The Common Cold: Immune Support With Quercetin

The common cold affects children, on average, 6-8 times a year while adults contract 4-6 colds per year.¹ Such cold viruses generally maintain their presence throughout all seasons and account for 40% of time lost from jobs and approximately 30% of absenteeism from school.^1(1289) Considering absenteeism from school, work, and associated unfavorable symptoms (chills, sniffles, lethargy), exploration of the common cold, and interventions to support the immune system, will be reviewed in the following sections.

Rhinovirus (RV) is a common driver of the majority of colds and is a single-stranded virus responsible for the majority of upper respiratory tract infections.² Such a virus is particularly problematic amongst individuals with compromised lung function, to include chronic obstructive pulmonary disease (COPD). Interestingly, Ganesan et al.²⁽²⁵⁸⁾ noted that RV has many steps between entry into a host cell and its ultimate replication, which could be inhibited.

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Chronic Obstructive Pulmonary Disease

Ganesan et al.²⁽²⁵⁸⁾ stated that a virus must first contact a cell receptor, then gain entry via endosomes (i.e., transporters of material), whereby its cellular and biochemical journey begins. During the pathway from the cell surface towards the nucleus/cytoplasm, viruses acidify the endosomal compartment, which is thought to allow escape (aka viral uncoating) of the virus/viral RNA (the recipe to produce more virus) into the cytoplasm of the cell.³ Timing is key so as to avoid lysosomes, which attach to endosomes and gather cell waste/recycle contents.³⁽²⁾

Once viral RNA is released into the cytoplasm of the cell, it begins translation; a process of making polyproteins by connecting amino acids together. Such is done to form a shell (aka capsid) and other components to eventually hold, protect, and maintain replicated viral genetic material.²⁽²⁵⁸⁾ Simultaneously, transcription (copying) of the entire viral genome (catalyzed by viral RNA polymerase) occurs, which migrates into the capsid.²⁽²⁵⁸⁾ Ultimately, said process produces more viral particles, which are then released from the cell and propagated throughout the host. Essentially, drugs/supplements which capture any of the steps of the viral life cycle could be of benefit.

Quercetin is a flavonoid that is found amongst several plants to include tea, onions, berries, apples, and broccoli.²⁽²⁵⁹⁾ Of particular interest is the antioxidant activity that it exerts, which can help protect cell structures and molecules (building blocks of humans).²⁽²⁵⁹⁾ Other, perhaps more relevant, qualities of quercetin include its ability to demonstrate antiviral activities in vitro (tested outside of the body); such has been demonstrated against parainfluenza virus, poliovirus type 1, adenovirus, and herpes simplex virus type 1.²⁽²⁵⁹⁾

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Antioxidants and Tracking Oxidative Stress

Quercetin has also been shown to inhibit proteases (help form/control polypeptide lengths used for producing more viral components) against SARS-CoV viruses as well as limiting the release of new viral particles out of host cells.²⁽²⁵⁹⁾ Quercetin flavonoids also reduced the susceptibility to influenza A infection in rat studies as well as controlling symptoms of upper respiratory tract infections in human (athletic) studies. Considering its potential within rat models, and some human research, the following will explore mechanisms behind quercetin and viruses in greater detail.

In the research of Ganesan et al.,²⁽²⁵⁸⁾ human airway epithelial cells (HAECs), in vitro, were infected by RV with varying protocols:

1. One group of HAECs received quercetin after infection, while other cells received DMSO (a solvent used to dissolve quercetin) after RV infection.²⁽²⁵⁹⁾
2. A second group of HAECs were pre-treated with quercetin or DMSO (for 1 hour), followed by RV infection (for 1 hour) and additional quercetin or DMSO thereafter.²⁽²⁵⁹⁾
3. A third group of HAECs were pre-treated with quercetin or DMSO overnight, followed by 8 hours in a quercetin-free medium, followed by RV infection, with no additional quercetin/DMSO thereafter.²⁽²⁵⁹⁾

Rat experiments, in-vivo, implementing RV infection and the effects of quercetin were explored in the following protocols:
1. One group of rats were infected with RV, followed by daily quercetin for 1 or 4 days.²⁽²⁵⁹⁾
2. A second group of rats underwent a sham procedure (researcher handles uninfected rats in the same fashion as those infected with RV) followed by daily quercetin for 1 or 4 days.²⁽²⁵⁹⁾
3. A third group of rats were infected with RV, followed by DMSO.
4. A fourth group of rats were pre-treated with quercetin or DMSO for 10 days, followed by RV infection or a sham procedure, two days after the last treatment of quercetin/DMSO.^2(259-260)

Findings suggested that pre-treatment of HAECs with quercetin inhibited RV entry into said cells.²⁽²⁶²⁾ Such is achieved by controlling activity of PI-3-kinase (PI3K); an enzyme responsible for controlling entry of substances into the cell, to include viruses.⁴ Thus, quercetin has been demonstrated to significantly inhibit PI3K activity/block viral entry/trafficking into the cell.²⁽²⁶²⁾ Quercetin also down-regulated RV-induced phosphorylation of AKT; an enzyme otherwise known as protein kinase B. AKT has many roles to include viral replication, but requires PI3K to move it towards the cell surface; blocking PI3K activity, therefore, blocks AKT activity.^3(262),4

Another characteristic of RV in increased inflammation during the common cold, driven by RV’s influence of the host cell.⁵ Individuals infected with RV have increased concentrations of pro-inflammatory cytokines, to include interleukin-8 (IL8); the more severe the symptoms of the cold, the higher the concentrations of said cytokine.^5(1885) Such inflammation is suggested to emanate from oxidative stress induced by RV. Results from Ganesan et al.²⁽²⁶²⁾ indicated that quercetin down-regulated PI3K/AKT activity (mentioned previously), which is responsible for controlling IL-8 activity. Thus, inflammation can be modulated by quercetin.

RV stops a host cell from producing its own proteins by cleavage of a key molecule, EIF4GI, responsible for regulating said process. This helps RV produce its own proteins and replication of its own genome.²⁽²⁶³⁾ Quercetin has been found to completely inhibit RV’s ability to cleave EIF4GI, thereby inhibiting RV’s ability to replicate on its own. After viral entry into a host cell, another mechanism to stop viral replication is by shutting global protein production. Such is initiated by a molecule known as EIF2 alpha.²⁽²⁶³⁾ Quercetin has been found to stimulate (via phosphorylation) EIF2 alpha, providing another means of stifling RV’s propagation.²⁽²⁶³⁾ Dosing between 250-500 mg of quercetin (twice daily) has been proposed as immune support for mild to severe forms of viral lung infections, to include management of COVID-19.⁶

In conclusion, the common cold affects children, on average, 6-8 times a year while adults contract 4-6 colds per year.Such cold viruses generally maintain their presence throughout all seasons and account for 40% of time lost from jobs and approximately 30% of absenteeism from school. However, the research presented by Ganesan et al.²⁽²⁶⁸⁾ demonstrated that quercetin was able to inhibit viral entry/viral replication and decrease inflammatory markers associated with RV both, in cell and rat models. Such research suggests quercetin’s potential implementation amongst individuals with the common cold.

References

1. Worrall G. Common cold. Can Fam Physician. 2011;57(11):1289-1290. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215607/. Accessed September 5, 2021.
2. Ganesan S, Faris AN, Comstock AT, et al. Quercetin inhibits replication in vitro and in vivo. Antiviral Res;2012:258-271. doi:1016/j.antiviral.2012.03.005.
3. Lagache T, Sieben C, Meyer T, et al. Stochastic model of acidification, activation of hemagglutinin and escape of influenza viruses from an endosome. Front Phys. 2017;5(25):1-15. doi:https://doi.org/10.3389/fphy.2017.00025.
4. Bhattacharya S, McElhanon KE, Gushchina L, et al. Role of phosphatidylinositol-4,5-bisphosphate 3-kinase signaling in vesicular trafficking. Life Sci. 2016;15:39-45. doi: doi:10.1016/j.lfs.2016.10.018.
5. Kaul P, Biagioli MC, Singh I, et al. Rhinovirus-induced oxidative stress and interleukin-8 elaboration involves p47-phox but is independent of attachment to intercellular adhesion molecule-1 and viral replication. J Infect Dis. 2000;181(6):1885-1890. doi: https://doi.org/10.1086/315504.
6. Luciano RM, Biancatelli C, Merrill M, et al. Quercetin and vitamin C: An experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related disease. Front Immunol. 2020;11(1451):1-11. doi:10.3389/fimmu.2020.01451.

-Michael McIsaac