Viral infection, including SARS-CoV, MERS-CoV, and SARS-CoV2, causes difficult to treat diseases that can be fatal because of lung failure and systemic cytokine storm.
The development of coronavirus-induced pneumonia is related to extreme inflammatory responses in the lung, known as “cytokine storms,” which results in pulmonary edema, atelectasis, and acute lung injury (ALI) or fatal acute respiratory distress syndrome (ARDS).
No drugs are available to subdue overly immune response-mediated lung injury effectively. But because of the low toxicity and its antioxidant, anti-inflammatory, and antiviral activity, it is possible to say that curcumin could be used as an option for viral pneumonia and ALI / ARDS.
Presymptomatic studies using animal models of lethal pneumonia where curcumin exerts protective effects by regulating the expression of both pro- and anti-inflammatory factors such as IL-6, IL-8, IL-10, and COX-2, promoting the apoptosis of PMN cells, and scavenging the reactive oxygen species (ROS), which aggravates the inflammatory response.
Studies provides a rationale hypothesis that curcumin can be used as a compound against pneumonia and ALI/ARDS in humans induced by viral infection.
History of Viral Infection
During the Spanish influenza pandemic in 1917–1918, it was found that the deaths were not just seen in the elderly with weak immunity, but also young people with normal immunity. As part of a strong immune response in severe cases, the virus activates overreaction of immune systems, producing an enormous amount of inflammatory factors, which causes severe damage to the lung and manifests acute respiratory distress syndrome (ARDS), resulting in high mortality.
The same damaging effects of immune overreaction were observed in outbreaks of severe acute respiratory syndrome coronavirus (SARS-CoV), middle east respiratory syndrome CoV (MERS-CoV), highly pathogenic avian influenza viruses (including H5N1 and H7N9)), and novel coronavirus (SARS-CoV2).
An inflammatory response, including overflow of immune cells and pro-inflammatory cytokines, is defined as the cytokine storm that usually occurs in viral infection and causes acute lung injury (ALI) and ARDS.
There is no effective mechanism for cytokine storm and resultant lung injury. Therefore, drugs to suppress the cytokine storm are urgently needed to treat deadly virus infection that causes lung damage and ARDS. Curcumin [(1E,6E)-1,7bis(4-hydroxy-3-methoxyphenyl)-1,6- heptadiene-3,5-dione] is a natural compound mainly extracted from plants of the Curcuma longa that has been used by humans in treating diseases without any side effects.
Numerous in vitro and in vivo studies indicate that curcumin has antiviral, antioxidant, anti-inflammatory, anti-cancer, and anti-diabetic activity. Several clinical investigations have shown beneficial effects in treating cardiovascular diseases, metabolic syndrome, or diabetes, and infectious diseases, especially viral infection. All of these clinical results point to that curcumin attenuate these diseases mainly via modulation of immune responses. Some studies have suggested that curcumin could inhibit the cytokine storm induced by the viral infection.
Curcumin Blocks Inflammatory Reaction
Various in vivo and in vitro studies have been shown that curcumin and its analogs noticebly inhibit the production and release of pro-inflammatory cytokines, such as IL-1, IL-6, IL-8, TNF-α. In compliance with this, have observed that direct pulmonary delivery of solubilized curcumin dramatically plummets pro-inflammatory cytokines IL-1β, IL-6, TNF-α in the BAL cells, the lung and serum of mice with severe pneumonia induced by Klebsiella.
Futhermore, curcumin also decreases expression of many other inflammatory mediators, including MCP1(CCL2), MIPI1 (CCL3), GROα (CXCL1), GROβ (CXCL2), IP10 (CXCL10), SDF1 (CXCL12), MMP-2, IFN-γ, and MMP-9, which regulate the activity of immune cells and inflammatory responses and promote fibrosis in the lung after infection.
Synchronization of Anti-inflammatory Cytokines
In contrast to its negative effect on pro-inflammatory molecules, curcumin has been shown to regulate anti-inflammatory cytokines positively, in particular IL-10.
The latter is an essential negative regulator for inflammatory responses and is emitted by the dendritic cells that bind to DAMP released from damaged cells during aseptic or antigenic inflammatory reactions. IL-10 acts on inflammatory monocytes to lessen the release of TNF-α, IL-6, and ROS, thereby alleviating tissue damage caused by the continuous inflammatory response.
Many researches have revealed that curcumin and curcuminoids potently increase the expression, production, and activity of IL-1. Scientists have illustrated the effect of curcumin on ALI/ARDS using cecal ligation and puncture (CLP)-induced ALI mouse model.
In this study, curcumin noticeably attenuates lung injury by inducing the differentiation of regulatory T cells (Tregs) and upregulating IL-10 production. Similar effects have been seen in the neuropathic model, colitis model, and other inflammatory diseases.
Therefore, in the state of inflammation, curcumin can act as a double-edged sword, downregulating pro-inflammatory cytokines, and upregulating anti-inflammatory IL-10.
Scavenges Reactive Oxygen Species (ROS)
It has been described that curcumin acts to directly hunt ROS as a polyphenolic antioxidant. Curcumin has two active groups, one hydroxyl-hydrogen on the benzene ring that has an anti-oxidation effect and the other a β-diketone moiety.
In vitro experiments have shown that curcumin effectively scavenges on ROS removal and anti-oxidation, curcumin has been shown effective at scavenging the superoxide anion radical produced by illuminating riboflavin and the OH– produced by the Fenton reaction. Curcumin also inhibits the peroxidation of lecithin and DNA oxidative damage caused by ROS.
Specific Antiviral Activity of Curcumin
Many studies have reported that curcumin disrupts the viral infection process via multiple mechanisms, including directly targeting viral proteins, inhibiting particle production & gene expression, & blocking the virus entry, replication, & budding.
A recent study in vitro study has demonstrated that curcumin inhibits respiratory syndrome virus (RSV) by blocking attachment to host cells. In this study, curcumin was also found to stop the replication of RSV in human nasal epithelial cells.
Additional evidence suggests that curcumin inhibits Porcine reproductive and RSV (PRRSV) attachment, possibly by damaging the fluidity of viral envelopes. Curcumin also barricades virus infection by inhibiting PRRSV-mediated cell fusion, virus internalization, and uncoating.
For a century, different subtypes of IAV, H1N1, H2N2, H3N2, and H5N1 have been the leading cause of pandemic outbreaks in the world. It has been reported that curcumin and its derivatives have a high binding affinity to hemagglutinin (HA), a major capsid glycoprotein of influenza virus that mediates virus attachment.
Scientists have demonstrated that curcumin interacts with HA and disturbs the integrity of membrane structure to block virus binding to host cells and prevent IAV entry. In another study with cells infected by IAV, it was found that curcumin directly inactivates various strains of IAV, disturbs their adsorption, and inhibits their replication.
Further, the study showed that curcumin inhibits IAV absorption and replication by activating the NF-E2-related factor 2 (Nrf2)-hemeoxygenase-1 (HO-1)-axis, a classical anti-inflammatory and antioxidative signaling, which possesses antiviral activity.
Furthermore, curcumin acts against SARS-CoV. Accordingly, a study on the anti-SARS-CoV activity of 221 phytocompounds revealed that 20 μM of curcumin exhibits significant inhibitory effects in a Vero E6 cell-based cytopathogenic effect (CPE) assay.
The authors presented evidence for a mild effect of curcumin against SARS-CoV replication and the inhibitory effect of curcumin on SARS-CoV 3CL protease activity, which is essential for the replication of SARS-CoV. This study provides promising evidence for curcumin as a potential anti-SARS-CoV agent .
Curcumin Reduces Lung Edema Caused by Inflammation
Inflammation plays a crucial role in the pathogenesis of lung complications of viral infection, as manifested by lung edema, hemorrhage, neutrophil infiltration, and alveolar thickening. Studies show that curcumin and its analogs are capable of attenuating lung injury.
Similar protective effects of curcumin have been reported in the rodent model of ventilator-induced lung injury and Staphylococcus S.aureus-induced ALI as evidenced by attenuation of inflammatory cell infiltration, lung edema due to its anti-inflammatory and antioxidant effects.
In a chronic obstructive pulmonary disease model, curcumin treatment effectively reduces the degree of airway inflammation and disrupts airway remodeling by inhibiting the proliferation of bronchial epithelial cells.
Mechanistically, curcumin shields the lung by inhibiting inflammation and production of ROS through regulation of multiple signaling pathways engaging peroxisome proliferator-activated receptor γ (PPARγ), JNK, NF-κB, and Nrf2.
Notably, the role of curcumin in regulating Nrf2/HO-1 has been reported in IAV infection. The Nrf2 enhances the expression of HO-1, an immunoregulatory and anti-inflammation molecule, and other enzymes for maintaining redox homeostasis.
Curcumin Suppresses Pulmonary Fibrosis
The ALI after the viral infection is often followed by pulmonary fibrosis, which can lead to the death. It has been reported that curcumin can inhibit pulmonary fibrosis. Thus, in paraquat-treated mice, collagen deposition in the lung causes diffuse fibrosis, while treatment with curcumin reduces collagen deposition and decelerates the development of pulmonary fibrosis.
In the radiation-induced lung damage model, cytokine accumulation and collagen deposition occur in the interstitial space, concurrent with fibrosis of the lung tissue. However, curcumin reduces the expression of cytokines such as IL-4 and TGF-β, inhibits the infiltration of macrophages and lymphocytes, and ameliorates fibrosis.
In another study on ALI using a mouse model infected with reovirus, curcumin treatment effectively inhibits the production of collagen and procollagen I mRNA. α-SMA, a marker of epithelial to mesenchymal transition, and Tenascin-C (TN-C), both of which are indicators of pulmonary fibrosis, are highly expressed in the adult lung parenchyma after ALI.
It was also demonstrated that curcumin directly reduces the expression of TGF-β protein and its mRNA. All these studies support that curcumin alleviates pulmonary fibrosis.
The Potential Role of Curcumin in the Prevention and Control of Viral Infection by targeting cytokine storm
Targeting cytokine storm is considered as an integral strategy for viral infections. In clinical settings, glucocorticoids have been used to treat deadly viral pneumonia and shown therapeutic benefits. In the treatment of patients with SARS in 2003, glucocorticoids were widely used to suppress the cytokine storm in severe cases.
However, it has been found that large doses of glucocorticoids create various side effects such as osteoporosis and secondary infection with other pathogenic microbes, and small doses have little effect on improving lung injury. These clinical findings indicate that it is increasingly important to seek alternative agents with effectiveness and low toxicity.
Many studies on virus-induced pneumonia have highlighted the potential usage of curcumin in the improvement of lung index and survival rate. Curcumin mitigates the severity of viral pneumonia through inhibiting the production of inflammatory cytokines and NF-κB signaling in macrophages.
Curcumin has also been shown to activate Nrf2 in association with reduced oxidative stress and inhibit TLR2/4, p38/JNK MAPK, and NF-κB in response to IAV infection; and as a result, pneumonia is improved.
Up to now, it has been claimed that curcumin benefits human health and prevents diseases. Studies suggested that a low dose of curcumin produced a variety of health-promoting actions, such as direct and indirect antioxidant actions. Additionally, gathering evidence from animal studies has shown that curcumin prevents the development of severe pneumonia.
The similar protective role of curcumin has been found in preclinical studies of viral-induced pneumonia. Treatment with curcumin (50 mg/kg/day) beginning at 5 days prior to reovirus 1/L infection protects CBA/J mice from the development of ALI/ARDS and suppresses subsequent fibrosis have reported that pre-infection or post-infection administration of curcumin significantly improves the lung index and prolongs the survival rate.
Interestingly, the fatality rate is also reduced by pre-administration with curcumin. All these studies suggest that curcumin administration could have both prophylactic and therapeutic effects on virus-induced pneumonia and mortality.
Clinical investigations have suggested that curcumin might be effective in improving inflammation and the treatment of virus infections. A clinical trial conducted by scientists have demonstrated that curcumin nanomicelle supplement ameliorates oxidative stress, and reduces inflammatory biomarkers, including TNF-α, compared to a placebo.
Ginger Fights Multiple Virus Infections
Research has now proven that ginger can combat a number of viral infections. While virus research has thus far focused on using pharmaceutical interventions, ginger continues to prove that it is a potent antiviral plant medicine.
Ginger’s safety is unquestionable given it is regularly consumed by billions of people around the world.
Ginger (Zingiber officinale) has also been used in traditional medicines around the world to reduce pain and fever.
For example, research shows that ginger matches NSAIDs for reducing pain.
Ginger root’s antiviral prowess is not just real: It has been proven out in the research.
SUMMARY
- Cytokine storm syndrome triggered by viral infections is the culprit of death.
- It is heightened by unchecked regulation of the production of pro-inflammatory cytokines and ROS, leading to pneumonia, ALI, multiple organs failures, and eventually death.
- No effective therapy is available for the cytokine storm syndrome and linked lung and other organ failures.
- Curcumin is a natural plant extract with high safety and low toxicity such that people take it as a dietary supplement, and growing evidence from studies demonstrates that it effectively attacks viral infection, alleviates the severity of lung injury through offsetting the cytokine storm, inhibits subsequent fibrosis, and increases survival rates.
- Additionally, its anti-SARS-CoV replication and 3CL protease have been reported in an in vitro study.