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Issue #37: Pathogenesis, infection and the ecosystem within

14 Dec 2020

Issue #37: Pathogenesis, infection and the ecosystem within

Setting it Straight - Issue #37

Last week I suggested that each and every one of us is a complex of interlinked ecosystems, with the inhabitants of our ‘land and sea scapes’ being the viruses, bacteria and other organisms that live in or on us. Considering the amount of DNA that we lug around each day, most of it is in the 100 trillion (1014) bacteria of our gut microbiome (#2). Thinking of the planetary ecosystem, human numbers are getting up to around eight billion (1010). The most numerous vertebrates are probably fish (1013+), with more than 1010 domestic chickens, and so forth. As with the vertebrate species that inhabit the earth, some ‘friendly’ (commensal) microbes serve our needs by providing nutrients (vitamins K, B12, riboflavin and thiamine) or are just passengers passing through, while a small minority are predators (pathogens) that invade and potentially do us harm. Across the planet while we might worry more about being attacked by sharks, which clean up the oceans and, like SARS-CoV-2, occasionally kill or maim fit young surfers and swimmers, human beings are the top predators.

Savannahs, oceans, caves and aquifers obviously offer very different ecosystems, as does our body, with the skin on the outside, the lumen of the gut and the lung being kind of inside/outside, while body organs like the liver, heart and kidney are definitely inside. Each of these bodily ‘ecosystems’ is further comprised of ‘microenvironments’ that in turn break down to ‘anatomical niches’.  What all vertebrate species share with some bacteria (aerobes vs anaerobes) is that they need oxygen (O2) to generate the energy essential for cell function. Accessing O2-rich inspired air in the terminal alveolar sacs of our lungs, red blood cells (RBCs) transport that as bright red oxyhemoglobin to all our ‘self-ecosystems’, internal or external, while removing the carbon dioxide (CO2) waste product to expired air (#36). From the atmosphere, photosynthetic plants on land and in the oceans (phytoplankton) utilise the C and release the O2 back into the air for us, and other aerobes, to use.

Lack of O2 is what kills us from pump damage - a heart attack, resulting from blood vessel blockade or arrythmia – stroke, where clots block the blood vessels to (say) the brain or, as is the case in influenza, when virus-induced damage to the lung combined with an over-effulgent inflammatory response leads to the alveoli being filled with froth and fluid to prevent O2/CO2 exchange. What I’m describing here for influenza is end-stage terminal ‘pathology’ (or damage). The pathway to that point is what we call ‘pathogenesis’. When a researcher like me (I’m an experimental pathologist/viral immunologist) studies ‘virus pathogenesis’ we’re looking at the progression with time that leads to death or, preferably, what happens when our adaptive immune system cuts in, clears the virus from our body and allows us to recover. Our job as scientists is to understand the mechanistic basis of pathology and develop products (chemists and vaccine developers) and procedures (physicians) to help tip that equation in a positive direction. Like everything in nature, it’s all down to numbers, and the sooner we reduce both the numbers of free virions and the numbers of infected cells (#21, #34), the more likely we are to feel better. Vaccines jump-start that elimination process.

When COVID-19 first hit, most physicians thought initially that it was like a ‘new bad flu’. People had trouble breathing and turned blue (cyanosis) due to the lack of oxygenated blood. And the radiologists could see hideous ‘ground glass’ consolidations (masses) in the lung that would obviously prevent air-access and O2/CO2 exchange. But then, the type of pathologists we encounter in the PM room in TV programs like CSI and Silent Witness, found that the reason the blood wasn’t oxygenating properly was due to the blood capillary network around the alveolar sacs being loaded with micro-clots. Unlike flu, the basic ‘plumbing problem’ in COVID-19 is more pipe blockage than flooding!

Unexpectedly, the neurologists were reporting an increased incidence of atypical, debilitating, sometimes fatal strokes due to big clots blocking low-down in the carotid arterial circulation to the brain. What’s even more disturbing is that strokes can occur late, even in younger people who have had a relatively mild, primary clinical course and seem to be well on the way to recovery. In short, SARS-CoV-2 is not just causing pneumonia. Beyond the typical respiratory tract damage characteristic of flu, COVID-19 can also be a primary coagulopathy. One of the reasons that survival rates have improved is that hospitalised patients are immediately treated with low-dose heparin, a cheap and readily available anticoagulant.

Then the cardiologists, nephrologists and, for those less fortunate, the pathologists, were also seeing evidence of substantial heart and kidney damage. Unlike the flu viruses which do not normally cause viraemia (blood-borne spread) in people, SARS-CoV-2 can be shown to be present in blood plasma. As a consequence, the virus can access, grow in and modify the surface of the ACE2+ endothelial cells that line the blood vessels, a likely cause of clot formation. And it can also invade the muscle cells of the heart to cause cardiomyopathy. Further problems can result from disruption of the heart’s neural control module with, as a consequence, interventional cardiologists opting to insert pacemakers, and even defibrillators, in some who have survived COVID-19. And the reason that diabetics are so likely to die from COVID-19 is that the virus is further damaging kidneys that are already compromised.

So that’s some of what we understand so far about the pathogenesis of COVID-19. And, with a significant incidence of clinical ‘long-haulers’ in young and old, along with much still to learn about very long-term effects, this is a disease that every sane person should try to avoid. Given the lack of specific antiviral drugs to limit the growth of SARS-CoV-2 – we do have these for the flu and they work well if administered early – plus the general lack of access to the wonderfully effective antiviral monoclonal antibodies that were used to treat Donald Trump (and likely other ‘important’ and elderly US Republicans) what options, other than isolation, do we have to avoid getting this disease? The obvious answer is vaccination. That’s where we’ll go next week as we discuss how immune response generated by infection, vaccination or a combination of both interface with the pathogenesis of SARS-CoV-2 infection.

Setting it Straight by Laureate Professor Peter Doherty Archive