Murine cytomegalovirus employs the mixed lineage kinases family to regulate the spiral ganglion neuron cell death and hearing loss

Menghua Li; Minyan Guo; Yice Xu; Liyuan Wu; Mengbing Chen; Yanfen Dong; Liting Zheng; Daishi Chen; Yuehua Qiao; Zhaoyang Ke; Xi Shi

doi:10.1016/j.neulet.2022.136990

Murine cytomegalovirus employs the mixed lineage kinases family to regulate the spiral ganglion neuron cell death and hearing loss

Neurosci Lett. 2023 Jan 10:793:136990. doi: 10.1016/j.neulet.2022.136990. Epub 2022 Nov 28.

Authors

Menghua Li¹, Minyan Guo¹, Yice Xu², Liyuan Wu³, Mengbing Chen⁴, Yanfen Dong⁵, Liting Zheng⁵, Daishi Chen¹, Yuehua Qiao⁶, Zhaoyang Ke⁷, Xi Shi⁸

Affiliations

¹ Department of Otolaryngology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, China; The First Affiliated Hospital, Jinan University, Guangzhou 510632, China.
² Department of Otolaryngology-Head and Neck Surgery, Xiaogan Hospital, Wuhan University of Science and Technology, Xiaogan 432000, China.
³ Artificial Auditory Laboratory of Jiangsu Province, Xuzhou Medical University, Xuzhou 221000, China; The Second Affiliated Hospital of Jiaxing University, Jiaxing 314000, China.
⁴ Ankang People's Hospital, Ankang 725000, China.
⁵ Artificial Auditory Laboratory of Jiangsu Province, Xuzhou Medical University, Xuzhou 221000, China.
⁶ Artificial Auditory Laboratory of Jiangsu Province, Xuzhou Medical University, Xuzhou 221000, China. Electronic address: yuehuaqiao001@163.com.
⁷ Department of Otolaryngology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen 518020, China; The First Affiliated Hospital, Jinan University, Guangzhou 510632, China. Electronic address: kezhaoyangsz@sina.com.
⁸ Artificial Auditory Laboratory of Jiangsu Province, Xuzhou Medical University, Xuzhou 221000, China. Electronic address: shixi19850112@163.com.

PMID: 36455693
DOI: 10.1016/j.neulet.2022.136990

Abstract

Cytomegalovirus (CMV)-induced sensorineural hearing loss (SNHL) is a worldwide epidemic. Recent studies have shown that the degree of spiral ganglion neuron (SGN) loss is correlated with hearing loss after CMV infection. We aimed to better understand the pathological mechanisms of CMV-related SGN death and to search for intervention measures. We found that both apoptosis and pyroptosis are involved in CMV-induced SGN death, which may be caused by the simultaneous activation of the p53/JNK and NLRP3/caspase-1 signaling pathways, respectively. Moreover, considering that mixed lineage kinase family (MLK1/2/3) are host restriction factors against viral infection and upstream regulators of the p53/JNK and inflammatory (including NLRP3-caspase1) signaling pathways, we further demonstrated that the MLKs inhibitor URMC-099 exhibited a protective effect against CMV-induced SGN death and hearing loss. These results indicate that MLKs signaling may be a key regulator and promising novel target for preventing apoptosis and even pyroptosis during the CMV infection of SGN cells and for treating hearing loss.

Keywords: Apoptosis; Cytomegalovirus; MLKs; Pyroptosis; SNHL.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Cytomegalovirus
Cytomegalovirus Infections* / metabolism
Cytomegalovirus Infections* / pathology
Deafness* / metabolism
Deafness* / pathology
Hearing Loss / metabolism
Hearing Loss / pathology
Hearing Loss, Sensorineural* / metabolism
Hearing Loss, Sensorineural* / pathology
MAP Kinase Kinase Kinases* / metabolism
Mice
Mitogen-Activated Protein Kinase Kinase Kinase 11
Muromegalovirus*
NLR Family, Pyrin Domain-Containing 3 Protein
Neurons
Spiral Ganglion / pathology
Tumor Suppressor Protein p53

Substances

NLR Family, Pyrin Domain-Containing 3 Protein
Tumor Suppressor Protein p53
Map3k9 protein, mouse
Map3k10 protein, mouse
MAP Kinase Kinase Kinases