University Of California Study Shows That Interleukin 13 Prevents SARS-CoV-2 Infection

A new study by researchers from the University of California-San Francisco has found that human bronchial epithelial cells stimulated with Interleukin 13 were less susceptible to infection by the SARS-CoV-2 coronavirus compared to cells not stimulated by Interleukin 13.


 
Interleukin 13 or IL-13 is a protein that in humans is encoded by the IL13 gene. IL-13 is a cytokine secreted by T helper type 2 (Th2) cells, CD4 cells, natural killer T cell, mast cells, basophils, eosinophils and nuocytes. Interleukin-13 is a central regulator in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis and chitinase up-regulation. It is a mediator of allergic inflammation and different diseases including asthma.
 
The study findings were published on a preprint server and have yet to be peer reviewed. https://www.biorxiv.org/content/10.1101/2021.02.25.432762v1
 
The coronavirus disease 2019 or COVID-19, the disease caused by the SARS-CoV-2 coronavirus, affects individuals differently. While some show no symptoms, others have a severe and often fatal version of the disease. Pre-existing medical conditions, being male, and being immunocompromised are some factors that affect disease outcomes.
 
Initially during the early stages of the pandemic there is also concern that individuals with asthma will have an increased risk for COVID-19, given previous experience with other respiratory viruses that worsen asthma.
 
Surprisingly however, some studies have found that the risk of being infected and hospitalized for COVID-19 is lower in people with asthma. Many factors, such as being careful to limit virus exposure, younger age, and other biological features, could provide protection. https://www.medrxiv.org/content/10.1101/2021.01.15.21249756v1.full
 
https://pubmed.ncbi.nlm.nih.gov/32522462/
 
https://pubmed.ncbi.nlm.nih.gov/33493416/
 
It has been found that the airway epithelium, a key SARS-CoV-2 infection site, is modified in people with asthma, with changes due to the cytokine Interleukin 13 (IL-13) observed in about half the patients.
 
Importantly IL-13 decreases the expression of the angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor in humans, and is known to protect against other RNA viruses.
 
In the research findings, the study team reported the results on whether IL-13 expression in asthma patients reduces their susceptibility to SARS-CoV-2 infection.
 
The researchers used primary human bronchial epithelial cells (HBEC) from 13 individuals and they cultured the cells with and without IL-3, and then infected them with the SARS-CoV-2 virus.
 
Interestingly from a list of 342 SARS-CoV-2 associa ted genes, the team found 332 of these genes in HBEC cultures without IL-13. Further analysis revealed that genes were expressed differently in the different cell types.
 
Significantly IL-13 increased TMPRSS2 expression in secretory cells but decreased it in ciliated cells. This different expression could affect infection outcomes in the different epithelial cells.
 
The study team then investigated if the SARS-CoV-2 genes were modified in asthma using data from asthmatic and healthy individuals using the three gene metric (TGM), a common method for measuring IL-13 induced airway inflammation in asthma.
 
The researchers found 24 of the 27 SARS-CoV-2 associated genes induced by IL-13 were positively correlated with the TGM and 16 of these were significantly associated with the TGM when age and sex were included.
 
The study results indicate SARS-CoV-2 associated genes induced by IL-13 are similar to those seen in people with asthma or chronic obstructive pulmonary disease (COPD).
 
More significant is the fact that when the study team tested for viral RNA in the HBEC cells infected with SARS-CoV-2 after 48 hours, the team found pre-stimulation with IL-13 significantly decreased viral infection by more than 95%. In addition, the presence of mucus decreased viral RNA detected in unstimulated cells by 74% compared to cells without mucus.
 
The study team next tested for the presence of double-stranded DNA (dsDNA), produced during viral replication and how it is affected by mucus and IL-13.
 
The team however did not see any dsDNA in IL-13 stimulated cultures, but small amounts of viral RNA was detected. This could be because the dsDNA test is less sensitive than qRT-PCR or IL-13 totally prevented viral replication, and the RNA detected is remnants of viral inoculum.
 
The study findings indicated strongly that IL-13 reduces SARS-CoV-2 infection.
 
As many of the modifications due to IL-13 on the SARS-CoV-2 associated genes were seen in cultured cells as well as samples obtained from individuals with type 2 asthma, this could be why individuals with asthma may be protected from COVID-19.
 
The study team also found associations between the genes and type 2 inflammations in smokers with and without COPD.
 
Importantly the effect of IL-13 on the genes was different from that of IFN-a, likely because they induce different antiviral mechanisms.
 
The study findings suggested not only IL-13, but the mucus gel may also protect against infection.
 
Professor Dr David J. Erle from the Lung Biology Center and Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine; University Of California-San Francisco told Thailand Medical News, “While effects of IL-13 on the airway epithelium are an important contributor to asthma pathogenesis, it is intriguing to speculate that IL-13 responses may have evolved at least in part to protect against viral infections.”
 
It is important to note that several different mechanisms may be responsible for SARS-CoV-2 inhibition by IL-13.
 
A past study showed a single cytokine could activate many antiviral pathways. The decrease in ACE2 expression by IL-13 could be a possible mechanism. The results also showed mucus helped prevent infection. IL-13 also regulates mucins, glycoproteins that form mucus, forming mucus gel on the epithelium.
Although the exact mechanism of IL-13 inhibiting SARS-CoV-2 is still unclear, understanding the antiviral pathways may help develop treatments for COVID-19.
 
A current commercial drug called Dupilumab or Dupixent which is a monoclonal antibody IL-13 carries a list price of US$37,000 in the United States and is manufactured once again by the famous duo Regeneron Pharmaceuticals and Sanofi!
 
The study is supported by grants from the US NIH which has close ties to these pharmaceutical companies!
 
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