Growth hormone attenuates the brain damage caused by ZIKV infection in mice

Zi-Da Zhen; Na Wu; Dong-Ying Fan; Jun-Hong Ai; Zheng-Ran Song; Jia-Tong Chang; Pei-Gang Wang; Yan-Hua Wu; Jing An

doi:10.1016/j.virs.2022.06.004

August 2022

Zi-Da Zhen, Na Wu, Dong-Ying Fan, Jun-Hong Ai, Zheng-Ran Song, Jia-Tong Chang, Pei-Gang Wang and Yan-Hua Wu. Growth hormone attenuates the brain damage caused by ZIKV infection in mice[J]. Virologica Sinica, 2022, 37(4): 601-609. doi: 10.1016/j.virs.2022.06.004

Citation: Zi-Da Zhen, Na Wu, Dong-Ying Fan, Jun-Hong Ai, Zheng-Ran Song, Jia-Tong Chang, Pei-Gang Wang, Yan-Hua Wu, Jing An. Growth hormone attenuates the brain damage caused by ZIKV infection in mice .VIROLOGICA SINICA, 2022, 37(4) : 601-609. http://dx.doi.org/10.1016/j.virs.2022.06.004

生长激素减轻寨卡病毒感染导致小鼠脑损伤的机制研究

甄自达 ^a ,
吴娜 ^b ,
范东瀛 ^a ,
艾军红 ^a ,
常佳瞳 ^a ,
王培刚 ^a ,
吴艳花 ^a,, ,
安静 ^a,,

首都医科大学基础医学院病原生物学系

通讯作者： 吴艳花, wuyanhua@ccmu.edu.cn; 安静, anjing@ccmu.edu.cn
收稿日期： 2022-01-15
录用日期： 2022-06-10

摘要

寨卡病毒（ZIKV）是蚊媒黄病毒家族成员之一，ZIKV可导致新生儿出现小头畸形和各种神经系统症状。此前，我们发现ZIKV可以感染下丘脑，导致乳鼠生长激素（GH）分泌减少、生长迟缓以及学习和记忆障碍。而早期给予GH治疗可以改善小鼠的生长发育迟缓和记忆障碍。因此，在本研究中，我们进一步研究了GH在乳鼠ZIKV感染中的保护作用机制。我们的研究结果表明，GH可以通过减少细胞凋亡和炎症反应而不是抑制病毒复制来有效减少ZIKV感染引起的脑损伤。我们的研究结果不仅为了解ZIKV相关神经系统症状的机制提供了重要证据，也为ZIKV感染的治疗提供了重要证据。
- 寨卡病毒
- , 生长激素
- , 细胞凋亡
- , 小头畸形

Growth hormone attenuates the brain damage caused by ZIKV infection in mice

a Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China;

Corresponding author: Yan-Hua Wu, wuyanhua@ccmu.edu.cn Jing An, anjing@ccmu.edu.cn
Received Date: 15 January 2022
Accepted Date: 10 June 2022

Abstract

As a member of vector-borne viruses, Zika virus (ZIKV) can cause microcephaly and various neurological symptoms in newborns. Previously, we found that ZIKV could infect hypothalamus, causing a decrease in growth hormone (GH) secretion, growth delay and deficits in learning and memory in suckling mice. Early administration of GH can improve the cognitive function of the mice. Therefore, in this study we further investigated the mechanism underlying the protective role of GH in ZIKV infection in suckling mice. Our results showed that GH could effectively reduce brain damage caused by ZIKV infection via reducing cell apoptosis and inflammatory response rather than inhibiting viral replication. Our results provide important evidences not only for understanding the mechanism underlying ZIKV-associated neurological symptoms but also for the treatment of ZIKV infection.
- Zika virus (ZIKV)
- , Growth hormone
- , Apoptosis
- , Microcephaly

References
1. Adachi, K., Romero, T., Nielsen-Saines, K., Pone, S., Aibe, M., Barroso de Aguiar, E., Sim, M., Brasil, P., Zin, A., Tsui, I., Gaw, S.L., Halai, U.A., Vasconcelos, Z., Pereira, J.P., Salles, T.S., Barbosa, C.N., Portari, E., Cherry, J.D., Pone, M., Moreira, M.E., 2020. Early clinical infancy outcomes for microcephaly and/or small for gestational age zika-exposed infants. Clin. Infect. Dis. 70, 2663–2672.
2. Aramburo, C., Alba-Betancourt, C., Luna, M., Harvey, S., 2014. Expression and function of growth hormone in the nervous system: a brief review. Gen. Comp. Endocrinol. 203, 35–42.
3. Cugola, F.R., Fernandes, I.R., Russo, F.B., Freitas, B.C., Dias, J.L., Guimaraes, K.P., Benazzato, C., Almeida, N., Pignatari, G.C., Romero, S., Polonio, C.M., Cunha, I., Freitas, C.L., Brandao, W.N., Rossato, C., Andrade, D.G., Faria Dde, P., Garcez, A.T., Buchpigel, C.A., Braconi, C.T., Mendes, E., Sall, A.A., Zanotto, P.M., Peron, J.P., Muotri, A.R., Beltrao-Braga, P.C., 2016. The brazilian zika virus strain causes birth defects in experimental models. Nature 534, 267–271.
4. Dang, J., Tiwari, S.K., Lichinchi, G., Qin, Y., Patil, V.S., Eroshkin, A.M., Rana, T.M., 2016. Zika virus depletes neural progenitors in human cerebral organoids through activation of the innate immune receptor tlr3. Cell Stem Cell 19, 258–265.
5. Devesa, P., Agasse, F., Xapelli, S., Almenglo, C., Devesa, J., Malva, J.O., Arce, V.M., 2014. Growth hormone pathways signaling for cell proliferation and survival in hippocampal neural precursors from postnatal mice. BMC Neurosci. 15, 100.
6. Ferraris, P., Cochet, M., Hamel, R., Gladwyn-Ng, I., Alfano, C., Diop, F., Garcia, D., Talignani, L., Montero-Menei, C.N., Nougairede, A., Yssel, H., Nguyen, L., Coulpier, M., Misse, D., 2019. Zika virus differentially infects human neural progenitor cells according to their state of differentiation and dysregulates neurogenesis through the notch pathway. Emerg. Microb. Infect. 8, 1003–1016.
7. Figueiredo, C.P., Barros-Aragao, F.G.Q., Neris, R.L.S., Frost, P.S., Soares, C., Souza, I.N.O., Zeidler, J.D., Zamberlan, D.C., de Sousa, V.L., Souza, A.S., Guimaraes, A.L.A., Bellio, M., Marcondes de Souza, J., Alves-Leon, S.V., Neves, G.A., Paula-Neto, H.A., Castro, N.G., De Felice, F.G., Assuncao-Miranda, I., Clarke, J.R., Da Poian, A.T., Ferreira, S.T., 2019. Zika virus replicates in adult human brain tissue and impairs synapses and memory in mice. Nat. Commun. 10, 3890.
8. Gabriel, E., Ramani, A., Karow, U., Gottardo, M., Natarajan, K., Gooi, L.M., GoranciBuzhala, G., Krut, O., Peters, F., Nikolic, M., Kuivanen, S., Korhonen, E., Smura, T., Vapalahti, O., Papantonis, A., Schmidt-Chanasit, J., Riparbelli, M., Callaini, G., Kronke, M., Utermohlen, O., Gopalakrishnan, J., 2017. Recent zika virus isolates induce premature differentiation of neural progenitors in human brain organoids. Cell Stem Cell 20, 397–406 e395.
9. Gong, Y., Luo, S., Fan, P., Zhu, H., Li, Y., Huang, W., 2020. Growth hormone activates pi3k/akt signaling and inhibits ros accumulation and apoptosis in granulosa cells of patients with polycystic ovary syndrome. Reprod. Biol. Endocrinol. 18, 121.
10. Han, X., Wang, J., Yang, Y., Qu, S., Wan, F., Zhang, Z., Wang, R., Li, G., Cong, H., 2021. Zika virus infection induced apoptosis by modulating the recruitment and activation of pro-apoptotic protein bax. J. Virol. 95 (8) e01445-20.
11. Keane, J., Tajouri, L., Gray, B., 2015. The effect of growth hormone administration on the regulation of mitochondrial apoptosis in-vivo. Int. J. Mol. Sci. 16, 12753–12772.
12. Khaiboullina, S., Uppal, T., Kletenkov, K., St Jeor, S.C., Garanina, E., Rizvanov, A., Verma, S.C., 2019. Transcriptome profiling reveals pro-inflammatory cytokines and matrix metalloproteinase activation in zika virus infected human umbilical vein endothelial cells. Front. Pharmacol. 10, 642.
13. Lee, J.K., Kim, J.A., Oh, S.J., Lee, E.W., Shin, O.S., 2020. Zika virus induces tumor necrosis factor-related apoptosis inducing ligand (trail)-mediated apoptosis in human neural progenitor cells. Cells 9, 2487.
14. Li, C., Xu, D., Ye, Q., Hong, S., Jiang, Y., Liu, X., Zhang, N., Shi, L., Qin, C.F., Xu, Z., 2016. Zika virus disrupts neural progenitor development and leads to microcephaly in mice. Cell Stem Cell 19, 120–126.
15. Li, P., Jiang, H., Peng, H., Zeng, W., Zhong, Y., He, M., Xie, L., Chen, J., Guo, D., Wu, J., Li, C.M., 2021. Non-structural protein 5 of zika virus interacts with p53 in human neural progenitor cells and induces p53-mediated apoptosis. Virol. Sin. 36, 1411–1420.
16. Lindboe, J.B., Langkilde, A., Eugen-Olsen, J., Hansen, B.R., Haupt, T.H., Petersen, J., Andersen, O., 2016. Low-dose growth hormone therapy reduces inflammation in hivinfected patients: a randomized placebo-controlled study. Inf. Disp. 48, 829–837.
17. Liu, B., Xu, Q., Wang, J., Lin, J., Pei, Y., Cui, Y., Wang, G., Zhu, L., 2019. Recombinant human growth hormone treatment of mice suppresses inflammation and apoptosis caused by skin flap ischemia-reperfusion injury. J. Cell. Biochem. 120, 18162–18171.
18. Liu, J., Li, Q., Li, X., Qiu, Z., Li, A., Liang, W., Chen, H., Cai, X., Chen, X., Duan, X., Li, J., Wu, W., Xu, M., Mao, Y., Chen, H., Li, J., Gu, W., Li, H., 2018. Zika virus envelope protein induces g2/m cell cycle arrest and apoptosis via an intrinsic cell death signaling pathway in neuroendocrine pc12 cells. Int. J. Biol. Sci. 14, 1099–1108.
19. Svensson, A.L., Bucht, N., Hallberg, M., Nyberg, F., 2008. Reversal of opiate-induced apoptosis by human recombinant growth hormone in murine foetus primary hippocampal neuronal cell cultures. Proc. Natl. Acad. Sci. U. S. A. 105, 7304–7308.
20. Tian, F.Y., Wu, B., Xu, T., Jiang, X.H., 2017. Systematic evaluation on effectiveness and safety of recombinant human growth hormone in treating adult patients with severe burn. Zhonghua Shaoshang Zazhi 33, 568–573.
21. Wang, J., Wu, J., Zhang, Y., Zhang, J., Xu, W., Wu, C., Zhou, P., 2021. Growth hormone protects against ovarian granulosa cell apoptosis: alleviation oxidative stress and enhancement mitochondrial function. Reprod. Biol. 21, 100504.
22. Wang, Z.Y., Wang, Z., Zhen, Z.D., Feng, K.H., Guo, J., Gao, N., Fan, D.Y., Han, D.S., Wang, P.G., An, J., 2017. Axl is not an indispensable factor for zika virus infection in mice. J. Gen. Virol. 98, 2061–2068.
23. Wu, Y.H., Cui, X.Y., Yang, W., Fan, D.Y., Liu, D., Wang, P.G., An, J., 2018. Zika virus infection in hypothalamus causes hormone deficiencies and leads to irreversible growth delay and memory impairment in mice. Cell Rep. 25, 1537–1547.e4.
24. Xu, D., Li, C., Qin, C.F., Xu, Z., 2019. Update on the animal models and underlying mechanisms for zikv-induced microcephaly. Annu Rev Virol 6, 459–479.
25. Zimmerman, M.G., Bowen, J.R., McDonald, C.E., Young, E., Baric, R.S., Pulendran, B., Suthar, M.S., 2019. Stat5: a target of antagonism by neurotropic flaviviruses. J. Virol. 93 e00665-19.
Proportional views
Electronic Supplementary Material

10.1016j.virs.2022.06.004-ESM.doc