Acute and Persistent Infection of Human Neural Cell Lines by Human Coronavirus OC43

Abstract

Human coronaviruses (HuCV) are recognized respiratory pathogens. Data accumulated by different laboratories suggest their neurotropic potential. For example, primary cultures of human astrocytes and microglia were shown to be susceptible to an infection by the OC43 strain of HuCV (A. Bonavia, N. Arbour, V. W. Yong, and P. J. Talbot, J. Virol. 71:800–806, 1997). We speculate that the neurotropism of HuCV will lead to persistence within the central nervous system, as was observed for murine coronaviruses. As a first step in the verification of our hypothesis, we have characterized the susceptibility of various human neural cell lines to infection by HuCV-OC43. Viral antigen, infectious virus progeny, and viral RNA were monitored during both acute and persistent infections. The astrocytoma cell lines U-87 MG, U-373 MG, and GL-15, as well as neuroblastoma SK-N-SH, neuroglioma H4, oligodendrocytic MO3.13, and the CHME-5 immortalized fetal microglial cell lines, were all susceptible to an acute infection by HuCV-OC43. Viral antigen and RNA and release of infectious virions were observed during persistent HuCV-OC43 infections (∼130 days of culture) of U-87 MG, U-373 MG, MO3.13, and H4 cell lines. Nucleotide sequences of RNA encoding the putatively hypervariable viral S1 gene fragment obtained after 130 days of culture were compared to that of initial virus input. Point mutations leading to amino acid changes were observed in all persistently infected cell lines. Moreover, an in-frame deletion was also observed in persistently infected H4 cells. Some point mutations were observed in some molecular clones but not all, suggesting evolution of the viral population and the emergence of viral quasispecies during persistent infection of H4, U-87 MG, and MO3.13 cell lines. These results are consistent with the potential persistence of HuCV-OC43 in cells of the human nervous system, accompanied by the production of infectious virions and molecular variation of viral genomic RNA.

Human coronaviruses: Viral and cellular factors involved in neuroinvasiveness and neuropathogenesis

“…neuroinvasive in humans and suggests that they establish a persistent infection in human CNS (Arbour et al, 2000). Furthermore, we have shown that these viruses are able to establish a persistent infection in human cells representative of the CNS (Arbour et al, 1999a(Arbour et al, , 1999b and that HCoV-OC43 RNA could be detected for at least a year in the CNS of infected mice that survived the acute encephalitis. A significant portion of these surviving mice exhibited abnormal reflexes shown by limb clasping, presented clinical signs of decreased activity in an open field test, and had a smaller hippocampus associated with a loss of hippocampal neurons, particularly in the CA1 and CA3 layers (Jacomy et al, 2006), similar to what is seen after neuroinvasion of the CNS by the influenza A virus (Jurgens et al, 2012).…”

“…Up until now, no clear specific association has ever been made with any known human neuropathology. However, even though the mechanism by which they reach the human CNS is still to be decrypted, at least three of the six coronaviruses that infect humans were shown to be neuroinvasive and neurotropic in humans: HCoV-229E and HCoV-OC43 (Arbour et al, 1999a(Arbour et al, , 1999b(Arbour et al, , 2000Bonavia et al, 1997), as well as SARS-CoV (Gu et al, 2005;Xu et al, 2005).…”

Survival of human coronaviruses 229E and OC43 in suspension and after drying onsurfaces: a possible source ofhospital-acquired infections

“…15 On skin, infectivity of parainfluenza virus decreased rapidly but remained detectable for up to 1 h. 15,18 On the other hand, RSV could be recovered from a skin surface for not more than 20 min 8 and rhinoviruses could survive for 1-3 h. 9 We have not tested survival of HCoV on human skin because of ethical concerns regarding the risk of acute respiratory tract infection and possible neurological damage. 19,20 To prevent or reduce the possibility of personto-person transmission of viruses via surfaces, their disinfection is important. Therefore, we tested the disinfecting activity against HCoV of four classes of disinfectants that are widely used in hospitals.…”

Hosts and Sources of Endemic Human Coronaviruses

“…Several recent descriptions of novel BetaCoV1 members or relatives in rodents suggest them as primordial hosts (Hu et al, 2017;Lau et al, 2015;Wang et al, 2015). HCoV-OC43 was found to have tropism for neural cells in vitro and in experimentally infected mice, resembling MHV (Arbour et al, 1999;Jacomy et al, 2006). Presence of virus in the central nervous system was reported in patients with chronic demyelinating disease and acute encephalomyelitis (Morfopoulou et al, 2016;Murray et al, 1992;Yeh et al, 2004).…”