Background/Aims: Coronavirus (CoV) infections induce respiratory tract illnesses and central nervous system (CNS) diseases. We aimed to explore the cytokine expression profiles in hospitalized children with CoV-CNS and CoV-respiratory tract infections. Methods: A total of 183 and 236 hospitalized children with acute encephalitis-like syndrome and respiratory tract infection, respectively, were screened for anti-CoV IgM antibodies. The expression profiles of multiple cytokines were determined in CoV-positive patients. Results: Anti-CoV IgM antibodies were detected in 22/183 (12.02%) and 26/236 (11.02%) patients with acute encephalitis-like syndrome and respiratory tract infection, respectively. Cytokine analysis revealed that the level of serum granulocyte colony-stimulating factor (G-CSF) was significantly higher in both CoV-CNS and CoV-respiratory tract infection compared with healthy controls. Additionally, the serum level of granulocyte macrophage colony-stimulating factor (GM-CSF) was significantly higher in CoV-CNS infection than in CoV-respiratory tract infection. In patients with CoV-CNS infection, the levels of IL-6, IL-8, MCP-1, and GM-CSF were significantly higher in their cerebrospinal fluid samples than in matched serum samples. Conclusion: To the best of our knowledge, this is the first report showing a high incidence of CoV infection in hospitalized children, especially with CNS illness. The characteristic cytokine expression profiles in CoV infection indicate the importance of host immune response in disease progression.

1.
Cabeca TK, Passos AM, Granato C, Bellei N: Human coronavirus ocurrence in different populations of Sao Paulo: a comprehensive nine-year study using a pancoronavirus RT-PCR assay. Braz J Microbiol 2013;44:335-339.
[PubMed]
2.
Ren L, Gonzalez R, Xu J, Xiao Y, Li Y, Zhou H, Li J, Yang Q, Zhang J, Chen L, Wang W, Vernet G, Paranhos-Baccala G, Wang Z, Wang J: Prevalence of human coronaviruses in adults with acute respiratory tract infections in Beijing, China. J Med Virol 2011;83:291-297.
[PubMed]
3.
Birch CJ, Clothier HJ, Seccull A, Tran T, Catton MC, Lambert SB, Druce JD: Human coronavirus OC43 causes influenza-like illness in residents and staff of aged-care facilities in Melbourne, Australia. Epidemiol Infect 2005;133:273-277.
[PubMed]
4.
Cabeca TK, Granato C, Bellei N: Epidemiological and clinical features of human coronavirus infections among different subsets of patients. Influenza Other Respir Viruses 2013; 7:1040-1047.
[PubMed]
5.
Gaunt ER, Hardie A, Claas EC, Simmonds P, Templeton KE: Epidemiology and clinical presentations of the four human coronaviruses 229E, HKU1, NL63, and OC43 detected over 3 years using a novel multiplex real-time PCR method. J Clin Microbiol 2010;48:2940-2947.
[PubMed]
6.
Shirato K, Yano T, Senba S, Akachi S, Kobayashi T, Nishinaka T, Notomi T, Matsuyama S: Detection of Middle East respiratory syndrome coronavirus using reverse transcription loop-mediated isothermal amplification (RT-LAMP). Virol J 2014;11:139.
[PubMed]
7.
Matoba Y, Abiko C, Ikeda T, Aoki Y, Suzuki Y, Yahagi K, Matsuzaki Y, Itagaki T, Katsushima F, Katsushima Y, Mizuta K: Detection of the human coronavirus 229E, HKU1, NL63, and OC43 between 2010 and 2013 in Yamagata, Japan. Jpn J Infect Dis 2015;68:138-141.
[PubMed]
8.
Lau KK, Yu WC, Chu CM, Lau ST, Sheng B, Yuen KY: Possible central nervous system infection by SARS coronavirus. Emerg Infect Dis 2004;10:342-344.
[PubMed]
9.
Arbour N, Day R, Newcombe J, Talbot PJ: Neuroinvasion by human respiratory coronaviruses. J Virol 2000;74:8913-8921.
[PubMed]
10.
Yeh EA, Collins A, Cohen ME, Duffner PK, Faden H: Detection of coronavirus in the central nervous system of a child with acute disseminated encephalomyelitis. Pediatrics 2004; 113:e73-e76.
[PubMed]
11.
Murray CJ, Lopez AD: Global mortality, disability, and the contribution of risk factors: global burden of disease study. Lancet 1997;349:1436-1442.
[PubMed]
12.
Tan le V, Thai le H, Phu NH, Nghia HD, Chuong LV, Sinh DX, Phong ND, Mai NT, Man DN, Hien VM, Vinh NT, Day J, Chau NV, Hien TT, Farrar J, de Jong MD, Thwaites G, van Doorn HR, Chau TT: Viral aetiology of central nervous system infections in adults admitted to a tertiary referral hospital in southern Vietnam over 12 years. PLoS Negl Trop Dis 2014;8:e3127.
[PubMed]
13.
Zhang Y, Li J, Zhan Y, Wu L, Yu X, Zhang W, Ye L, Xu S, Sun R, Wang Y, Lou J: Analysis of serum cytokines in patients with severe acute respiratory syndrome. Infect Immun 2004;72:4410-4415.
[PubMed]
14.
Dodd DA, Giddings TH, Kirkegaard K: Poliovirus 3A protein limits interleukin-6 (IL-6), IL-8, and beta interferon secretion during viral infection. J Virol 2001;75:8158-8165.
[PubMed]
15.
Kaplanski G, Teysseire N, Farnarier C, Kaplanski S, Lissitzky JC, Durand JM, Soubeyrand J, Dinarello CA, Bongrand P: IL-6 and IL-8 production from cultured human endothelial cells stimulated by infection with Rickettsia conorii via a cell-associated IL-1 alpha-dependent pathway. J Clin Invest 1995;96:2839-2844.
[PubMed]
16.
Bell MD, Taub DD, Perry VH: Overriding the brain's intrinsic resistance to leukocyte recruitment with intraparenchymal injections of recombinant chemokines. Neuroscience 1996;74:283-292.
[PubMed]
17.
Wong CK, Lam CW, Wu AK, Ip WK, Lee NL, Chan IH, Lit LC, Hui DS, Chan MH, Chung SS, Sung JJ: Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol 2004;136:95-103.
[PubMed]
18.
Sheng WH, Chiang BL, Chang SC, Ho HN, Wang JT, Chen YC, Hsiao CH, Hseuh PR, Chie WC, Yang PC: Clinical manifestations and inflammatory cytokine responses in patients with severe acute respiratory syndrome. J Formos Med Assoc 2005;104:715-723.
[PubMed]
19.
Yu D, Zhu H, Liu Y, Cao J, Zhang X: Regulation of proinflammatory cytokine expression in primary mouse astrocytes by coronavirus infection. J Virol 2009;83:12204-12214.
[PubMed]
20.
Gregory AD, Hogue LA, Ferkol TW, Link DC: Regulation of systemic and local neutrophil responses by G-CSF during pulmonary pseudomonas aeruginosa infection. Blood 2007;109:3235-3243.
[PubMed]
21.
Eyles JL, Hickey MJ, Norman MU, Croker BA, Roberts AW, Drake SF, James WG, Metcalf D, Campbell IK, Wicks IP: A key role for G-CSF-induced neutrophil production and trafficking during inflammatory arthritis. Blood 2008;112:5193-5201.
[PubMed]
22.
Brand HK, Ferwerda G, Preijers F, de Groot R, Neeleman C, Staal FJ, Warris A, Hermans PW: CD4+ T-cell counts and interleukin-8 and CCL-5 plasma concentrations discriminate disease severity in children with RSV infection. Pediatr Res 2013;73:187-193.
[PubMed]
23.
Shiomi A, Usui T: Pivotal roles of GM-CSF in autoimmunity and inflammation. Mediators Inflamm 2015;2015:568543.
[PubMed]
24.
Croxford AL, Spath S, Becher B: GM-CSF in neuroinflammation: licensing myeloid cells for tissue damage. Trends Immunol 2015;36:651-662.
[PubMed]
25.
Yavarian J, Gavvami N, Mamishi S: Detection of human herpesvirus 6 in cerebrospinal fluid of children with possible encephalitis. Jundishapur J Microbiol 2014;7:e11821.
[PubMed]
26.
Burgess AW, Camakaris J, Metcalf D: Purification and properties of colony-stimulating factor from mouse lung-conditioned medium. J Biol Chem 1977;252:1998-2003.
[PubMed]
27.
Hercus TR, Thomas D, Guthridge MA, Ekert PG, King-Scott J, Parker MW, Lopez AF: The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease. Blood 2009;114:1289-1298.
[PubMed]
28.
Tsuboi K, Kimura T, Sugiura K, Hashimoto I, Nishikawa M, Uyama M, Fujisawa JI: Granulocyte-macrophage colony-stimulating factor expressed in T cells mediates immunity against herpes simplex virus type 1 encephalitis. J Infect Dis 1998;178:16-26.
[PubMed]
29.
Sakagami T, Uchida K, Suzuki T, Carey BC, Wood RE, Wert SE, Whitsett JA, Trapnell BC, Luisetti M: Human GM-CSF autoantibodies and reproduction of pulmonary alveolar proteinosis. N Engl J Med 2009;361:2679-2681.
[PubMed]
30.
Uchida K, Beck DC, Yamamoto T, Berclaz PY, Abe S, Staudt MK, Carey BC, Filippi MD, Wert SE, Denson LA, Puchalski JT, Hauck DM, Trapnell BC: GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis. N Engl J Med 2007;356:567-579.
[PubMed]
31.
van Strijp JA, van Kessel KP, Miltenburg LA, Fluit AC, Verhoef J: Attachment of human polymorphonuclear leukocytes to herpes simplex virus-infected fibroblasts mediated by antibody-independent complement activation. J Virol 1988;62:847-850.
[PubMed]
32.
Bingham EL, Fenger TW, Sugar A, Smith JW: Dependence on antibody for induction of chemiluminescence in polymorphonuclear leukocytes by herpes simplex virus. Invest Ophthalmol Vis Sci 1985;26:1236-1243.
[PubMed]
33.
Winter PM, Dung NM, Loan HT, Kneen R, Wills B, Thu le T, House D, White NJ, Farrar JJ, Hart CA, Solomon T: Proinflammatory cytokines and chemokines in humans with Japanese encephalitis. J Infect Dis 2004;190:1618-1626.
[PubMed]
34.
Campbell IL, Stalder AK, Chiang CS, Bellinger R, Heyser CJ, Steffensen S, Masliah E, Powell HC, Gold LH, Henriksen SJ, Siggins GR: Transgenic models to assess the pathogenic actions of cytokines in the central nervous system. Mol Psychiatry 1997;2:125-129.
[PubMed]
35.
Kalita J, Srivastava R, Mishra MK, Basu A, Misra UK: Cytokines and chemokines in viral encephalitis: a clinicoradiological correlation. Neurosci Lett 2010;473:48-51.
[PubMed]
36.
Singh A, Kulshreshtha R, Mathur A: Secretion of the chemokine interleukin-8 during Japanese encephalitis virus infection. J Med Microbiol 2000;49:607-612.
[PubMed]
37.
D'Aversa TG, Weidenheim KM, Berman JW: CD40-CD40L interactions induce chemokine expression by human microglia: implications for human immunodeficiency virus encephalitis and multiple sclerosis. Am J Pathol 2002;160:559-567.
[PubMed]
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