- A new study assessed the dynamics of the replication of the new coronavirus, SARS-CoV-2, in the upper respiratory tract and the body’s early immune response.
- The study reports that SARS-CoV-2 replicates exponentially immediately after infection and results in an immune response that lags by a few days.
- The results suggest that an early and robust immune response may inhibit viral replication.
- Pre-infection with a different respiratory tract virus — such as a cold virus — inhibited SARS-CoV-2 replication, suggesting that interactions between viruses may influence their transmission.
The coronavirus responsible for the ongoing COVID-19 pandemic, SARS-CoV-2, is prone to mutations or changes in its genetic sequence. Such mutations have resulted in the emergence of new, more transmissible SARS-CoV-2 variants.
SARS-CoV-2 is most transmissible
The body’s initial response to the SARS-CoV-2 infection involves the activation of the innate immune response, which is rapid and not specific to any particular virus.
Thus, to understand the differences in transmissibility of SARS-CoV-2 variants, it is essential to characterize the interaction between the virus and the innate immune system.
After entering the body, SARS-CoV-2 initially replicates in the upper respiratory tract. This replication triggers an antiviral response involving interferons, a family of proteins that play a role in the innate immune response. Interferon production, in turn, switches on the expression of interferon-stimulated genes (ISG) that inhibit viral replication.
Although a robust interferon response can help
Dr. Ellen Foxman, an assistant professor at Yale School of Medicine in New Haven, CT, led a recent study that sought to clarify the ability of the interferon response to restrict SARS-CoV-2 replication.
The study found that as the viral load, or amount, of SARS-CoV-2 in organoids made from upper respiratory tract tissue rose and fell, the expression levels of ISG also increased and then declined. Furthermore, the results suggest that the timing and magnitude of the interferon response, which the team measured using ISG expression levels, could influence the progression of the SARS-CoV-2 infection.
Speaking with Medical News Today, Dr. Foxman explained that the interactions between the virus and the immune system might also explain why some individuals develop severe illness, whereas others have mild or no symptoms.
The study appears in the Journal of Experimental Medicine.
Dynamics of the interferon response
To understand the interplay between SARS-CoV-2 replication and the interferon response, the researchers collected nasopharyngeal swabs from patients at various stages of COVID-19.
The researchers measured SARS-CoV-2 levels in the swab samples by quantifying viral RNA levels, whereas they measured the levels of a protein called CXCL10 to track ISG expression levels. This was possible because CXCL10 levels in the upper respiratory tract had a positive correlation with ISG expression levels.
While the CXCL10 levels correlated with upper respiratory tract virus levels in people with SARS-CoV-2, CXCL10 production started a few days after the onset of viral replication.
To delineate the time course of changes in SARS-CoV-2 and the interferon response in more detail, the scientists used laboratory cultures called organoids, which comprise human epithelial cells that line the respiratory tract. They used a 3D culture system to create the organoid, which is a way of investigating the behavior of a collection of cells that simulate the human respiratory tract in the laboratory.
The researchers infected the organoid cells with SARS-CoV-2 and measured the viral load and the CXCL10 and ISG expression levels.
The cell culture data showed that SARS-CoV-2 replicated exponentially during the initial 72 hours and then plateaued. The viral load doubled in approximately 6 hours during this period.
In contrast, CXCL10 protein levels and ISG expression levels gradually increased during the initial 72 hours before rapidly increasing over the next 24 hours.
These data suggest that SARS-CoV-2 levels rose rapidly after entering the body and gave rise to a strong interferon response that lagged by a few days.
Viral interference
Next, the scientists wanted to determine whether the interferon response was capable of inhibiting viral replication.
They infected the organoid culture with a rhinovirus, which is the predominant cause of the common cold, to enhance the ISG expression levels. After 3 days, the scientists infected the rhinovirus-infected cells with the SARS-CoV-2 virus.
Pre-infection with the rhinovirus completely inhibited SARS-CoV-2 replication. Moreover, the organoid cells that the researchers infected with the rhinovirus and then SARS-CoV-2 showed higher ISG and interferon expression levels than the cells that they infected with SARS-CoV-2 alone.
This suggests that the interferon response that the rhinovirus infection elicited could have interfered with SARS-CoV-2 replication.
To confirm this, the researchers used a drug called BX795 to block the interferon response.
Pretreatment with BX795 diminished the ability of the rhinovirus to inhibit SARS-CoV-2 replication in organoid cells. Thus, an increase in ISG expression was, indeed, responsible for blocking SARS-CoV-2 replication.
Scientists have used the term “viral interference” to describe the phenomenon by which a recent infection with one virus, such as rhinovirus, can protect the individual from subsequent infection with a different virus, such as SARS-CoV-2.
However, in other cases, infection with one virus may increase susceptibility to another virus.
The authors intend to investigate the topic of viral interaction in subsequent studies.
Dr. Foxman noted, “We would like to understand how the interactions among viruses, like the ones that we describe in this study, affect susceptibility to respiratory viruses in general.”
“These interactions may also be shaping how cold and flu viruses spread throughout the world each year. Understanding how one infection impacts susceptibility to another could lead to new therapies for respiratory viruses and new ways to protect against future pandemics,” she added.
Early interferon response
The scientists also assessed the effects of blocking the interferon response on SARS-CoV-2 replication in the absence of rhinovirus.
They found that blocking the interferon response using BX795 enhanced SARS-CoV-2 replication. However, this occurred only when they used lower doses of SARS-CoV-2 to infect the organoids. In other words, the organoid cells did produce an interferon response that was effective against lower viral loads.
This suggests that the interferon response can slow the progression of COVID-19, especially during the early stages of infection when SARS-CoV-2 levels are lower.
The authors speculate that SARS-CoV-2 variants with increased transmissibility may carry mutations that result in an enhanced ability to block the interferon response.
Potential clinical implications
The authors conclude that innate immune responses can inhibit SARS-CoV-2 replication during the early stages of infection. Furthermore, they note that “airway innate immunity is dynamic, with innate immune defense rapidly changing in response to current and recent viral infections.”
Elaborating on the study’s clinical implications, Dr. Foxman said:
“Our study shows that even a small change in how fast natural antiviral defenses activate at the start of an infection can make a huge difference in the outcome. Therapeutics that help activate these defenses quickly could be a good approach to protect against illnesses from respiratory viruses, particularly for emerging viruses like [SARS-CoV-2].”
“Also, identifying other factors that affect how fast these defenses activate can help people take actions to boost their own immunity — for example, warmer temperatures and higher humidity appear to boost these defenses,” she noted.
Strengths and limitations
“A strength of this study is that we were able to observe both the infection and the body’s defense in patients very close to the start of infection, which is difficult to do because, at this point in the infection, patients usually have few or no symptoms,” added Dr. Foxman.
“However,” she explained, “we used lab-grown airway tissue to look at interactions between the common cold and COVID-19, since we didn’t want to infect people with viruses!”
Describing the limitations of the study, Dr. Foxman noted, “Also, we could not ask whether the common cold virus blocks COVID-19 in natural settings due to the very low rates of common cold viruses over the past year related to social distancing.”
“This will be something that is important to look for going forward. The relative timing of infections and specific types of common cold virus (there are a lot of varieties) could make a difference in terms of how a recent common cold infection will impact susceptibility to COVID-19.”
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