A new USC study suggests that temporarily suppressing the body’s immune system during the early stages of COVID-19 could help a patient avoid severe symptoms.
That’s because the research, just published online in the Journal of Medical Virology, shows that an interaction between the body’s two main lines of defense may be causing the immune system to go into overdrive in some patients.
The body’s first line of defense, the innate immune response, starts right after an infection, like an infantry going after a foreign invader, killing the virus and any cells damaged by it.
The second line of defense, the adaptive immune response, kicks in days later if any virus remains, employing what it has learned about the virus to mobilize a variety of special forces such as T cells and B cells.
Using the “target cell-limited model,” a common mathematical model developed to understand the dynamics of viral infections, the researchers examined how the two immune responses work in COVID-19 patients compared to patients who have the flu.
The flu is a fast-moving infection that attacks certain target cells on the surface of the upper respiratory system and kills almost all of the target cells within two to three days.
The death of these cells deprives the virus of more targets to infect and allows the innate immune response time to clear the body of almost all of the virus before the adaptive system comes into play.
Adaptive immune response kicking in too soon
But COVID-19, which targets surface cells throughout the respiratory system including in the lungs, has an average incubation of six days and a much slower disease progression.
Mathematical modeling suggests that the adaptive immune response may kick in before the target cells are depleted, slowing down the infection and interfering with the innate immune response’s ability to kill off most of the virus quickly.
“The danger is, as the infection keeps going on, it will mobilize the whole of the adaptive immune response with its multiple layers,” said Weiming Yuan, associate professor in the Department of Molecular Microbiology and Immunology at the Keck School of Medicine of USC, and co-corresponding author of the study.
“This longer duration of viral activity may lead to an overreaction of the immune system, called a cytokine storm, which kills healthy cells, causing tissue damage.”
The interaction of the innate and the adaptive immune responses might also explain why some COVID-19 patients experience two waves of the disease, appearing to get better before eventually getting much worse.
“Some COVID-19 patients may experience a resurgence of the disease after an apparent easing of symptoms,” said Sean Du, adjunct researcher and lead author of the study.
“It’s possible that the combined effect of the adaptive and the innate immune responses may reduce the virus to a low level temporarily. However, if the virus is not completely cleared, and the target cells regenerate, the virus can take hold again and reach another peak.”
The most provocative result of the research is the kind of treatment it suggests to prevent this interaction between the two immune responses.
“Based on the results of the mathematical modeling, we proposed a counterintuitive idea that a short regimen of a proper immunosuppressant drug applied early in the disease process may improve a patient’s outcome,” said Du.
“With the right suppressive agent, we may be able to delay the adaptive immune response and prevent it from interfering with the innate immune response, which enables faster elimination of the virus and the infected cells.”
Small studies out of China, including a recent one of COVID-19 patients and one of SARS patients in 2003 show patients who received immunosuppressants such as corticosteroids had better results than those who did not.
The researchers said a possible next step could be to take daily measurements of viral loads and other biomarkers in COVID-19 patients, to see if the data validates the mathematical modeling. More preclinical studies including experiments in animal models will also be needed to prove the efficacy of an early immune suppressing treatment.
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 . 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) . 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 . 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) . Finally, the resulted so-called “cytokine storm” further weakens the immune system through IFN-1-mediated T cell apoptosis .
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 . Immune cells are not an exception. In this article, c-ATP is the index of cellular energy.
Evaluation of the hypothesis
Here, we show how c-ATP repletion can counteract with defensive mechanisms of COVID-19 and promote the immune system to the enhancement pathway.
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 . Therefore, ATP-depleted cells are more susceptible to this effect of COVID-19.
ATP facilitates IFN signaling
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 trans-phosphorylation . Obviously, c-ATP depletion interferes with this process and further impairs transformation to “antiviral state”.
ATP prevents the cytokine storm
Following deactivation of “initial alarm”, COVID-19 easily proliferates in-situ. Among the passive host-cells, 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 .
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 . Second, persistence profound inflammatory responses may lead to immune exhaustion . 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.
ATP prevents T-cell apoptosis
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 . 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 . 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 . 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 . Moreover, aging can wane the ability of immune cells to secrete IFN following viral infection . 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 . 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 . 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) . 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.
Serious chronic medical conditions
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 . 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 O2) 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).
Approaches to improvement in c-ATP
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 .
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 . On the other hand, several studies have reported the positive effect of xanthine oxidoreductase inhibitors on c-ATP .
Consequences of the hypothesis
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.
1. Lu R., Zhao X., Li J., Niu P., Yang B., Wu H. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. The Lancet. 2020;395(10224):565–574. [Google Scholar]
3. de Wit E., van Doremalen N., Falzarano D., Munster V.J. SARS and MERS: recent insights into emerging coronaviruses. Nature Reviews Microbiology. 2016;14(8):523. [PMC free article] [PubMed] [Google Scholar]
4. Prompetchara E., Ketloy C., Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol. 2020 [Google Scholar]
5. Channappanavar R., Fehr A.R., Vijay R., Mack M., Zhao J., Meyerholz D.K. Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice. Cell Host Microbe. 2016;19(2):181–193. [PMC free article] [PubMed] [Google Scholar]
7. Zhang C., He H., Wang L., Zhang N., Huang H., Xiong Q. Virus-triggered ATP release limits viral replication through facilitating IFN-β production in a P2X7-dependent manner. The Journal of Immunology. 2017;199(4):1372–1381. [PubMed] [Google Scholar]
8. Seif F., Khoshmirsafa M., Aazami H., Mohsenzadegan M., Sedighi G., Bahar M. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Communication and Signaling. 2017;15(1):23. [PMC free article] [PubMed] [Google Scholar]
9. Cervantes-Barragan L., Züst R., Weber F., Spiegel M., Lang K.S., Akira S. Control of coronavirus infection through plasmacytoid dendritic-cell–derived type I interferon. Blood. 2007;109(3):1131–1137. [PubMed] [Google Scholar]
10. Perl A., Gergely P., Jr, Nagy G., Koncz A., Banki K. Mitochondrial hyperpolarization: a checkpoint of T-cell life, death and autoimmunity. Trends in immunology. 2004;25(7):360–367. [PMC free article] [PubMed] [Google Scholar]
12. Desler C., Hansen T.L., Frederiksen J.B., Marcker M.L., Singh K.K., Juel Rasmussen L. Is there a link between mitochondrial reserve respiratory capacity and aging? Journal of aging research. 2012;2012. [Google Scholar]
13. Qian F., Wang X., Zhang L., Lin A., Zhao H., Fikrig E. Impaired interferon signaling in dendritic cells from older donors infected in vitro with West Nile virus. Journal of Infectious Diseases. 2011;203(10):1415–1424. [PMC free article] [PubMed] [Google Scholar]
14. Malińska D., Więckowski M.R., Michalska B., Drabik K., Prill M., Patalas-Krawczyk P. Mitochondria as a possible target for nicotine action. Journal of bioenergetics and biomembranes. 2019;51(4):259–276. [PMC free article] [PubMed] [Google Scholar]
15. Jin J-M, Bai P, He W, Wu F, Liu X-F, Han D-M, et al. Gender differences in patients with COVID-19: Focus on severity and mortality. medRxiv. 2020.
16. Kassi E., Moutsatsou P. Estrogen receptor signaling and its relationship to cytokines in systemic lupus erythematosus. BioMed Research International. 2010;2010 [Google Scholar]
17. Zhou F., Yu T., Du R., Fan G., Liu Y., Liu Z. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet. 2020 [Google Scholar]
18. Burelle Y., Hochachka P.W. Endurance training induces muscle-specific changes in mitochondrial function in skinned muscle fibers. Journal of Applied Physiology. 2002;92(6):2429–2438. [PubMed] [Google Scholar]
Funding: This study was supported by the National Institute of Allergy and Infectious Diseases (R21AI149365) and partially supported by a National Institutes of Health (P30CA014089) grant to the University of Southern California Norris Comprehensive Cancer Center.