A group of tiny RNAs that are expected to attack the virus causing COVID-19 when it tries to infect the body decreases with age and with chronic health conditions, a decrease that probably explains why the elderly and those with conditions Pre-existing medical populations are vulnerable, according to report investigators.
MicroRNAs play an important role in our bodies in controlling gene expression, and are also on the front line when viruses invade, cling to and cut RNA, the genetic material of the virus, says Dr. Sadanand Fulzele , aging researcher in the Department of Medicine and Center for Healthy Aging at the Medical College of Georgia at Augusta University.
But with age and certain chronic medical conditions, the number of attacking microRNAs decreases, which reduces our ability to respond to viruses, explains Dr. Carlos M. Isales, co-director of the MCG Center for Healthy Aging and Head of the Division of endocrinology MCG, Diabetes and metabolism.
Just like not having enough troops on the ground in a real war, the coronavirus is then better able to do what it does naturally, which diverts our cellular machinery so that it can reproduce, say researchers reporting in the journal. Aging and disease what appears to be a key microRNA involved in the response to this virus. Their longer-term goal is to identify the biggest hitters and rebuild those troops.
They examined the RNA sequence of two coronaviruses, SARS, which surfaced in 2002, and SARS-CoV-2, which causes COVID-19, and the sequence of microRNAs that appeared to attack the virus, and then used a computer simulation to find what would logically fit together like puzzle pieces. Their review included four SARS samples and 29 SARS-CoV-2 samples, taken between January and April 2020 from five continents covering 17 countries from the United States to Germany and Thailand.
They found 848 microRNAs that target the SARS genome and 873 microRNAs that target the SARS-CoV-2 genome. They found 558 of the SARS-fighting microRNAs also present in SARS-CoV-2, while 315 microRNAs were unique to SARS-CoV-2 and 290 were unique to SARS. The microRNAs most competent to attack SARS-CoV-2 have shown more than 10 target sites and could ultimately be judged to be the most competent to fight the virus, which in a few months has changed much of the way the world works.
They also found that microRNAs targeting SARS-CoV-2 were associated with more than 72 biological processes – from the production of molecules to the immune response – and that many are known to become deregulated and / or decrease in number with age and with underlying medical conditions like diabetes and cardiovascular disease, a likely factor in the increased presentation of the disease and the death rates seen in these people, say the investigators.
An example is microRNAs like miR-15b-5p, which has a high affinity for SARS-CoV-2, but which are downregulated in coronary artery disease, says correspondent author Fulzele. In healthy and younger people, these microRNAs, the nature of which binds to the virus, are better able to do as they should and prevent their replication, he adds.
In the 29 global samples of SARS-CoV-2, 19 had identical microRNAs, indicating that the virus has a fairly uniform presence internationally and that any effective treatment or vaccine should have a large impact, says Isales.
The next steps include studies on culture and laboratory animals to ensure that the results are consistent with the computer analysis of human microRNAs in this study.
“The most important and striking feature of COVID-19 is the increased fatality rate among seniors,” write the investigators, with the CDC reporting that almost half of those requiring hospitalization are 65 years of age. and more, and these older people account for about 80% of deaths. Fulzele, Isales and their colleagues wanted to know more about why.
“My view is that there is a key set of microRNAs that are important in triggering this abnormal response, in making older patients more vulnerable,” said lead author Isales. “We are looking at microRNAs in general, but there is a specific subset that is essential. The question is whether we can target them as therapy. ”
Cocktails of multiple key microRNAs, potentially administered through the nose, could help restore sufficient levels of the main fighters of the virus, according to investigators.
They are already moving towards the production of synthetic microRNAs that could complement this weakened frontline by age or disease, says Fulzele. Future studies also include determining the microRNA that would have the most impact as an adjunct therapy, for example with the drug remdesivir, currently under study for COVID-19, which aims to prevent piracy by the virus healthy cellular machinery.
Another question to ask is whether some younger people, who are also critically ill with SARS-CoV-2 infection, are not already producing enough of some of the key protective microRNAs, says Isales.
The microRNA present in the cells of our body generally targets both the 3′-UTR region (first three untranslated regions) of the virus, the section of messenger RNA which contains regulatory regions which influence gene expression and the function of proteins, as well as the coding region that ultimately produces a protein, unless they are more numerous.
“Normally your immune cells come in and destroy them, but you have this big viral load because they keep replicating and you have all this abrupt inflammatory response,” says Isales, which ultimately results in cytokine storms that help destroy rather than protect organs. He believes that the reduced number of micro-RNAs essential to the body attacking the virus is a catalyst for the catastrophe that may follow.
The SARS and SARS-CoV-2 sequences used in the study were received from the National Biotechnology Information Center and GISAID, an international initiative to share data from influenza viruses and the SARS strain. CoV-2. The genome sequence for SARS and SARS-CoV-2 was extracted from GenBank, the genetic sequence database of the National Institutes of Health. Scientists used the entire viral genome sequence to analyze microRNA targets.
SARS, or severe acute respiratory syndrome, first appeared in China and spread worldwide, but if it was more deadly than the current coronavirus, it was not as infectious, so less people eventually died and died from COVID-19, explains Isales. Globally, 8,098 people were infected with SARS and 774 died, according to the Centers for Disease Control and Prevention. By the end of the first week in May, nearly 1.3 million cases of SARS-CoV-2 had been confirmed in the United States alone and more than 76,000 deaths.
People 65 and older and people of all ages with underlying health conditions are considered to be at higher risk for serious illness from COVID-19, according to the Centers for Disease Control and Prevention. The underlying medical conditions include problems such as severe heart disease, chronic lung disease and moderate to severe asthma, and people with compromised immune systems, such as people with cancer or who have had a transplant. organ, according to the CDC. Obesity, diabetes, chronic kidney disease requiring dialysis and liver disease are among the other conditions.
Other key contributors include Dr. Bikash Sahay, Department of Infectious Diseases and Immunology, University of Florida College of Veterinary Medicine in Gainesville, Florida; and Drs. Ashok Sharma and Tae Jin Lee of the MCG Center for Biotechnology and Genomic Medicine. The research was funded in part by the National Institutes of Health.
See the full study here.