Defend yourself!… against the common cold: how smoking can blunt your antiviral response

Written By: Padmini Pillai

Original Article: Mihaylova et al. Cell Reports 2018

The Gist of It:

As the cold season is upon us, it’s time we think about how to protect ourselves against rhinovirus, the most frequent cause of the common cold. Rhinovirus enters the respiratory tract through the nasal passages and can spread down to larger airways of the lungs called bronchi. Epithelial cells, which line the respiratory tract, can detect rhinovirus and trigger immune responses. Although nasal and bronchial epithelial cells can be infected by rhinovirus, a study published this week demonstrates that they respond to infection in different ways.
The authors obtained human nasal and bronchial airway epithelial cells and infected them with rhinovirus. After infection, nasal epithelial cells produced significantly more interferon, a key antiviral molecule that turns on a plethora of genes to stop the virus. On the other hand, bronchial cells produced less interferon but higher amounts of a molecule called NRF2. NRF2 protects cells against damage triggered by injury and inflammation, and is often found in large amounts in the lungs of smokers.
Therefore, immune responses by cell types in different parts of the respiratory tract, from the nose down to the lungs, react to stimuli differently. This makes sense — your nasal passage encounters many pathogens and serves as the entry point for viruses into the respiratory tract, as well as your frontline defense against them, so interferon is critical for protection there. Further down in the bronchi, the consequences of inflammation and damage to the delicate lining in large airways responsible for carrying oxygen into the body is far too great, so pathways preventing damage and promoting survival to bronchial cells are of utmost importance.
Interestingly, the authors also discovered that NRF2 inhibits antiviral responses. If nasal cells were exposed to an extract of cigarette smoke and then infected with rhinovirus, they saw increased NRF2 and enhanced viral replication.  So here’s the take-home message: cigarette smoking or exposure to other airway irritants such as car exhaust or environmental pollutants could inhibit your antiviral responses by turning on NRF2, making you susceptible to respiratory infections such as the common cold. Prior research from Dr. Ellen Foxman showed that lower temperatures in the nasal passage also inhibit production of interferon by nasal epithelial cells (looks like the old wives’ tale to cover your nose in the cold may be true!). So this winter, try to stay away from smokers and keep those nasal passages warm to protect yourself from the common cold!
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Different places in your airways respond differently to viruses — and in case you needed more evidence — don’t smoke! If you smoke you’re more vulnerable to viral infections.

The Nitty Gritty:

The authors cultured primary human nasal and bronchial epithelial cells. After inoculation with rhinovirus 1b or transfection with the RIG-I ligand SLR14, nasal cells produced significantly more IFNλ1 and upregulated IFNβ and ISG expression. RNA-seq and ingenuity pathway analysis revealed that stimulation with SLR14 led to a dominant interferon response in nasal cells, while bronchial cells exhibited transcripts related to the NRF2 pathway. Knockdown of NRF2 in bronchial cells resulted in increased IFN and ISG expression. Pretreatment of nasal cells with the NRF2 activator sulforaphane significantly decreased interferon and ISG transcripts after SLR14 stimulation. siRNA knockdown of NRF2 in nasal cells inoculated with rhinovirus led to enhanced ISG induction and even stronger viral restriction. Nasal epithelial cells pretreated with cigarette smoking extract and inoculated with rhinovirus had higher viral tiers, increased expression of NRF2, and decreased expression of the ISG IFIT2. This study demonstrates two different defense mechanisms in airway epithelial cells from different regions of the respiratory tract and reveals that activation of NRF2 by oxidative stress can inhibit antiviral responses.
Original Research Article: Mihaylova, Valia T., et al. “Regional Differences in Airway Epithelial Cells Reveal Tradeoff between Defense against Oxidative Stress and Defense against Rhinovirus.” Cell Reports 24.11 (2018): 3000-3007.

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