Issue #82: Viruses, vaccines and COVID-19: revisiting the basics for SARS-CoV-2

Written by Nobel Laureate Professor Peter Doherty

With occasional digressions to tell a little of the history and the human story, the past 19 months have had me writing weekly ‘lay explainers’ about virus infections, vaccines, treatments and immunity. Infectious diseases are complex and, for both the writer and the reader, clarifying the underlying interactions can be a challenging exercise. Without exception, we’ve all been on a steep learning curve. Though my professional focus for more than five decades has been on virus infections and how we respond to them, engaging with some key topics – how clinical trials work for example (#53-58) – has had me starting from ground zero. No matter what our expertise, the reality of dealing with COVID-19 has taught us all new lessons.

Now, with vaccination rates heading upwards of 80 per cent for all Australians over 12 years of age, the country is progressively relaxing restrictions as we transition from keeping the infection out, to living with the disease. Borrowing from Winston Churchill, we all hope we’re at the ‘beginning of the end’, not the ‘end of the beginning’! As a consequence, it seems a good time to summarise some of the key points we’ve discussed previously, while at the same time conveying the essence of the more in-depth understanding that’s emerged as we’ve dealt with and, dissected, the novel infectious disease we call COVID-19 (#1). That’s my main writing task from now until Christmas, and likely beyond.

To begin at the beginning. The ultimate parasites, viruses (#2) are tiny, inert particles that package the genetic information (genome) required for their own reproduction in a protective coat made of protein and lipid (fat), with bits of carbohydrate (sugars) attached. Viruses can’t move themselves around and, in order to multiply and survive in nature, they must gain access to living cells. Once inside, they shed their protein and lipid to release their RNA or DNA genome (sequence of nucleic acid base pairs, #6) that will effectively take over the host cell and turn it into a virus production factory.

The infected cell then assembles and releases newly made virus particles (or virions) that will, in turn, enter other cells within a multicellular organism or be released into the ‘environment’ to infect different individuals. With most, though not all, viruses the ‘factory cell’ will first lose its normal (physiological) functions, then die. Once ‘out there’ in the air or in water, free virions are also very vulnerable to destruction by heat (#13), drying and so forth, with some types of viruses being much more resilient than others.

The SARS-CoV-2 virus that causes COVID-19 is thought to be an innocuous infection of one or other type of bat that has, probably after infecting some ‘intermediate’ and transient mammalian host, jumped across into us. This virus, that likely evolved over thousands of years to replicate in bat cells while causing minimal damage (pathology, #37) in its ‘maintaining’ (in nature) host is an opportunistic ‘pathogen’ (disease causing parasite) that just happens to grow well in us. If you aren’t convinced of the randomness of events, and how tenuous our place is in the world around us, just reflect a little on that!

Somehow, one or more SARS-CoV-2 virus particles got into a human nose as recently as December 2019 to begin what was to become a global pandemic. The ‘power of one’: there’s pretty much zero possibility we’ll ever identify that ‘index case’! The inert SARS-CoV-2 virion was either breathed in or inserted (finger to nose) to transit through the protective layer of nasal mucus (slime and snot, #10) to ‘find’ a ubiquitous protein called ACE2 (angiotensin converting enzyme 2) on the surface of an epithelial cell in the nasal mucosa (#11). The virus would never have ‘seen’ ACE2 before but, on its surface ‘spike’ (or S protein) it just happens to carry a particular molecular configuration (the receptor binding domain, or RBD #19) that attaches very tightly to ACE2. That ‘high affinity’ interaction in turn exposes the virus to a cell protein (a furin-like protease) that ‘cleaves’ the S protein into two ‘subunits’, S1 (has the RBD) and S2, which triggers the fusion of virus and cell membranes that enables virus entry into the cell cytoplasm. Once inside, the virus ‘loses’ its lipid/protein coat and starts making more copies (#44) of its RNA genome plus the mRNA template for the new, protective proteins. In all, the SARS-CoV-2 RNA encodes for some 29 different proteins that are made during the virus replication process, with four of these – spike, membrane (M), envelope (E) and nucleoprotein (N) being the main structural components of the new virions. Elements of the S, M and E proteins are exposed on the surface of the virus, while the N wraps around the RNA and is buried within. Next week, we’ll get to the vaccines.