In an effort to further understand and predict the health effects that can arise following infection by SARS-CoV-2, which is the infection that causes the disease COVID-19, many researchers have reevaluated the pathogenesis associated with coronaviruses that have already been identified. One type of coronavirus that has infected individuals around the world is HCoV-OC43.
Image Credit: ungvar/Shutterstock.com
A history of coronaviruses
In 1965, the first human coronavirus (HCoV) strain, which was eventually named B814, was identified from a patient’s nasal discharge. Since then, over 30 different HCoV strains have been isolated, the most notable of which include HCoV-229E, HCoV-NL63, HCoV-HLU1, and HCoV-0C43.
In addition to the aforementioned human-infecting coronavirus strains, several highly pathogenic zoonotic strains such as the severe acute respiratory syndrome coronavirus (SARS-CoV) of 2002, the Middle East respiratory syndrome coronavirus (MERS-CoV) of 2011 and the novel coronavirus COVID-19 that has, as of June 18, 2020, infected 8.24 million people and claimed the lives of over 446,000 thousand individuals around the world.
Classification of HCoV-OC43
Within the virus order of Nidiovirules is the suborder of Cornidovirineae. Within Cornidovirineae are two subfamilies known as Letovirinae and Orthocoronairinae.
All coronaviruses are within the subfamily of Orthocornavirinae; however, specific coronavirus strains can be further classified into one of four genera including Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. Whereas HCoV and HCoV-NL63 are found in the Alphacoronavirus genus, HCoV-OC43, as well as HCoV-HKU1, MERS-CoV, SARS-CoV and SARS-CoV-2 are all classified within the Betacoronavirus genus.
How does HCoV-OC43 enter cells?
The entry of HCoV-OC43 into human cells is largely achieved through the caveolin-1-dependent pathway of endocytosis; however, virus-containing vesicles at the cell surface can also undergo scission to also penetrate human cells.
Notably, while host factors like interferon-inducible transmembrane proteins (IFITMs) often prevent the entry of coronaviruses like HCoV-229E, -NL63, SARS-CoV and MERS-CoV from entering cells through its various antiviral functions, IFITM2 and IFITM3 promote the entry and subsequent infection of HCoV-OC43 into human cells.
Infection mechanisms
Once HCoV-OC43 enters the cell, infection is primarily due to a stress response by the endoplasmic reticulum (ER). Under normal circumstances, the ER is responsible for performing the synthesis, folding and post-translational modifications of many proteins; however, when the processing capacity of the ER is reached, accumulation of misfolded or unfolded proteins will occur, thereby leading to a stress response by this vital organelle.
Otherwise referred to as an unfolded protein response (UPR), the ER stress response by HCoV specifically activates inositol requiring enzyme 1 (IRE1) and induces X-box protein 1 (XBP1) mRNA splicing.
Furthermore, the S proteins of HCoV-OC43 can introduce two-point mutations of H183R and Y241H into the human cells, both of which further contribute to XBP1 mRNA splicing and an overall greater extent of apoptotic death in the infected cell.
The apoptosis of cells caused by HCoV-OC43 has also been shown to arise due to the mitochondrial translocation of Bcl-2-associated X protein (BAX).
In addition to its direct role in inducing the ER stress response, HCoV-OC43 has also been shown to downregulate over 30 genes that are involved in the innate immune response, some of which include MAP kinases, toll-like receptors, interferons, interleukins, and signal transduction proteins.
Clinical features
Along with HCoV-229E, -NL63 and -HKU1, HCoV-OC43 is responsible for up to 30% of all common colds in adults; however, more severe forms of these viral infections can lead to upper respiratory tract disease.
Like many other respiratory tract infections, HCoV-OC43 typically mild respiratory tract infections that can be spread to other individuals by coughing and sneezing.
The similarity in clinical symptoms of patients with both HCoV-OC43 and HCoV-229E often cause these infections to be indistinguishable from each other; however, sore throat manifestations are more commonly associated with HCoV-OC43 than HCoV-229E, which typically causes a greater extent of nasal inflammation.
Although most of the replication of HCoV-OC43 occurs in the epithelial cells of the upper respiratory tract, this virus is unique in its ability to tolerate mutations and even cause infection in the brain.
Rather than utilizing the BAX protein to induce apoptosis within neuronal cells, research has shown that HCoV-OC43 infection within the brain is most likely due to the necroptosis-inducing actions of the RIP1 and MLK1 proteins.
The ability of HCoV-OC43 to enter and infect neurons has been shown to induce acute encephalitis in mice that can be accompanied by various neurological disabilities post-infection, some of which include abnormal limb clasping reflex and decreased motor activity.
In addition to its most notable effects on the upper respiratory tract and possible neuronal infiltration, a 2001 outbreak of HCoV-OC43 in Normandy, France found that this virus can also cause a wide range of digestive problems to occur.
More specifically, this outbreak found that up to 57% of patients with HCoV-OC43 experienced vomiting, diarrhea, and abdominal pain.
In addition to upper respiratory tract effects, patients with HCoV-OC43 in this French study also experienced several lower respiratory tract symptoms, of which included bronchitis, bronchiolitis, and pneumonia in 17%, 1-%, and 6.7% of all patients.
References and Further Reading
- Liu, D. X., Liang, J. Q., & Fung, T. S. (2020). Human Coronavirus-229E, -OC43, -NL63, and -HKU1. Reference Module in Life Sciences. doi:10.1016/B978-0-12-809633-8.21501-X.
- Jacomy, H., Fragoso, G., Amazan, G., Mushynski, W. E., & Talbot, P. J. (2006). Human coronavirus OC43 infection induces chronic encephalitis leading to disabilities in BALB/C mice. Virology 349(2); 335-346. doi:10.1016/j.virol.2006.01.049.
- Vabret, A., Mourez, T., Gouarin, S., Petitjean, J., & Freymuth, F. (2003). An Outbreak of Coronavirus OC43 Respiratory Infection in Normandy, France. Clinical Infectious Diseases 36(8); 985-989. doi:10.1086/374222.
Further Reading
Genetic risk factors for long-COVID uncovered in a large multi-ethnic study