Antimicrobials and COVID-19: Strategies for Treating a Pandemic
On March 19, 2020, Former U.S. President Donald Trump presented chloroquine, a medication on the WHO Model List of Essential Medicines, and hydroxychloroquine, its derivative, as possible treatment options for the novel coronavirus, SARS-CoV-2. Positive results from preliminary studies indicated that hydroxychloroquine, an antimalarial drug, had the potential to improve disease outcomes and possibly slow COVID-19’s progression. However, officials stated that additional data were needed before the drug could be approved as an effective treatment for the disease.
Since the time of this announcement, the spotlight has been thrown on hydroxychloroquine. What’s so special about this medicine? How does it affect SARS-CoV-2? And what other medications are candidates for treating this new virus?
To answer these questions, we need to start with a basic understanding of how viruses work. Viruses are microscopic agents that consist of genetic material (DNA or RNA), a protein coat called a capsid and sometimes, a lipid envelope. They can only replicate inside living host cells, which means they must hijack host cell machinery in order to replicate and spread.
What It Takes for a Virus to Hijack Cells and Cause Infection
- Attachment. Find and attach to a host cell.
- Penetration. Inject genetic material into that cell.
- Synthesis of viral components. Copy viral DNA or RNA and make viral proteins using host cell materials.
- Assembly. Build additional viral particles from newly synthesized viral parts.
- Release. Escape the host cell and search for new cells to infect.
What We Know About COVID-19SARS-CoV-2 is a novel virus. We had no knowledge, experience or immunity to this pathogen when it first made its appearance in late 2019. The fact that SARS-CoV-2 spreads so rapidly has added to the already formidable challenges associated with combating a novel virus. Amazingly, researchers, health care professionals and advocates have made tremendous strides to better understand COVID-19 over the past couple of months. Because of their efforts, we have learned a lot in a short amount of time.
- SARS-CoV-2 is part of the Coronaviridae family. Like MERS-CoV and SARS-CoV, it is a Betacoronavirus. It likely originated in bats and can cause severe respiratory disease in humans.
- The genome of SARS-CoV-2 is ~30kb in size. It is an enveloped, positive-sense, single-stranded RNA virus.
- The human receptor for SARS-CoV-2 is Angiotensin-converting enzyme 2 (ACE2). This enzyme is involved in the regulation of blood pressure and is expressed by cells of the heart, lungs, kidneys and intestines.
- SARS-CoV-2 binds to ACE2 through mushroom-shaped surface proteins called spike proteins. These spike proteins are what give the virus its crown-like appearance and are where the name ‘coronavirus’ comes from.
- Many symptoms associated with COVID-19 are caused by the patient’s immune system, not the virus itself.
Chloroquine and Hydroxychloroquine
One possible strategy for treating SARS-CoV-2 is to control the host’s immune system. Evidence shows that high levels of inflammation accompany the most severe cases of COVID-19. Hyperactive (uncontrolled) immune responses can lead to Cytokine Storm Syndrome, Acute Respiratory Distress Syndrome and eventual organ failure. Decreasing inflammation helps keep the lungs and other organs functioning properly during viral infection.
The Mechanism: Immune Suppression
Chloroquine and hydroxychloroquine reduce autophagy (self-regulated destruction of host cells), interfere with Toll-like receptor (TLR) signaling and decrease cytokine production. As a result, inflammation is controlled and immune responses are less severe.
Evidence suggests that chloroquine and hydroxychloroquine may also interfere with the glycosylation of SARS-CoV-2 cellular receptors and prevent virus/cell fusion by increasing endosomal pH.
Both of these drugs are currently FDA approved for the treatment of malaria, rheumatoid arthritis and lupus and have shown in vitro activity against SARS-CoV and SARS-CoV-2.
A preliminary trial involving 36 COVID-19 patients in France showed encouraging results. 6 patients in the study were asymptomatic, 22 showed symptoms of upper respiratory tract infections and 8 showed symptoms of lower respiratory tract infections. 20 were treated with hydroxychloroquine (600 mg daily, in a hospital setting). Within 6 days, the virus was no longer detectable in 70% of samples taken from patients who received treatment. In contrast, only 12.5% of patients who did not receive the hydroxychloroquine treatment had cleared the virus.
Another trial involving 100 patients in China reported that chloroquine was effective at decreasing pneumonia and shortening the duration of disease.
Larger controlled trials to determine the effectiveness of these medications as treatments for COVID-19 are taking place as we speak.
Another possible strategy for treating SARS-CoV-2 is to prevent replication of the virus. If the viral genome isn’t copied, the virus can’t reproduce, and the infection will be cleared. It should be noted that this is not a one-size-fits-all approach. Not all antiviral medications work on all viruses. Microbes have unique, and often distinguishing, properties that must be taken into consideration when developing treatment plans.
The Mechanism: Inhibition of Replication Machinery
Remdesivir is a broad-spectrum antiviral drug that inhibits RNA-dependent RNA polymerase, the virus-encoded enzyme responsible for copying SARS-CoV-2’s genetic code. Blocking an enzyme necessary for RNA replication prevents the virus from making copies of itself and allows the body to mount an effective response to eliminate it.
Remdesivir has shown prophylactic and therapeutic activity against MERS-CoV in non-human primates as well as in vitro activity against SARS-CoV-2.
The University of California Davis Medical Center in Sacramento, Calif., reported successful treatment of a female patient with COVID-19 using remdesivir. This patient had one of the first recorded community-spread COVID-19 infections in the United States. Doctors confirmed that the patient’s condition was critical before treatment, but she began to show signs of improvement the day after remdesivir was administered. Samples of the patient’s blood were frozen and held for testing when supplies become sufficiently available.
In the meantime, a number of clinical trials to evaluate the efficacy of remdesivir as a treatment for COVID-19 are underway in the U.S. and China. Results of these trials are expected as early as April 2020.
Another strategy for treating SARS-CoV-2 is to attack the virus directly. Blocking a virus’s ability to recognize, attach to or penetrate host cells will prevent infection altogether. In many cases, our bodies do this naturally through the production of antibodies. Antibodies are proteins that recognize and bind to foreign particles, called antigens, on pathogens. When an antibody binds to an antigen, it can neutralize the microbe directly, preventing host cell infection, or flag it for destruction by the immune system. Antibodies are naturally produced through exposure and recovery from infections.
The Mechanism: Enhance Immune Recognition
SARS-CoV-2 is a novel virus. That means people who haven’t been infected with it have no antibodies to this virus in their immune memory banks. But people who have recovered from COVID-19 infections do, and if functional copies (called monoclonal antibodies) can be engineered and reproduced in a laboratory setting, they can serve as substitute antibodies to enhance or mimic the immune system’s attack on SARS-CoV-2.
A company called Regeneron is preparing for large-scale manufacture of monoclonal antibodies targeting the SARS-CoV-2 spike protein. If they’re successful, blocking spike proteins will prevent viral attachment to host cells and could cripple the virus entirely.
This strategy has been especially effective at treating certain types of cancers, and clinical trials of monoclonal antibodies designed to treat a number of bacterial and viral infections including Escherichia coli, Clostridium difficile, HIV, respiratory syncitial virus (RSV) and rabies virus are currently in progress.
Clinical data are pending, but Regeneron claims to have isolated hundreds of virus-neutralizing antibodies from mice and recovered COVID-19 patients. The company will begin manufacturing by mid-April with hopes of initiating human trials early this summer.
We’ve learned a lot about the novel coronavirus, SARS-CoV-2, in a short amount of time, but there’s still much to learn. These preliminary results should serve as fuel for additional research and continued pursuit of effective COVID-19 treatments. The world is waiting with baited breath.
A minireview and a short article, published in Antimicrobial Agents and Chemotherapy, a journal of the American Society for Microbiology, suggest that therapeutic drugs targeting SARS-CoV-2 directly will be most effective.