Uncoating the enemy

No one knew them until they started making us sick. Then some died. Like some unknown enemy out of a Hollywood movie, Coronavirus became an overnight sensation.

Coronaviruses are a large family of viruses that are common in many different species of animals, including camels, cattle, cats and bats. Rarely, animal coronaviruses can infect people and then spread between peoples such as with MERS, SARS and now with 2019-nCoV.

http://www.cdc.gov/coronavirus/2019-ncov/summary.html

First isolated in 1937, coronaviruses are the second leading cause of colds (after rhinovirus). There are 4 major categories, and they are known by the greek letters – alpha, beta, delta and gamma. Only alpha and beta cause diseases in humans. The 2019-nCoV is a betacoronavirus. Seven (7) human coronaviruses have been identified so far. This includes SARS-CoV, MERS-CoV and the novel coronavirus.

Coronaviruses are zoonotic. Meaning they are transmissible between humans and animals, but most infect only their specific host. SARS killed about 10% of the people it infected. MERS killed around 35% of those that came down with this viral infection. The good news is that SARS has relatively disappeared from the limelight. MERS on the other hand remains an ongoing viral organism to contend with. Transmission of coronavirus is between people who were in close contact with patients. Hence, post a greater risk to the healthcare worker.

Clinically, this virus can manifest with just a sneeze, a cold, or at worse, become complicated enough to cause pneumonia. Whether patients die because of the virus or complications from the viral infection is another story altogether.

http://www.health.clevelandclinic.org

They’re called coronaviruses for a reason. Under electron microscopy, they look like halos. They are part of the RNA (ribonucleic acid) viruses family. Typically they are single stranded, 32 kb (kilobases) long, and is the largest known RNA virus genome. In reality, they’re actually dumb viruses. They cannot last on their own and will need to find hosts in order to replicate. Coronaviruses are promiscuous. They mutate and change at a very high rate. Meaning they are bad when it comes to reproduction. While the virus is dumb, evolution is smart. Mutations are random. Thoughtless. This process makes the organism more suitable to survive. And while most of the other viruses die, the few that survive make the virus more successful quickly take over.

Coronaviruses mutate less rapidly than other RNA viruses because they have a genome that’s 2-3x bigger than other RNA viruses. They are more complex. Accuracy in reproduction is more important for them. They are the only RNA virus family with a ‘proofreading’ capability.

Peter Coy, “The Global Battle to Force the Coronavirus Below It’s Tipping Point”, Bloomberg Businessweek, January 30, 2020

What information can be derived from knowing the enemy?

For one, the fact that the viruses mutate and change at a high rate is a dilemma for both diagnostic detection as well as treatment and development of vaccines against them.

Coronaviruses have an unusual replication process, which involves a 2-step replication mechanism. Many RNA virus genomes contain a single open reading frame (ORF) which is then translated as a single polyprotein that is then catalytically cleaved into smaller functional viral proteins, but coronaviruses can contain up to 10 separate ORFs. Most ribosomes translate the biggest one of these ORFs, called replicase, which alone is twice the size of many other RNA viral genomes. The replicase gene encodes a series of enzymes that use the rest of the genome as a template to produce a set of smaller, overlapping messenger RNA molecules, which are then translated into the structural proteins – the building blocks of new viral particles.

Rodney Rohde, “2019 Novel Coronavirus (2019-nCoV) Update: Uncoating the Virus”, American Society for Microbiology, January 31, 2020

Dr. Mark Denison, director of the division of pediatric infectious diseases at Vanderbilt University School of Medicine points out that the effort at slowing down this virus can only succeed not on what people do, but on how successful science is at addressing the virus. Because Coronavirus are dumb and cannot reproduce on their own, they hijack the reproductive machinery of the cells they attack. Man vs. Microbe scenario.

Remember the ‘proofreading’ capability of coronaviruses? That function seems to be able to be switched off if the virus is under evolutionary pressure. Here is where antiviral drugs theoretically can be useful. The antiviral that targets RNA will allow disruption in proofreading. Locking in that function makes the virus unadaptable, mutate faster, and essentially fall apart. Drug development takes into consideration knowing the enemy in order to eliminate them. An adenosine analogue that incorporates into nascent viral RNA chains resulting in premature termination is Remdesivir. Interesting is the potential of an old friend in Chloroquine. Chloroquine is used for the treatment of malaria and some diseases of the autoimmune system. Some data have shown that it also has potential as a broad-spectrum antiviral agent. The antiviral activity of chloroquine works by increasing endosomal pH for viral/cell fusion and interfering with glycosylation of cellular receptors of SARS-CoV. Chloroquine in addition has immune-modulating activity that can synergistically enhances its antiviral effect in vivo. [Manli Wang, Ruiyuan Can, Leike Zhang, Xinglou Yang, Jia Liu, Mingyue Xu, Zhengli Shi, Zhihong Hu, Wu Zhong, & Gengfu Xiao, “Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro:, Cell Research, 04 February 2020, as Letter to the Editor].

These are difficult times between man and microorganism. Science has come a long way. Technology and modern scientific and laboratory tools have paved the way at treating various infectious diseases using a more scientific approach. Gone are the days of hit and miss. Now we know the enemy, our next move is to destroy it expeditiously and precisely. Because in the end, only one can survive.

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