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Case Reports
. 2005 Oct 15;41(8):1089-96.
doi: 10.1086/444461. Epub 2005 Sep 12.

Detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine mig in pathogenesis

Jun Xu  1 , Shuqing Zhong, Jinghua Liu, Li Li, Yong Li, Xinwei Wu, Zhijie Li, Peng Deng, Jingqiang Zhang, Nanshan Zhong, Yanqing Ding, Yong Jiang
Affiliations
Case Reports

Detection of severe acute respiratory syndrome coronavirus in the brain: potential role of the chemokine mig in pathogenesis

Jun Xu et al. Clin Infect Dis. .

Abstract

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- gamma (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- gamma -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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Figures

Figure 1
Figure 1
A CT scan of different brain sections shows a diffuse brain edema with multiple high-density lesions (A–F). Arrows, high-density lesions.
Table 1
Table 1
Results of general laboratory examination of the patient with severe acute respiratory syndrome (SARS), by number of days after onset of illness.
Figure 2
Figure 2
Histochemistry stains showing neuron denaturation and necrosis with striated encephalomalacia (A; original magnification, ×100) (B; original magnification, ×400), vasocongestion with widening peripheral space the around vessel (C; original magnification, ×200), and focal hemorrhage (D; original magnification, ×100) and gliosome formation in the brain tissue (E; original magnification, ×200). Arrows, pathological alterations described above.
Figure 3
Figure 3
Identification of severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) in the brain tissue of the patient with SARS. A, Results of nested RT-PCR for BNI-1 fragment (108 base pairs) of SARS-CoV in the supernatants obtained from cultured Vero-E6 cells with cytopathic effect. Lane 1, DNA standard; lane 2, Vero-E6 cell culture inoculated with the lung suspension; lane 3, Vero-E6 cell culture used as negative control; lane 4, Vero-E6 cell culture inoculated with the brain suspension. B, Transmission electronic microscopy reveals the presence of enveloped virus particles with morphology compatible with coronavirus. Extracellular particles were found clustering and adhering to the surface of the plasma membrane.
Figure 4
Figure 4
Immunohistochemistry stains for N protein of severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) in a specimen of brain tissue obtained from the patient with SARS during autopsy. A monoclonal antibody against N protein of SARS-CoV and the secondary antibody of horseradish peroxidase (HRP) conjugated goat antimouse were used for the immunohistochemical staining of brain tissue specimens obtained from the patient with SARS (A; original magnification, ×200) and a patient who died in a traffic accident (B; original magnification, ×200). Staining was performed with diaminobenzidine (brown). Arrows, positive staining cells.
Figure 5
Figure 5
Immunohistochemistry and double immunofluoresence staining of specimens of brain tissue sections obtained from the patient with severe acute respiratory syndrome during autopsy. Antibodies against IFN-Γ–inducible protein 10 (IP-10) (A; original magnification, ×200), monokine induced by IFN-Γ (Mig) (B; original magnification, ×200), CD68 (C; original magnification, ×200), and CD3 (D; original magnification, ×200) were used in the immunohistochemical staining. Antibodies against Mig (E; original magnification, ×400) and glial fibrillary acidic protein (F; original magnification, ×400) were used in double immunofluoresence staining. A, Brain tissues without evidence of IP-10 from staining. B, Mig-positive staining cells detected in the brain tissue. C, Infiltration of CD68+ monocyte/macrophage cells. D, A few CD3+ T lymphocytes. E–G, A double immunofluoresence stain showing that glial fibrillary acidic protein positive cells (F) were expressing Mig (E) and displaying yellow immunofluoresence (G; original magnification, ×400) when the 2 images were merged. Arrows, positive staining cells. A–D were stained by diaminobenzidine. E–G were stained by both tetramethylrhodamine isothiocyanate (red) and FITC (green), respectively.
Figure 6
Figure 6
The profile of cytokines and chemokines in the blood of the patient with severe acute respiratory syndrome (SARS). Each cytokine/chemokine is expressed as a ratio of that of the patient with SARS to the average among control subjects. Of all the detected cytokines/chemokines, only IFN-Γ–inducible protein 10 (IP-10) and monokine induced by IFN-Γ (Mig) showed highly increased production.
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References

    1. Compton SR, Barthold SW, Smith AL. The cellular and molecular pathogenesis of coronaviruses. Lab Anim Sci. 1993;43:15–28. - PubMed
    1. Hensley LE, Holmes KV, Beauchemin N, Baric RS. Virus-receptor interactions and interspecies transfer of a mouse hepatitis virus. Adv Exp Med Biol. 1998;440:33–41. - PubMed
    1. Arbour N, Day R, Newcombe J, Talbot PJ. Neuroinvasion by human respiratory coronaviruses. J Virol. 2000;74:8913–21. - PMC - PubMed
    1. Chinese SARS Molecular Epidemiology Consortium. Molecular evolution of the SARS coronavirus during the course of the SARS epidemic in China. Science. 2004;303:1666–9. - PubMed
    1. Lau KK, Yu WC, Chu CM, Lau ST, Sheng B, Yuen KY. Possible central nervous system infection by SARS coronavirus. Emerg Infect Dis. 2004;10:342–4. - PMC - PubMed

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