Detection of SARS Coronavirus RNA in the Cerebrospinal Fluid of a Patient with Severe Acute Respiratory Syndrome

Hung, Emily C.W.; Chim, Stephen S.C.; Chan, Paul K.S.; Yu, Tong; Ng, Enders K. O.; Chiu, Rossa W.K.; Leung, Chi Bon; Sung, Joseph J.Y.; Tam, John S.; Lo, Y.M. Dennis

doi:10.1373/clinchem.2003.025437

Cited by 240 publications

(234 citation statements)

References 5 publications

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“…As in the lung, viral infection of the brain was associated with local inflammatory chemokine induction (e.g., CCL5), but the repertoire and temporal pattern were different and no leukocyte infiltration could be detected. Consistent with our results in mice, SARS-CoV has been identified in patient cerebrospinal fluid by quantitative PCR (42), and in brain neurons by immunohistochemistry at autopsy (43). However, to date virus has not been cultured from human CNS specimens.…”

Section: Discussionsupporting

confidence: 90%

Mechanisms of Host Defense following Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) Pulmonary Infection of Mice

Glass¹,

Subbarao

Murphy

et al. 2004

The Journal of Immunology

332

325

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We describe a model of severe acute respiratory syndrome-coronavirus (SARS-CoV) infection in C57BL/6 mice. A clinical isolate of the virus introduced intranasally replicated transiently to high levels in the lungs of these mice, with a peak on day 3 and clearance by day 9 postinfection. Viral RNA localized to bronchial and bronchiolar epithelium. Expression of mRNA for angiotensin converting enzyme 2, the SARS-CoV receptor, was detected in the lung following infection. The virus induced production in the lung of the proinflammatory chemokines CCL2, CCL3, CCL5, CXCL9, and CXCL10 with differential kinetics. The receptors for these chemokines were also detected. Most impressively, mRNA for CXCR3, the receptor for CXCL9 and CXCL10, was massively up-regulated in the lungs of SARS-CoV-infected mice. Surprisingly Th1 (and Th2) cytokines were not detectable, and there was little local accumulation of leukocytes and no obvious clinical signs of pulmonary dysfunction. Moreover, beige, CD1−/−, and RAG1−/− mice cleared the virus normally. Infection spread to the brain as it was cleared from the lung, again without leukocyte accumulation. Infected mice had a relative failure to thrive, gaining weight significantly more slowly than uninfected mice. These data indicate that C57BL/6 mice support transient nonfatal systemic infection with SARS-CoV in the lung, which is able to disseminate to brain. In this species, proinflammatory chemokines may coordinate a rapid and highly effective innate antiviral response in the lung, but NK cells and adaptive cellular immunity are not required for viral clearance.

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Section: Discussionsupporting

confidence: 90%

Mechanisms of Host Defense following Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) Pulmonary Infection of Mice

Glass¹,

Subbarao

Murphy

et al. 2004

The Journal of Immunology

332

325

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“…SARS-CoV was detected in the cerebrospinal fluid and serum samples of two cases with status epilepticus [34,35]. The data suggest that a severe acute neurological syndrome might occasionally accompany SARS.…”

Section: Clinical Featuresmentioning

confidence: 99%

SARS: clinical presentation, transmission, pathogenesis and treatment options

2006

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SARS (severe acute respiratory syndrome) appeared as the first emerging infectious disease of this century. It is fortunate that the culprit virus can be grown without much difficulty from a commonly used cell line, allowing an unlimited supply of isolates for further molecular studies and leading to the development of sensitive diagnostic assays. How the virus has successfully jumped the species barrier is still a mystery. The superspreading events that occurred within hospital, hotel and high-density housing estate opens a new chapter in the mechanisms and routes of virus transmission. The old practice of quarantine proved to be still useful in controlling the global outbreak. Despite all the available sophisticated tests, alertness with early recognition by healthcare workers and prompt isolation of suspected cases is still the most important step for containing the spread of the infection. Although the rapidly evolving outbreak did not allow the conducting of systematic clinical trails to evaluate treatment options, the accumulated experience on managing SARS patients will improve the clinical outcome should SARS return. Although SARS led to more than 700 deaths worldwide, the lessons learnt have prepared healthcare systems worldwide to face future emerging and re-emerging infections.

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“…CoVs, which cause respiratory diseases, have also been associated with neurological complications (Arabi et al, 2015;Arbour et al, 2000;Burks et al, 1980;Hung et al, 2003;Netland et al, 2008), with HCoV-OC43 even causing fatal encephalitis (Jacomy et al, 2006;Jacomy and Talbot, 2003;Morfopoulou et al, 2016); however, the mechanisms responsible for their dissemination and penetration in the host CNS remain unclear. Therefore, easily observable, living animal models are required to identify the mechanisms of HCoV infection in the CNS and enable the development of antiviral drugs for treating and preventing CoV infection and their associated severe CNS pathologies.…”

Section: Discussionmentioning

confidence: 99%

“…In 2012, a SARSlike disease emerged that resulted in a mortality rate of 30%, the causative agent of which was identified as Middle East respiratory syndrome CoV (MERS-CoV) (Gralinski and Baric, 2015;Milne-Price et al, 2014). Despite their status as infectious respiratory pathogens, CoVs can also damage the CNS and cause neurological diseases (Arabi et al, 2015;Arbour et al, 2000;Burks et al, 1980;Hung et al, 2003;Morfopoulou et al, 2016;Netland et al, 2008), with HCoV-OC43, HCoV-229E, and SARS-CoV detected in the cerebrospinal fluid of patients with multiple sclerosis (Arbour et al, 2000;Burks et al, 1980;Hung et al, 2003). Recently, severe neurological syndromes were identified as associated with MERS-CoV (Arabi et al, 2015), SASR-CoV reportedly exhibits neuroinvasive properties in the CNS of mice (Netland et al, 2008), and HCoV-OC43 is associated with fatal encephalitis (Morfopoulou et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Non-invasive bioluminescence imaging of HCoV-OC43 infection and therapy in the central nervous system of live mice

et al. 2020

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Human coronaviruses (HCoVs) are important pathogens that cause upper respiratory tract infections and have neuroinvasive abilities; however, little is known about the dynamic infection process of CoVs in vivo, and there are currently no specific antiviral drugs to prevent or treat HCoV infection. Here, we verified the replication ability and pathogenicity of a reporter HCoV-OC43 strain expressing Renilla luciferase (Rluc; rOC43-ns2DelRluc) in mice with different genetic backgrounds (C57BL/6 and BALB/c). Additionally, we monitored the spatial and temporal progression of HCoV-OC43 through the central nervous system (CNS) of live BALB/c mice after intranasal or intracerebral inoculation with rOC43-ns2DelRluc. We found that rOC43-ns2DelRluc was fatal to suckling mice after intranasal inoculation, and that viral titers and Rluc expression were detected in the brains and spinal cords of mice infected with rOC43-ns2DelRluc. Moreover, viral replication was initially observed in the brain by non-invasive bioluminescence imaging before the infection spread to the spinal cord of BALB/c mice, consistent with its tropism in the CNS. Furthermore, the Rluc readout correlated with the HCoV replication ability and protein expression, which allowed quantification of antiviral activity in live mice. Additionally, we validated that chloroquine strongly inhibited rOC43-ns2DelRluc replication in vivo. These results provide new insights into the temporal and spatial dissemination of HCoV-OC43 in the CNS, and our methods provide an extremely sensitive platform for evaluating the efficacy of antiviral therapies to treat neuroinvasive HCoVs in live mice.

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Detection of SARS Coronavirus RNA in the Cerebrospinal Fluid of a Patient with Severe Acute Respiratory Syndrome

Cited by 240 publications

References 5 publications

Mechanisms of Host Defense following Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) Pulmonary Infection of Mice

Mechanisms of Host Defense following Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) Pulmonary Infection of Mice

SARS: clinical presentation, transmission, pathogenesis and treatment options

Non-invasive bioluminescence imaging of HCoV-OC43 infection and therapy in the central nervous system of live mice

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