Detection of Severe Acute Respiratory Syndrome Coronavirus in the Brain: Potential Role of the Chemokine Mig in Pathogenesis

Clinical Infectious Diseases, Oct 2005

Background. Previous studies have shown that common human coronavirus might be neurotropic, although it was first isolated as a pathogen of the respiratory tract. We noticed that a few patients with severe acute respiratory syndrome (SARS) experienced central nervous symptoms during the course of illness. In the present study, we isolated a SARS coronavirus strain from a brain tissue specimen obtained from a patient with SARS with significant central nervous symptoms. Methods. Using transmission electronic microscopy and nested reverse transcription–polymerase chain reaction, the causative pathogen was identified in cultures of a brain tissue specimen obtained from the patient with SARS. Histopathologic examination of the brain tissue was performed using the methods of immunohistochemistry analysis and double immunofluorescence staining. Fifteen cytokines and chemokines were detected in the blood of the patient with SARS by means of a bead-based multiassay system. Results. A fragment specific for SARS human coronavirus was amplified from cultures of the brain suspension, and transmission electronic microscopy revealed the presence of an enveloped virus morphologically compatible with a coronavirus isolated in the cultures. Pathologic examination of the brain tissue revealed necrosis of neuron cells and broad hyperplasia of gliocytes. Immunostaining demonstrated that monokine induced by interferon-Γ (Mig) was expressed in gliocytes with the infiltration of CD68+ monocytes/macrophages and CD3+ T lymphocytes in the brain mesenchyme. Cytokine/chemokine assay revealed that levels of interferon-Γ–inducible protein 10 and Mig in the blood were highly elevated, although the levels of other cytokines and chemokines were close to normal. Conclusions. This study provides direct evidence that SARS human coronavirus is capable of infecting the central nervous system, and that Mig might be involved in the brain immunopathology of SARS.

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Detection of Severe Acute Respiratory Syndrome Coronavirus in the Brain: Potential Role of the Chemokine Mig in Pathogenesis

Jun Xu 0 2 4 5 7 Shuqing Zhong 0 2 4 5 7 Jinghua Liu 0 2 3 4 7 Li Li 0 2 4 5 7 Yong Li 0 2 4 5 7 Xinwei Wu 0 1 2 4 7 Zhijie Li 0 2 3 4 7 Peng Deng 0 2 3 4 7 Jingqiang Zhang 0 2 4 6 7 Nanshan Zhong 0 2 4 5 7 Yanqing Ding 0 2 3 4 7 Yong Jiang 0 2 3 4 7 0 229E and OC43, which cause up to one-third of all 1 Guangzhou Center for Diseases Control and Prevention 2 CNS diseases [1 , 2]. Two known human coronaviruses 3 Key Laboratory of Functional Proteomics of Guangdong Province, Southern Medical University 4 causing upper respiratory, gastrointestinal, hepatic 5 Guangzhou Institute of Respiratory Diseases 6 Electronic Microscope Center, Sun Yatsen University , Guangzhou, People's Republic of China 7 cases of common cold, were also found to infect the Background. Previous studies have shown that common human coronavirus might be neurotropic, although it was first isolated as a pathogen of the respiratory tract. We noticed that a few patients with severe acute respiratory syndrome (SARS) experienced central nervous symptoms during the course of illness. In the present study, we isolated a SARS coronavirus strain from a brain tissue specimen obtained from a patient with SARS with significant central nervous symptoms. Methods. Using transmission electronic microscopy and nested reverse transcription-polymerase chain reaction, the causative pathogen was identified in cultures of a brain tissue specimen obtained from the patient with SARS. Histopathologic examination of the brain tissue was performed using the methods of immunohistochemistry analysis and double immunofluorescence staining. Fifteen cytokines and chemokines were detected in the blood of the patient with SARS by means of a bead-based multiassay system. Results. A fragment specific for SARS human coronavirus was amplified from cultures of the brain suspension, and transmission electronic microscopy revealed the presence of an enveloped virus morphologically compatible with a coronavirus isolated in the cultures. Pathologic examination of the brain tissue revealed necrosis of neuron cells and broad hyperplasia of gliocytes. Immunostaining demonstrated that monokine induced by interferon-g (Mig) was expressed in gliocytes with the infiltration of CD68+ monocytes/macrophages and CD3+ T lymphocytes in the brain mesenchyme. Cytokine/chemokine assay revealed that levels of interferon-g-inducible protein 10 and Mig in the blood were highly elevated, although the levels of other cytokines and chemokines were close to normal. Conclusions. This study provides direct evidence that SARS human coronavirus is capable of infecting the central nervous system, and that Mig might be involved in the brain immunopathology of SARS. The causative pathogen of severe acute respiratory syndrome (SARS) has been identified as a new member of the coronavirus family that exhibits a broad range of hosts, infecting many mammalian and avian species and - CNS [3]. Our recent study of the SARS epidemic found that the spike protein, a surface antigen determining the tropism of coronavirus, had the strongest response to positive selection pressure [4]. We noticed that a few patients with SARS in hospitals in Guangzhou City, China, exhibited central nervous symptoms during the course of their illnesses. Lau and colleagues [5] reported that a CSF sample obtained from a 32-year-old woman with SARS tested positive for SARS coronavirus (SARSCoV) by RT-PCR, indicating that SARS-CoV might cause an infection in the CNS of patients with SARS. In the present study, we isolated a SARS-CoV strain from a brain tissue specimen obtained during autopsy from a patient with SARS who became severely sick and showed significant central nervous symptoms during the course of his illness. Furthermore, we investigated the immunopathological mechanism of brain damage in the patient with SARS. In this study, we detected a high level of monokine induced by IFN-g (Mig), a member of CXC family [6, 7], in the patients brain and found that gliocytes were a major source for Mig production in the brain. All results suggested that Mig was involved in the immunopathology of the brain on invasion of SARS-CoV. CASE REPORT A 39-year-old doctor who was in charge of treatment of patients with SARS in the respiratory intensive care unit of the Chest Hospital (Guangzhou, China) developed a sudden onset of fever, chills, malaise, headache, dizziness, and myalgia and was hospitalized on 2 April 2003. Physical examination showed a temperature of 38.5 C, clear lungs, and no obvious focus of infection. His fever resolved with treatment with ribavirin and methylprednisolone (dosage, 120 mg per day), and his condition improved during the first week of treatment. A chest radiograph obtained on day 11 after the onset of symptoms revealed left lower lobe infiltrates. A complete blood count demonstrated an elevated WBC count of 16.4 109 cells/L, an increased level of neutrophils (15.5 109 cells/L), and lymphopenia (lymphocyte count, 0.4 109 (...truncated)


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Jun Xu, Shuqing Zhong, Jinghua Liu, Li Li, Yong Li, Xinwei Wu, Zhijie Li, Peng Deng, Jingqiang Zhang, Nanshan Zhong, Yanqing Ding, Yong Jiang. Detection of Severe Acute Respiratory Syndrome Coronavirus in the Brain: Potential Role of the Chemokine Mig in Pathogenesis, Clinical Infectious Diseases, 2005, pp. 1089-1096, 41/8, DOI: 10.1086/444461