How the common cold can provide protection against COVID-19

By Benedette Cuffari, M.Sc.Jun 17 2021

In a recent study conducted at Yale University School of Medicine, researchers found that prior infection with the rhinovirus, which is the virus that is most commonly responsible for the common cold, can provide a more rapid and effective immune response against severe acute respiratory coronavirus syndrome 2 (SARS-CoV-2) infection.

Common Cold. Image Credit: fizkes/Shutterstock.com

The IFN response to viruses

Upon binding to the angiotensin-converting enzyme 2 (ACE2) receptor, the SARS-CoV-2, which is the virus responsible for the coronavirus disease 2019 (COVID-19), begins to replicate in the upper respiratory tract. Within the first week of infection, the levels of SARS-CoV-2 genetic material typically reach their peak.

Traditional viruses like the rhinovirus, which is the most frequent cause of the common cold, often elicit innate immune responses like the antiviral interferon (IFN) response. This IFN response is often initiated when pattern recognition receptors within both epithelial and immune cells detect common viral features, such as the viral ribonucleic acid (RNA) structure.

Upon the recognition of these viruses, the IFN response leads to the expression of both type I and type III IFNs, as well as IFN-stimulated genes (ISGs). These IFNs then bind to cell surface receptors located on nearby cells, which amplifies the expression of ISGs and subsequently causes an antiviral state to arise in the mucosal barrier.

Altered immune response to COVID-19

A majority of respiratory viruses have been shown to induce this IFN response in the airway. SARS-CoV-2, however, has been shown to both antagonize and delay the IFN response. While the kinetics of the IFN response is often delayed following SARS-CoV-2 infection, this virus has been found to trigger both IFN secretion and ISG expression.

Some studies have found that while pretreatment with exogenous IFN successfully blocked SARS-CoV-2 infection, the IFN response was much less effective when added after the infection has already been established. Interestingly, the single-cell analysis of epithelial cells that have been obtained from patients with mild-to-moderate COVID-19 have exhibited ISG induction.

The same epithelial cell samples were obtained from patients with severe COVID-19 disease; however, these samples did not show any ISG induction, thereby suggesting that patients with severe disease are more likely to have genetic or acquired deficiencies in their IFN signaling pathways.

Measuring IFN levels in COVID-19 patients

These findings indicate that while the IFN response has the potential to protect the host against severe COVID-19, the timing and magnitude of this specific immune response that is needed to prevent viral replication must still be better understood. To better understand the early host-virus dynamics in the human nasopharynx following infection by SARS-CoV-2, a group of researchers at the Yale School of Medicine used both transcriptomics and biomarker-based tracking in serial patient nasopharyngeal samples.

In this study published in the Journal of Experimental Medicine, the researchers performed RNA sequencing on the nasopharyngeal swabs from a total of 30 patients who had previously tested positive for SARS-CoV-2, as well as 8 SARS-CoV-2-negative healthcare workers. The protein-coding genes that were found to be the most significantly enriched in the nasopharynx of SARS-CoV-2 patients were known ISGs. Furthermore, ISG expression appeared to be loosely correlated with the viral load, in which patients with the highest viral loads tended to have higher ISG expressions.  

In addition to comparing ISG expression levels between the COVID-19 positive patients and the control group, the researchers also sought to evaluate the expression of CXCL10. The researchers previously identified CXCL10 in the viral transport medium following other acute viral respiratory infections that correlated with ISGs at the mRNA level.

Similarly, a positive correlation between nasopharyngeal CXCL10 protein levels and the ISG expression levels at the RNA level. Notably, no correlation was found to exist between age and CXCL10 levels; rather, a rise in CXCL10 levels was instead found to be primarily influenced by the viral load.

How the common cold prevents SARS-CoV-2 replication

The researchers of the current study were also interested in identifying whether other physiological exposures, such as a prior infection with a different virus, could play a role in an individual’s ISG expression levels following SARS-CoV-2 infection. The researchers focused on rhinovirus for these experiments, as it is the most commonly detected virus in the human respiratory tract.    

Briefly, the researchers infected airway epithelial organoid cultures with human rhinovirus and evaluated the effect that this virus had on the expression of ACE2. Following the rhinovirus infection, the truncated form of ACE2 known as dACE2 was found to increase significantly.

In a second study, the researchers infected the same type of organoid cultures with SARS-CoV-2, with or without a prior infection by the rhinovirus. Three days after the initial infection, rhinovirus-infected cells were found to induce the expression of ISGs while simultaneously maintaining a healthy appearance at the same time. Comparatively, SARS-CoV-2 infected organoids that were not previously exposed to rhinovirus experienced a dramatic increase in their viral load.

Furthermore, SARS-CoV-2 infected organoid cultures that were previously infected with rhinovirus exhibited a significant increase in IFN1 levels as compared to organoid cultures that were not previously infected with the rhinovirus. At early parts in the infection, pre infected cultures were found to exhibit a greater expression of ISGs as compared to organoids that were not previously infected with the rhinovirus.

The researchers found that at the start of infection with SARS-CoV-2, the viral RNA material replicates at an exponential rate that induces ISG expression levels. When previously infected by the rhinovirus, the induction of ISG expression is much more rapid, thereby allowing the innate immune system to more quickly inhibit SARS-CoV-2 replication.

Overall, the studies performed by the researchers demonstrate that prior infection with a rhinovirus protects against the replication of SARS-CoV-2 as a result of the intact antiviral response that was already present at the time of the infection by SARS-CoV-2.