key: cord-254411-e9vvjv8w
authors: Taghizadeh-Hesary, Farzad; Akbari, Hassan
title: The Powerful Immune System Against Powerful COVID-19: A Hypothesis
date: 2020-04-22
journal: Med Hypotheses
DOI: 10.1016/j.mehy.2020.109762
sha: 
doc_id: 254411
cord_uid: e9vvjv8w

On March 11, 2020, the World Health Organization declared the coronavirus outbreak a pandemic. Since December 2019, the world has experienced an outbreak of coronavirus disease 2019 (COVID-19). Epidemiology, risk factors, and clinical characteristics of patients with COVID-19 have been reported but the factors affecting the immune system against COVID-19 have not been well described. In this article, we provide a novel hypothesis to describe how an increase in cellular adenosine triphosphate (c-ATP) can potentially improve the efficiency of innate and adaptive immune systems to either prevent and fight off COVID-19.

Today, the rapid outbreak of Corona Virus Disease 2019 (COVID-19 or SARS-CoV-2) is the leading health issue. There is a paucity of studies investigating the factors affecting immune response to COVID-19. In addition, there has been no detailed report for this immune response. Given the genomic similarity of 79% with Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), nearly the same reaction to the immune system is expected for COVID-19 (1) . In response to SARS-CoV, both innate and adaptive immune systems are involved. SARS-CoV applies several mechanisms to overcome the immune response. First, it inhibits the rapid expression of interferon type 1 (IFN-1) (2). IFN-1 is known as the "initial alarm" upon encounter with the virus that modulates the immune cells to the so-called "antiviral state". Moreover, SARS-CoV interferes with IFN-1 signaling through inhibition of STAT-1 phosphorylation (3). The third defensive mechanism of SARS-CoV is immune exhaustion through exaggerated and prolonged IFN-1 production by plasmacytoid dendritic cells (pDCs). This process leads to the influx of activated neutrophils and inflammatory monocytes/macrophages, that in turn, results in lung immunopathology (e.g. acute respiratory distress syndrome) (4). Finally, the resulted so-called "cytokine storm" further weakens the immune system through IFN-1-mediated T cell apoptosis (5) . In this article, we aim to provide a new hypothesis to describe how the repletion of cellular adenosine triphosphate (c-ATP) can promote immunity against COVID-19. Thereafter, we justify the current knowledge regarding the characteristics of COVID-19 infection by our hypothesis and give several approaches to improve the c-ATP.

Considering the pivotal role of ATP in cellular function, c-ATP depletion can lead to cellular dysfunction (6) . Immune cells are not an exception. In this article, c-ATP is the index of cellular energy.

Here, we show how c-ATP repletion can counteract with defensive mechanisms of COVID-19 and promote the immune system to the enhancement pathway.

3.1. ATP facilitates IFN production COVID-19 interferes with a rapid rise in IFN-1. Therefore, it deactivates the so-called "initial alarm" of the innate immune system, by unknown mechanisms. This facilitates its replication. Zhang et al. have demonstrated that enhancement in the c-ATP can reverse this process. This occurs by the facilitation of IFN secretion through P38/JNK/ATF-2 signaling pathway (7) . Therefore, ATP-depleted cells are more susceptible to this effect of COVID-19.

Following IFN-1 secretion, fundamental changes occur in the immune cells that transform them into the so-called "antiviral state". One of the signaling pathways that take part in this process is the JAK/STAT pathway. JAKs are ATP-dependent enzymes that are bound to the cytoplasmic regions of cytokine receptors. Following attachment of IFN-1 to the cytokine receptor, JAK activates the STAT through transphosphorylation (8) . Obviously, c-ATP depletion interferes with this process and further impairs transformation to "antiviral state".

Following deactivation of "initial alarm", COVID-19 easily proliferates in-situ. Among the passive hostcells, there are exceptions that can react to the COVID-19, the pDCs. They detect the virus by toll-like receptor 7 (TLR-7). Upon attachment to viral nucleic acids, TLR7 induces profound IFN-1 expression. This response recruits other immune cells and causes massive local inflammation (9) . At first glance, this robust immune response is beneficial for the elimination of COVID-19. However, two factors prevent it. First, impairment of IFN-1 signaling results in impairment of immune cell transformation to the "antiviral state". Therefore, they are not so effective in eliminating existing viruses (8) . Second, persistence profound inflammatory responses may lead to immune exhaustion (4) . The depletion of c-ATP can potentially enhance these detrimental processes in the following ways. In 2016, Rebbapragada et al. demonstrated the effect of ATP in the function of TLR7 by controlling the endo-lysosomal PH. They showed that ATP-depletion can increase the endo-lysosomal PH and improve the efficacy of TLR7. Therefore, ATP-depletion can potentially enhance profound IFN-1 secretion. Secondly, ATP-depletion can potentially prone the recruited immune cells to earlier exhaustion against COVID-19. Therefore, one may conclude that ATP-repletion can prevent the so-called "cytokine storm" and improve the cellular energy to better counteract with COVID-19.

Channappanavar et al. demonstrated that COVID-19 can promote T-cells to IFN-induced apoptosis, resulting in reduced numbers of virus-specific CD8 and CD4 T-cells (5) . From the perspective of cellular energy, this process potentially occurs through IFN-mediated T-cell activation that results in c-ATP depletion. In line with this hypothesis, Perl et al. have shown that following IFN-γ stimulation, mitochondrial hyperpolarization and ATP depletion occurs in T-cells that results in apoptosis (10) . Therefore, ATP-repletion can potentially prevent T-cell apoptosis following "cytokine storm".

In the following section, we use our hypothesis to demonstrate why specific groups of people are more susceptible to be infected with COVID-19 and why they have a worse prognosis.

The case-fatality rate of COVID-19 is the highest (14.8%) in elderly-population. In contrast, children have the lowest risk for both infection and mortality rates (11) . This difference can be demonstrated from the cellular energy concept. Aging may potentially attenuate the respiratory capacity of mitochondria. This condition may be either due to impairment of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) or age-related accumulation of mitochondrial DNA mutations (12) . Moreover, aging can wane the ability of immune cells to secrete IFN following viral infection (13) . As noted earlier, this may be due to ATP-depletion. Therefore, one can conclude that a gradual decline in prognosis with age may rely on a gradual decrease in c-ATP.

The risk of long-lasting and serious COVID-19 infection is more among tobacco smokers. Apart from a direct effect on lung parenchyma and a decrease in pulmonary capacity, tobacco smoke can potentially induce immune dysfunction through a decrease in ATP content of immune cells. This can be due to nicotine-induced mitochondrial dysfunction (14) . The resultant ATP-depletion increase the risk of immune dysregulation by COVID-19 (refer to the aforementioned defensive mechanisms of COVID-19).

While men and women have the same susceptibility to COVID-19, men are more prone to higher morbidity and mortality independent of age (15) . This difference can be justified by the cell energy hypothesis. Estrogens (as the main sex steroid of females) are potent stabilizers of ATP production during oxidative stress (e.g. during COVID-19-induced inflammation) (16) . Therefore, it seems that women are more capable to maintain the c-ATP of their immune cells during the immune response to COVID-19. With this notion in mind, men are more susceptible to immune dysregulation following COVID-19 infection.

Recent reports have highlighted some chronic illnesses that increase the mortality of COVID-19. They include underlying conditions such as hypertension, diabetes, coronary heart disease, chronic obstructive lung disease, cancer, and chronic kidney disease (17) . Apart from a decline in cardiovascular reserve, the effect of these chronic conditions on the prognosis of COVID-19 can be justified by our hypothesis. Human cells need nutrients (including glucose, free fatty acids, essential amino acids, and O 2 ) to maintain their c-ATP level. The aforementioned illnesses impede the regular distribution of the nutrients secondary to compromising the function and structure of small and large vessels. Therefore, the human cells (including in-situ immune cells) confront ATP-depletion and results in further immune dysregulation (as mentioned above).

In light of these considerations, the c-ATP level can potentially be considered as a crucial component in the infectivity and prognosis of COVID-19. With enhancing the c-ATP, improvement in both innate and cytotoxic immune systems is expected. Moreover, an increase in c-ATP can potentially have either preventive and therapeutic effects. The preventive effect through activation of initial IFN-1 secretion and signaling, as "initial alarm" of the innate immune system. The therapeutic effect through the prevention of "cytokine storm" and T-cell apoptosis. There are several approaches to improve c-ATP. Most of them are easily available through a change in lifestyle. First, regular exercise improves mitochondrial respiratory capacity through an increase in PGC-1α (18) . Smoking cessation is the second approach to improve mitochondrial capacity and improvement in c-ATP (as mentioned above). Consuming foods with low specific dynamic action (SDA), as the energetic budget for consuming food, can potentially boost the immune system through improving the c-ATP. In 2016, Luoma et al. demonstrated the effect of low-SDA meals in the up-regulation of the innate immune system in corn snakes (19) . On the other hand, several studies have reported the positive effect of xanthine oxidoreductase inhibitors on c-ATP (6).

This hypothesis provides a new concept to improve the immune system against COVID-19. It demonstrates how an increase in c-ATP can decrease the effect of COVID-19 on immune dysregulation. Considering the strategies to enhance cellular ATP, improvement of the immune system against COVID-19 is possible. It is hoped that this hypothesis will serve as a stimulus for further investigation into this issue.

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SARS and MERS: recent insights into emerging coronaviruses

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Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice

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The authors have no conflicts of interest.

Not applicable.
