Chapter 20 : Pathogenesis of Human Coronaviruses Other than Severe Acute Respiratory Syndrome Coronavirus

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Human coronaviruses (HCoVs) are endemic, and infections mainly occur in the winter and early spring. The most probable route of entry of HCoV appears to be the nasal mucosa, and horizontal transmission via small aerosols is possible, at least for HCoV-229E. Although HCoVs other than SARS-CoV are primarily associated with mild upper and lower respiratory tract disease, with the common cold the typical HCoV-induced pathology, HCoV was regularly associated with severe respiratory distress in newborns and recognized as an important trigger of acute asthma exacerbations. More recently, both previously (229E and OC43) and newly (NL63 and HKU1) described HCoVs have been associated with more severe acute lower respiratory tract infection, including pneumonia, in both infants and immunocompromised patients. Moreover, various reports have implicated the 229E and OC43 groups in other pathologies, such as myocardites and meningitis and severe diarrhea. Over the years, several reports have also suggested a possible link between the presence of HCoV within the human central nervous system (CNS) and various neurological disorders such as multiple sclerosis (MS), Parkinson’s disease (PD), and encephalitis. As for virus infections in general, the development of vaccines against HCoVs is the best way to prevent infection and disease. This chapter deals with recent advances in research and development on inhibitors that act at various steps of the virus replication cycle, from receptor binding to release of progeny infectious particles.

Citation: Talbot P, Jacomy H, Desforges M. 2008. Pathogenesis of Human Coronaviruses Other than Severe Acute Respiratory Syndrome Coronavirus, p 313-324. In Perlman S, Gallagher T, Snijder E (ed), Nidoviruses. ASM Press, Washington, DC. doi: 10.1128/9781555815790.ch20
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Image of Figure 1.
Figure 1.

Human monocytic cells are susceptible to productive HCoV-229E infection, are activated following infection, and could serve as a viral reservoir for access to the CNS. Infected monocytic cells are activated and can produce TNF-α, which can induce the up-regulation of the adhesion molecule ICAM-1 on endothelial cells forming the blood-brain barrier (BBB), facilitating adhesion and passage of monocytes into the CNS. Infected and activated monocytic cells can also produce MMP-9. This metalloproteinase can induce an increased permeabilization of the BBB, also facilitating the passage of leukocytes into the CNS. Infection may also induce an up-regulation of chemokine receptors at the cell surface, also facilitating the passage of leukocytes into the CNS.

Citation: Talbot P, Jacomy H, Desforges M. 2008. Pathogenesis of Human Coronaviruses Other than Severe Acute Respiratory Syndrome Coronavirus, p 313-324. In Perlman S, Gallagher T, Snijder E (ed), Nidoviruses. ASM Press, Washington, DC. doi: 10.1128/9781555815790.ch20
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Image of Figure 2.
Figure 2.

Neuroinvasive properties of HCoV-OC43 in mice. Fourteen-day-old C57BL/6 mice were infected intranasally with HCoV-OC43 (5,000 50% tissue culture infective doses [TCID]). Five animals were sacrificed every 24 h, and virus titers were measured in the CNS and lung. Infectious HCoV-OC43 was detectable in the brain as soon as 3 days postinfection and reached its maximum titer a few days later. Virus was also detected in the lungs. The detection limit of the assay was 10 TCID/g. Inhalation of virus led to a generalized infection of the CNS and 90% mortality from encephalitis, demonstrating the neuroinvasiveness and neurovirulence of HCoV-OC43.

Citation: Talbot P, Jacomy H, Desforges M. 2008. Pathogenesis of Human Coronaviruses Other than Severe Acute Respiratory Syndrome Coronavirus, p 313-324. In Perlman S, Gallagher T, Snijder E (ed), Nidoviruses. ASM Press, Washington, DC. doi: 10.1128/9781555815790.ch20
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Image of Figure 3.
Figure 3.

HCoVs and the molecular mimicry hypothesis in human neuropathology. Following infection by an HCoV, viral peptides are presented by antigen-presenting cells (APC) to T cells (T) specific for viral or myelin antigens. T cells become activated (aT) and can up-regulate adhesion molecules, which will promote interaction with cells from the blood-brain barrier (BBB) and facilitate penetration into the CNS. These activated T cells can then interact with the CNS-resident APC, microglia, which can present peptides derived from myelin components that can be recognized by virus-specific T cells, or vice versa, on the basis of shared similar sequences or conformations. Such myelin-virus cross-reactive T cells may therefore generate an autoimmune response with possible downstream immunopathological consequences. Chemokine secretion by activated T cells increases leukocyte recruitment, with potential amplification of the immune response. Gamma interferon (IFN-γ) production by activated T cells can increase cytokine (TNF-α) and nitric oxide (NO) production by glial cells (astrocytes and microglia), with potential damage to neurons and myelin-producing oligodendrocytes. Activated T cells may also cause direct cytotoxicity to neurons or oligodendrocytes.

Citation: Talbot P, Jacomy H, Desforges M. 2008. Pathogenesis of Human Coronaviruses Other than Severe Acute Respiratory Syndrome Coronavirus, p 313-324. In Perlman S, Gallagher T, Snijder E (ed), Nidoviruses. ASM Press, Washington, DC. doi: 10.1128/9781555815790.ch20
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Image of Figure 4.
Figure 4.

Inflammatory response following intracerebral HCoV-OC43 inoculation. Immunohistological staining of the brains of 21-day-old HCoV-OC43-infected BALB/c mice. At 6 days postinfection, infected hippocampal neurons (stained in black) (A) and microglial activation (revealed by Mac-2 staining) (B) are evident in the same region, demonstrating the strong inflammatory reaction in infected regions.

Citation: Talbot P, Jacomy H, Desforges M. 2008. Pathogenesis of Human Coronaviruses Other than Severe Acute Respiratory Syndrome Coronavirus, p 313-324. In Perlman S, Gallagher T, Snijder E (ed), Nidoviruses. ASM Press, Washington, DC. doi: 10.1128/9781555815790.ch20
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