV71-specific CD4⁺ T cell epitope is highly conserved among human enteroviruses. PLoS One. 7:e519572012. View Article : Google Scholar : PubMed/NCBI
12	Liang Y, Zhou X, Yang E, Pu J, Che Y, Wang J, Ma N, Liu L, Ding D, Tang D, et al: Analysis of the Th1/Th2 reaction in the immune response induced by EV71 inactivated vaccine in neonatal rhesus monkeys. J Clin Immunol. 32:1048–1058. 2012. View Article : Google Scholar : PubMed/NCBI
13	Dong C, Liu L, Zhao H, Wang J, Liao Y, Zhang X, Na R, Liang Y, Wang L and Li Q: Immunoprotection elicited by an enterovirus type 71 experimental inactivated vaccine in mice and rhesus monkeys. Vaccine. 29:6269–6275. 2011. View Article : Google Scholar : PubMed/NCBI
14	Lei X, Sun Z, Liu X, Jin Q, He B and Wang J: Cleavage of the adaptor protein TRIF by enterovirus 71 3C inhibits antiviral responses mediated by Toll-like receptor 3. J Virol. 85:8811–8818. 2011. View Article : Google Scholar : PubMed/NCBI
15	Zhang J, Wang J, Pang L, Xie G, Welte T, Saxena V, Wicker J, Mann B, Soong L, Barrett A, et al: The co-stimulatory effects of MyD88-dependent Toll-like receptor signaling on activation of murine γδ T cells. PLoS One. 9:e1081562014. View Article : Google Scholar : PubMed/NCBI
16	Zou J and Shankar N: Roles of TLR/MyD88/MAPK/NF-κB signaling pathways in the regulation of phagocytosis and proinflammatory cytokine expression in response to E. faecalis infection. PLoS One. 10:e01369472015. View Article : Google Scholar : PubMed/NCBI
17	Choi HG, Kim WS, Back YW, Kim H, Kwon KW, Kim JS, Shin SJ and Kim HJ: Mycobacterium tuberculosis RpfE promotes simultaneous Th1- and Th17-type T-cell immunity via TLR4-dependent maturation of dendritic cells. Eur J Immunol. 45:1957–1971. 2015. View Article : Google Scholar : PubMed/NCBI