The link between Autophagy and COVID-19
Currently, the expansion of the novel human respiratory coronavirus (known as: SARS-CoV-2) has focused all attention to finding therapeutic alternatives to alleviate and stop this new epidemic . On March 20th, there are over 252 000 confirmed cases of COVID-19 and 10 405 total deaths worldwide. As one of the drugs that has entered the clinical phase of study is a well-known autophagy inhibitor (chloroquine), I would like to present for the general public what autophagy is and why these autophagy inhibitors are being tested in clinical trials for a putative COVID-19 treatment.
Autophagy is a cellular recycling mechanism that plays a central role in the maintenance of cellular homeostasis. The process relies on lysosomes for the clearance and recycling of proteins or organelles. As a quality control mechanism for cytoplasmic components, autophagy dysregulation plays important roles in a variety of human diseases, including neurodegenerative diseases, cancer, cardiovascular disease, diabetes and infectious and inflammatory diseases .
Autophagy relies on lysosomes for the final degradation of the cargo. Lysosomes are membrane-enclosed organelles that contain a variety of enzymes capable of breaking down all types of biological polymers such as proteins, nucleic acids, lipids, and carbohydrates. Lysosomes function as the digestive system of the cell, serving both to degrade material taken up from outside the cell and to digest obsolete components of the cell itself .
Lysosomal lumen alkalizers (chloroquine, hydroxychloroquine) are used to block autophagic progress by impairing lysosomal function. At present, chloroquine and its analog hydroxychloroquine are the only clinically available autophagy inhibitors . Chloroquine and hydroxychloroquine are used to prevent and treat malaria and are efficacious as anti-inflammatory agents for the treatment of rheumatoid arthritis and lupus erythematosus . A very recent study has revealed that they also have potential broad-spectrum antiviral activities by increasing the endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV. In addition, the anti-viral and anti-inflammatory activities of chloroquine and hydroxychloroquine may account for their potent effectiveness in treating patients with COVID-19 pneumonia . As of February 23, 2020, a number of subsequent clinical trials have been quickly conducted for using of chloroquine or hydroxychloroquine to treat COVID-19 (http://www.chictr.org.cn/searchprojen.aspx) .
Up to now, results from more than 100 patients have demonstrated that chloroquine is superior to the control treatment in ameliorating pneumonia, improving lung imaging findings, and shortening the disease course according to the recent information . This would represent the first successful use of chloroquine in humans for the treatment of an acute viral disease, and is undoubtedly excellent news, since this drug is cheap and widely available. However, it should be considered carefully before drawing definitive conclusions, since no data has been provided yet to support this announcement .
Hydroxychloroquine has also been demonstrated to have an anti-SARS-CoV activity in vitro . Hydroxychloroquine clinical safety profile is better than that of chloroquine (during long-term use) and allows higher daily dose and has fewer concerns about drug-drug interactions. A French group showed that hydroxychloroquine is efficient in eliminating the virus in COVID-19 patients in only three to six days. They have also tested the synergistic effect of the combination of hydroxychloroquine and azithromycin and have proved that this combination was significantly more efficient for virus elimination. Azithromycin is a widely used antibiotic that has also been shown to be effective against Zika and Ebola viruses and in preventing severe respiratory tract infections when administrated to patients suffering viral infection . A total of 26 patients received hydroxychloroquine and among them six have also received azithromycin to prevent bacterial super-infection. After six days, 100% of patients treated with the combination of hydroxychloroquine and azithromycin were virologically cured comparing with 57.1% in patients treated with hydroxychloroquine only .
To conclude, hydroxychloroquine and azithromycin could be a possible treatment for COVID-19 patients in order to cure their infection and to limit the transmission of the virus to other people to counteract the spread of SARS-CoV-2 in the world.
Author: Petra Terešak
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