Volume 41 Issue 5
Sep.  2020
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Tian-Zhang Song, Hong-Yi Zheng, Jian-Bao Han, Lin Jin, Xiang Yang, Feng-Liang Liu, Rong-Hua Luo, Ren-Rong Tian, Hou-Rong Cai, Xiao-Li Feng, Chao Liu, Ming-Hua Li, Yong-Tang Zheng. Delayed severe cytokine storm and immune cell infiltration in SARS-CoV-2-infected aged Chinese rhesus macaques. Zoological Research, 2020, 41(5): 503-516. doi: 10.24272/j.issn.2095-8137.2020.202
Citation: Tian-Zhang Song, Hong-Yi Zheng, Jian-Bao Han, Lin Jin, Xiang Yang, Feng-Liang Liu, Rong-Hua Luo, Ren-Rong Tian, Hou-Rong Cai, Xiao-Li Feng, Chao Liu, Ming-Hua Li, Yong-Tang Zheng. Delayed severe cytokine storm and immune cell infiltration in SARS-CoV-2-infected aged Chinese rhesus macaques. Zoological Research, 2020, 41(5): 503-516. doi: 10.24272/j.issn.2095-8137.2020.202

Delayed severe cytokine storm and immune cell infiltration in SARS-CoV-2-infected aged Chinese rhesus macaques

doi: 10.24272/j.issn.2095-8137.2020.202
#Authors contributed equally to this work
Funds:  This work was supported by the National Key Research and Development Program of China (2020YFC0842000)
More Information
  • Corresponding author: E-mail: zhengyt@mail.kiz.ac.cn
  • Received Date: 2020-07-22
  • Accepted Date: 2020-07-30
  • Published Online: 2020-08-06
  • Publish Date: 2020-09-18
  • As of June 2020, Coronavirus Disease 2019 (COVID-19) has killed an estimated 440 000 people worldwide, 74% of whom were aged ≥65 years, making age the most significant risk factor for death caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To examine the effect of age on death, we established a SARS-CoV-2 infection model in Chinese rhesus macaques (Macaca mulatta) of varied ages. Results indicated that infected young macaques manifested impaired respiratory function, active viral replication, severe lung damage, and infiltration of CD11b+ and CD8+ cells in lungs at one-week post infection (wpi), but also recovered rapidly at 2 wpi. In contrast, aged macaques demonstrated delayed immune responses with a more severe cytokine storm, increased infiltration of CD11b+ cells, and persistent infiltration of CD8+ cells in the lungs at 2 wpi. In addition, peripheral blood T cells from aged macaques showed greater inflammation and chemotaxis, but weaker antiviral functions than that in cells from young macaques. Thus, the delayed but more severe cytokine storm and higher immune cell infiltration may explain the poorer prognosis of older aged patients suffering SARS-CoV-2 infection.
  • #Authors contributed equally to this work
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  • [1]
    Brien JD, Uhrlaub JL, Hirsch A, Wiley CA, Nikolich-Žugich J. 2009. Key role of T cell defects in age-related vulnerability to West Nile virus. Journal of Experimental Medicine, 206(12): 2735−2745. doi: 10.1084/jem.20090222
    Center for Disease Control and Prevention Weekly (American CDC). 2020. Severe outcomes among patients with coronavirus disease 2019 (COVID-19) — United States, February 12–March 16, 2020. Morbidity and Mortality Weekly Report, 69(12): 343−346. doi: 10.15585/mmwr.mm6912e2
    Chan JFW, Yuan SF, Kok KH, To KKW, Chu H, Yang J, et al. 2020. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. The Lancet, 395(10223): 514−523. doi: 10.1016/S0140-6736(20)30154-9
    Channappanavar R, Fehr AR, Vijay R, Mack M, Zhao JC, Meyerholz DK, et al. 2016. Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice. Cell Host & Microbe, 19(2): 181−193.
    Channappanavar R, Fehr AR, Zheng J, Wohlford-Lenane C, Abrahante JE, Mack M, et al. 2019. IFN-I response timing relative to virus replication determines MERS coronavirus infection outcomes. The Journal of Clinical Investigation, 129(9): 3625−3639. doi: 10.1172/JCI126363
    Chu H, Chan JFW, Wang YX, Yuen TTT, Chai Y, Hou YX, et al. 2020. Comparative replication and immune activation profiles of SARS-CoV-2 and SARS-CoV in human lungs: an ex vivo study with implications for the pathogenesis of COVID-19. Clinical Infectious Diseases. doi: 10.1093/cid/ciaa410.
    Colman RJ. 2018. Non-human primates as a model for aging. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1864(9): 2733−2741. doi: 10.1016/j.bbadis.2017.07.008
    Davidson S, Maini MK, Wack A. 2015. Disease-promoting effects of type I interferons in viral, bacterial, and coinfections. Journal of Interferon & Cytokine Research, 35(4): 252−264.
    Franceschi C, Salvioli S, Garagnani P, de Eguileor, Monti D, Capri M. 2017. Immunobiography and the heterogeneity of immune responses in the elderly: a focus on inflammaging and trained immunity. Frontiers in Immunology, 8: 982. doi: 10.3389/fimmu.2017.00982
    Fulop T, Larbi A, Dupuis G, Le Page A, Frost EH, Cohen AA, et al. 2017. Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes?. Frontiers in Immunology, 8: 1960.
    Gao WT, Tamin A, Soloff A, D'Aiuto L, Nwanegbo E, Robbins PD, Bellini WJ, et al. 2003. Effects of a SARS-associated coronavirus vaccine in monkeys. The Lancet, 362(9399): 1895−1896. doi: 10.1016/S0140-6736(03)14962-8
    Haagmans BL, Kuiken T, Martina BE, Fouchier RAM, Rimmelzwaan GF, van Amerongen G, et al. 2004. Pegylated interferon-α protects type 1 pneumocytes against SARS coronavirus infection in macaques. Nature Medicine, 10(3): 290−293. doi: 10.1038/nm1001
    Huang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC, et al. 2005. An interferon-γ-related cytokine storm in SARS patients. Journal of Medical Virology, 75(2): 185−194. doi: 10.1002/jmv.20255
    Kai L, Chen Y, Lin RZ, Han KY. 2020. Clinical features of COVID-19 in elderly patients: a comparison with young and middle-aged patients. Journal of Infection, 80(6): e14−e18. doi: 10.1016/j.jinf.2020.03.005
    Kovacs EJ, Boe DM, Boule LA, Curtis BJ. 2017. Inflammaging and the lung. Clinics in Geriatric Medicine, 33(4): 459−471. doi: 10.1016/j.cger.2017.06.002
    Lau SKP, Lau CCY, Chan KH, Li CP, Chen HL, Jin DY, et al. 2013. Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment. Journal of General Virology, 94(12): 2679−2690. doi: 10.1099/vir.0.055533-0
    Law HKW, Cheung CY, Ng HY, Sia SF, Chan YO, Luk W, et al. 2005. Chemokine up-regulation in SARS-coronavirus-infected, monocyte-derived human dendritic cells. Blood, 106(7): 2366−2374. doi: 10.1182/blood-2004-10-4166
    Lee JS, Park S, Jeong HW, Ahn JY, Choi SJ, Lee H, et al. 2020. Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19. Science Immunology, 5(49): eabd1554. doi: 10.1126/sciimmunol.abd1554
    López J, Perez-Rojo G, Noriega C, Carretero I, Velasco C, Martinez-Huertas JA, et al. 2020. Psychological well-being among older adults during the Covid-19 outbreak: a comparative study of the young-old and the old-old adults. International Psychogeriatrics. doi: 10.1017/S1041610220000964.
    Lu SY, Zhao Y, Yu WH, Yang Y, Gao JH, Wang JB, et al. 2020. Comparison of SARS-CoV-2 infections among 3 species of non-human primates. bioRxiv. doi: 10.1101/2020.04.08.031807.
    Mahbub S, Brubaker AL, Kovacs EJ. 2011. Aging of the innate immune system: an update. Current Immunology Reviews, 7(1): 104−115. doi: 10.2174/157339511794474181
    McGonagle D, Sharif K, O'Regan A, Bridgewood C. 2020. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmunity Reviews, 19(6): 102537. doi: 10.1016/j.autrev.2020.102537
    Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. 2020. COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet, 395(10229): 1033−1034. doi: 10.1016/S0140-6736(20)30628-0
    Mikami T, Miyashita H, Yamada T, Harrington M, Steinberg D, Dunn A, et al. 2020. Risk factors for mortality in patients with COVID-19 in New York City. Journal of General Internal Medicine. doi: 10.1007/s11606-020-05983-z.
    Munster VJ, Feldmann F, Williamson BN, van Doremalen N, Pérez-Pérez L, Schulz J, et al. 2020. Respiratory disease in rhesus macaques inoculated with SARS-CoV-2. Nature. doi: 10.1038/s41586-020-2324-7.
    Ongrádi J, Kövesdi V. 2010. Factors that may impact on immunosenescence: an appraisal. Immunity & Ageing, 7: 7.
    Park A, Iwasaki A. 2020. Type I and Type III Interferons - induction, signaling, evasion, and application to combat COVID-19. Cell Host & Microbe, 27(6): 870−878.
    Pritchard GH, Kedl RM, Hunter CA. 2019. The evolving role of T-bet in resistance to infection. Nature Reviews Immunology, 19(6): 398−410. doi: 10.1038/s41577-019-0145-4
    Rockx B, Baas T, Zornetze GA, Haagmans B, Sheahan T, Frieman M, et al. 2009. Early upregulation of acute respiratory distress syndrome-associated cytokines promotes lethal disease in an aged-mouse model of severe acute respiratory syndrome coronavirus infection. Journal of Virology, 83(14): 7062−7074. doi: 10.1128/JVI.00127-09
    Ron-Harel N, Notarangelo G, Ghergurovich JM, Paulo JA, Sage PT, Santos D, et al. 2018. Defective respiration and one-carbon metabolism contribute to impaired naive T cell activation in aged mice. Proceedings of the National Academy of Sciences of the United States of America, 115(52): 13347−13352. doi: 10.1073/pnas.1804149115
    Salam N, Rane S, Das R, Faulkner M, Gund R, Kandpal U, et al. 2013. T cell ageing: effects of age on development, survival & function. The Indian Journal of Medical Research, 138(5): 595−608.
    Shan C, Yao YF, Yang XL, Zhou YW, Gao G, Peng Y, et al. 2020. Infection with novel coronavirus (SARS-CoV-2) causes pneumonia in Rhesus macaques. Cell Research. doi: 10.1038/s41422-020-0364-z.
    Smith JS, Nicholson LT, Suwanpradid J, Glenn RA, Knape NM, Alagesan P, et al. 2018. Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation. Science Signaling, 11(555): eaaq1075. doi: 10.1126/scisignal.aaq1075
    Smithey MJ, Renkema KR, Rudd BD, Nikolich-Žugich J. 2011. Increased apoptosis, curtailed expansion and incomplete differentiation of CD8+ T cells combine to decrease clearance of L. monocytogenes in old mice. European Journal of Immunology, 41(5): 1352−1364. doi: 10.1002/eji.201041141
    Smits SL, de Lang A, van den Brand JMA, Leijten LM, van IJcken WF, Eijkemans MJC, et al. 2010. Exacerbated innate host response to SARS-CoV in aged non-human primates. PLoS Pathogens, 6(2): e1000756. doi: 10.1371/journal.ppat.1000756
    Stone SL, Peel JN, Scharer CD, Risley CA, Chisolm DA, Schultz MD, et al. 2019. T-bet transcription factor promotes antibody-secreting cell differentiation by limiting the inflammatory effects of IFN-γ on B cells. Immunity, 50(5): 1172−1187. doi: 10.1016/j.immuni.2019.04.004
    Tang XL, Wu CC, Li X, Song YH, Yao XM, Wu XK, et al. 2020. On the origin and continuing evolution of SARS-CoV-2. National Science Review, 7(6): 1012−1023. doi: 10.1093/nsr/nwaa036
    The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. 2020. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) —China, 2020. China CDC Weekly, 2(8): 113−122. doi: 10.46234/ccdcw2020.032
    Trouillet-Assant S, Viel S, Gaymard A, Pons S, Richard JC, Perret M, et al. 2020. Type I IFN immunoprofiling in COVID-19 patients. The Journal of Allergy and Clinical Immunology, 146(1): 206−208. doi: 10.1016/j.jaci.2020.04.029
    Wang C, Zheng XX, Gai WW, Zhao YK, Wang HL, Wang HJ, et al. 2017. MERS-CoV virus-like particles produced in insect cells induce specific humoural and cellular imminity in rhesus macaques. Oncotarget, 8(8): 12686−12694. doi: 10.18632/oncotarget.8475
    Wang XH, Song TZ, Li L, Tian RR, Zheng YT. 2020. Successful implementation of intestinal resection and anastomosis in non-human primates suggests the possibility of longitudinal Intestinal research. Zoological Research, 41(4): 449−454. doi: 10.24272/j.issn.2095-8137.2020.049
    Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE, et al. 2020. OpenSAFELY: factors associated with COVID-19 death in 17 million patients. Nature. doi: 10.1038/s41586-020-2521-4.
    Woolsey C, Borisevich V, Prasad AN, Agans KN, Deer DJ, Dobias NS, et al. 2020. Establishment of an African green monkey model for COVID-19. bioRxiv. doi: 10.1101/2020.05.17.100289.
    World Health Organization (WHO). 2020. Coronavirus disease (COVID-19): Situation Report–175. Geneva: WHO.
    Xu L, Yu DD, Ma YH, Yao YL, Luo RH, Feng XL, et al. 2020. COVID-19-like symptoms observed in Chinese tree shrews infected with SARS-CoV-2. Zoological Research, 41(5): 517−526. doi: 10.24272/j.issn.2095-8137.2020.053
    Xu YS, Jia ZC, Zhou LY, Wang L, Li JT, Liang YF, et al. 2007. Evaluation of the safety, immunogenicity and pharmacokinetics of equine anti-SARS-CoV F(ab')2 in macaque. International Immunopharmacology, 7(13): 1834−1840. doi: 10.1016/j.intimp.2007.09.011
    Yoshida K, Cologne JB, Cordova K, Misumi M, Yamaoka M, Kyoizumi S, et al. 2017. Aging-related changes in human T-cell repertoire over 20 years delineated by deep sequencing of peripheral T-cell receptors. Experimental Gerontology, 96: 29−37. doi: 10.1016/j.exger.2017.05.015
    Yu P, Qi FF, Xu YF, Li FD, Liu PP, Liu JY, et al. 2020a. Age-related rhesus macaque models of COVID-19. Animal Models and Experimental Medicine, 3(1): 93−97. doi: 10.1002/ame2.12108
    Yu WB, Tang GD, Zhang L, Corlett RT. 2020b. Decoding the evolution and transmissions of the novel pneumonia coronavirus (SARS-CoV-2 / HCoV-19) using whole genomic data. Zoological Research, 41(3): 247−257. doi: 10.24272/j.issn.2095-8137.2020.022
    Yuki K, Fujiogi M, Koutsogiannaki S. 2020. COVID-19 pathophysiology: a review. Clinical Immunology, 215: 108427. doi: 10.1016/j.clim.2020.108427
    Zhang LT, Tian RR, Zheng HY, Pan GQ, Tuo XY, Xia HJ, et al. 2016. Translocation of microbes and changes of immunocytes in the gut of rapid- and slow-progressor Chinese rhesus macaques infected with SIV mac239. Immunology, 147(4): 443−452. doi: 10.1111/imm.12574
    Zhang MX, Song TZ, Zheng HY, Wang XH, Lu Y, Zhang HD, et al. 2019. Superior intestinal integrity and limited microbial translocation are associated with lower immune activation in SIVmac239-infected northern pig-tailed macaques (Macaca leonina). Zoological Research, 40(6): 522−531. doi: 10.24272/j.issn.2095-8137.2019.047
    Zhang XL, Pang W, Hu XT, Li JL, Yao YG, Zheng YT. 2014. Experimental primates and non-human primate (NHP) models of human diseases in China: Current status and progress. Zoological Research, 35(6): 447−464.
    Zhao MM, Wang ML, Zhang JS, Gu J, Zhang PA, Xu Y, et al. 2020. Comparison of clinical characteristics and outcomes of patients with coronavirus disease 2019 at different ages. Aging, 12(11): 10070−10086. doi: 10.18632/aging.103298
    Zheng HY, Zhang M, Yang CX, Zhang N, Wang XC, Yang XP, et al. 2020. Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients. Cellular & Molecular Immunology, 17(5): 541−543.
    Zheng HY, Zhang MX, Pang W, Zheng YT. 2014. Aged Chinese rhesus macaques suffer severe phenotypic T- and B-cell aging accompanied with sex differences. Experimental Gerontology, 55: 113−119. doi: 10.1016/j.exger.2014.04.004
    Zhu TT, Wang YJ, Zhou SC, Zhang N, Xia LM. 2020. A comparative study of chest computed tomography features in young and older adults with corona virus disease (COVID-19). Journal of Thoracic Imaging, 35(4): W97−W101. doi: 10.1097/RTI.0000000000000513
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