The body’s immune system has an incredible mechanism capable of responding to various pathogens, but it can go too far. New research from a team in the UAE has found that Covid-19 infections can affect the way the genes moderating this immune response are expressed, which may be why infections range from asymptomatic to severe.
When the body is confronted with an infection, an immune response is triggered, sending immune cells to the region to attack the virus. This causes localized inflammation that reduces once the body has treated the attack. Sometimes, however, this immune response can go into overdrive, resulting in hyper-inflammation. While this sounds fairly innocuous, this can seriously harm or even kill the person.
This is how contracting the flu can kill a patient. In the context of Covid-19, one of the great mysteries of the pandemic was why some people only contracted a mild disease, but for others it was a fatal infection.
Evidence suggests that those with a severe infection suffer more damage from a cytokine storm than from the virus itself. Cytokines are small proteins released by many different cells in the body as an immune response and a cytokine storm is an overreaction from the body’s immune system.
Some cytokines trigger cell death to prevent a virus spreading to other cells, but when lots of cells do this, a lot of tissue can die. In Covid-19 patients, that tissue is mostly in the lungs. As the tissue breaks down, the tiny air sacs fill with fluid, causing pneumonia and starving the blood of oxygen. Respiratory distress syndrome follows, other organs start to fail, and the patient dies.
Now, research from a team in the UAE has found that the Covid-19 driven inflammation is exaggerated by the production of reactive oxygen species, the biological mechanisms that cause oxidative stress and that are combated by antioxidants. While most well-known for their anti-ageing properties, antioxidants are the components that keep oxidative stress in check during an immune response, and in Covid-19 patients, this balance is disrupted, contributing to the cytokine storm.
Dr. Habiba Alsafar, Associate Professor and Director of the Khalifa University Center for Biotechnology, collaborated with Prof. Rabih Halwani, who is Principal Investigator on the project, along Prof. Qutayba Hamid, Dr. Narjes Saheb Sharif-Askari, Dr. Fatemah Saheb Sharif-Askari, and Bushra Mdkhana, from Sharjah Institute of Medical Research and College of Medicine, University of Sharjah; Hawra Ali Hussain Alsayed from the Dubai Health Authority Pharmacy Department; and Dr. Zeyad Faoor Alrais from the Dubai Health Authority Anaesthesia and Intensive Care Unit. Their results were published in Free Radical Biology and Medicine.
“When patients suffer high levels of oxidative stress while infected with a respiratory disease, their prognosis tends to not be very good,” Dr. Alsafar said. “We know that the virus causing Covid-19 enters the cells by binding to the host ACE2 receptors, and these receptors are found in abundance in the lungs. When this virus infects the cells, there is an extreme drop in ACE2 levels, and this is bad news because ACE2 plays a critical role in regulating the oxidative balance. A lack of ACE2 means the production of reactive oxygen species is stepped up. Moreover, activated inflammatory cells that infiltrate the infected lung tissue produce large amount of these oxygen species. Where a healthy cell would then activate an antioxidant response, this mechanism is suppressed in patients with a severe Covid-19 infection. There is evidence to suggest this is a targeted effect of the Covid-19 virus to enhance its survival in a patient.”
The UAE research team measured the gene expression levels of 125 genes known to be associated with inflammatory and oxidation activities in the body from Covid-19 patients and compared their levels with those seen in influenza (IAV) patients and respiratory syncytial virus (RSV) patients. They also compared the severe Covid-19 infections against non-severe Covid-19 infections.
“We wanted to know how Covid-19 infection may affect the expression of these genes in patients and found that the genes that caused the production of reactive oxygen species were ‘significantly upregulated’ in patients with Covid-19,” Prof. Halwani said. “While the oxidative genes were upregulated, the antioxidant genes were found to be downregulated.”
The researchers found that the Covid-19 virus entering the lungs activated a vicious cycle where a burst of reactive oxygen species and inflammatory cytokines eventually trigger further tissue injury, cytokine release and an over-reactive immune response. In severe Covid-19 cases, the antioxidant resources were completely depleted in the infected cells, resulting in a further increase in reactive oxygen species products and a cytokine storm.
“Targeting one or more of these oxidative stress genes could be an effective therapeutic approach for treating Covid-19,” Dr. Alsafar said. “This could help prevent the progression of the disease to a cytokine storm, stopping an over-reactive immune response before it happens. We could also give patients direct doses of antioxidants to help combat the oxidative stress seen in infections.”
“Interestingly, three of the oxidative genes that were significantly upregulated in severe cases could be detected in saliva samples, suggesting that the saliva level of these genes could be used as non-invasive markers for Covid-19 disease severity,” Prof. Halwani said. While further studies are needed to confirm these findings, they represent a significant step towards understanding the Covid-19 disease mechanisms and a possible treatment plan.
28 November 2021