Nitric Oxide, BCG, and COVID-19's Weakness
— Clinical trials might reveal a common link
While our attention is focused on the re-purposing of approved drugs to treat COVID-19 and to develop a durable vaccine to safeguard against SARS-CoV-2, the clinical outcomes of inhaled nitric oxide gas and BCG immunotherapy will likely emerge to be effective and provide insight as to coronavirus' vulnerability: nitric oxide sensitivity.
Several device companies have recently received FDA's blessing for emergency expanded access to offer inhaled nitric oxide gas for treating COVID-19. During the 2003 SARS outbreak, inhalation of nitric oxideimproved lung oxygenation and shortened the length of ventilatory support. Aside from improving lung function, nitric oxide also showed direct antiviral activity as well as druggable targets including nitrosylating cysteine of viral protease to interfering with S-protein-ACE-2 interaction. Inhaled nitric oxide provided to COVID-19 infected patients will likely prove to be lifesaving through both a pulmonary vasodilator effect and a direct antiviral effect.
Trials are also underway to test BCG's ability to rev-up the primitive innate arm of the immune system with the hope to provide early protection against SARS-CoV-2. In the case protecting against COVID-19, BCG is not a vaccine but an immunostimulant of non-specific immunity. BCG is a weakened, live bacterium, Bacille Calmette-Guérin, that is a distant relative of the pathologic mycobacteria that cause leprosy and tuberculosis (TB). It has been administrated for over 100 years as a vaccine against TB with mixed outcomes. Reportedly, 100 million newborns are vaccinated each year with BCG. What is most striking is that BCG reduces infant mortality independent of its effects on TB. There is suggestive evidence that countries with a BCG policy also had significantly slower growth of both cases and deaths resulting from COVID-19 as compared to countries that do not vaccinate with BCG.
Previous studies reported nearly a 50% reduction in mortality in children vaccinated with BCG, an effect that is too big to be explained by protection against TB alone. And since the 1990s, BCG was the first FDA-approved immunotherapy to reduce the risk of bladder cancer recurrence by stimulating a non-specific immune response that targets bladder cancer cells where cells within the bladder are immune stimulated to produce nitric oxide gas within a few days after inoculation. Approximately 70% of bladder cancer patients go into remission after BCG immunotherapy. Based on the capacity of BCG to also reduce the incidence of respiratory tract infections in children, to exert antimicrobial effects against intracellular microorganisms as diverse as Leishmania major, Francisella tularensis, and Plasmodium species in experimental models, and to reduce viremia in experimental human models of viral infection, BCG may prove to be equally effective as a prophylactic against SARS-CoV-2.
In studies when evaluated for nitric oxide, it was found that BCG triggers cytokine-dependent, IFN-γ and TNF-α and/or IL1-β, inducible nitric oxide synthase pathways (NOS) expression and nitric oxide release by both alveolar macrophages and non-immune cells, including airway epithelial cells. The efficacy of BCG to improve the clinical course of COVID-19 infection and to prevent absenteeism in order to safeguard continuous patient care is the primary endpoint for studies underway. To flush out the role of nitric oxide, it would be worthwhile to include secondary endpoints of exhaled nitric oxide and serum and saliva nitric oxide metabolites, nitrate and nitrite, which can serve as helpful biomarkers for nitric oxide generation under certain situations.
Assuming exogenously inhaled nitric oxide gas and BCG-immunologically boosted endogenous nitric oxide proves to be effective as a treatment and preventative, a dietary approach could be equally effective at elevated nitric oxide levels within the lung. The dietary nitrate-nitrite-nitric oxide pathway is independent of the arginine/citrulline iNOS. As to the latter, supplementing with arginine or citrulline during advance disease would be of little value, especially since arginase and methylarginines would be elevated thereby diminishing NOS activity.
However, bypassing the NOS pathway via dietary inorganic nitrate would restore nitric oxide as shown in hypertensives who are nitric oxide deficient. Here, nitric oxide is produced through the chemical transformation of dietary inorganic nitrate. It is well understood that dietary inorganic nitrates behave as a pro-drug in which the body converts inorganic nitrate to nitric oxide through a series of well-defined steps beginning with the friendly microflora on the tongue reducing nitrate to nitrite, which is subsequently reduced to nitric oxide in the gut, blood stream, and various organs, including the lung. The formation of inorganic nitrite in this pathway is absorbed into the circulation where it acts as a transitory storage pool for subsequent nitric oxide production. The conversion of inorganic nitrite to nitric oxide is expedited in conditions of acidosis or hypoxemia which occurs in regions of the pulmonary vasculature in lungs of COPD patients and those that exhibit acute respiratory distress syndrome as observed in coronavirus infected lungs.
If nitric oxide emerges as the linchpin in the BCG trials, such results, together with clinical studies of inhaled nitric oxide, these outcomes would usher in new drug design and disease targeting based on nitric oxide through inhalation, immune adjuvants, and dietary approaches.
Shawn J. Green, PhD, is a clinical scientist in the cardiology group at the Lundquist Institute at Harbor-UCLA Medical Center and published some of the very first observations on how the immune system makes nitric oxide to combat intracellular pathogens such as tularemia, leishmania, and malaria while serving at Walter Reed Army Institute of Research.
Last Updated May 08, 2020
No comments:
Post a Comment