Issue #118: Persistence of SARS-CoV-2 and Long COVID - A spectrum of immune dysregulation

Written by Nobel Laureate Professor Peter Doherty

Over the past few weeks ( #112-117 ), we’ve looked at evidence supporting the idea that part, or all, of the SARS-CoV-2 virus is persisting in those suffering at least some forms of Long COVID (LC). While a measure of LC may result from substantial tissue and organ damage following an acute course of severe clinical compromise that requires hospitalisation, and even time in an intensive care unit (ICU), the form of debilitating LC – with brain fogs, tiredness, muscle pains, gastrointestinal issues and so forth – that develops after a relatively mild initial course of infection is more difficult to understand.

For an immunologist like me, an obvious thought is that this could reflect a continuing confrontation between persistent virus and the immune cells and antibodies that are trying to eliminate it from our bodies, but are not quite succeeding in doing so. A spectrum of viruses ( #111 #112 ), particularly the herpesviruses (HVs), do have well established mechanisms for developing latency in us, with occasional reactivation to produce infectious progeny. And some HVs, especially the ubiquitous Epstein Barr Virus, have long been associated with the intractable, LC-like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Not surprisingly, there is a lot of very serious work in progress looking at the immune status of people who tested positive (by PCR) for SARS-CoV-2 infection, then developed the classical LC symptomatology. Generally, these are longitudinal studies requiring repeated sampling of the same subjects. They lack the baseline observation of what someone’s immune profile looked like before they contracted the disease and tested positive by PCR for transient presence of the SARS-CoV-2 spike (S) protein, but they should all have a ‘matched control (MC)’ group of those who experienced COVID-19 but then recovered fully. Because LC is a ‘long problem’, much of this is a work in progress. But we can say a little about some studies that have been reporting via the peer-reviewed literature.

One of most substantial to date is the ADAPT study co-ordinated from the Kirby Institute at the University of New South Wales and Sydney’s St Vincent’s Hospital. Headed by Kirby Institute Director Tony Kelleher and clinician Gail Mathews, ADAPT was initiated in 2020 and has since recruited further subjects .

If you’re not a scientist and you try to read this research paper, you will likely come to two early conclusions. The first is that it looks very complicated, while the second is that there’s a mass of information and you aren’t all that clear where it is going. That’s not meant as a criticism, but it reflects the ‘state of the art’ in this field. Modern technology and informatics (computational strategies) allow us to analyse a very broad spectrum of parameters. Generating such data involves the use of very sophisticated, commercially available assays for detecting various cytokines, chemokines and secreted products made by immune cells and other cell types. Additional to that, the characterisation of molecular expression profiles on the surface of circulating white blood cells – detected by staining with fluorochrome-labelled monoclonal antibodies in a flow cytometer, #34 #73 – gives us some indication of their functional status. We should also recognise the limitation that, because this is a longitudinal clinical study in people, the overall molecular and cellular ‘landscapes’ we view via the available window of the blood provides clues, but does not necessarily define what’s going on in the body organs and tissue.

Their overall conclusion reached by comparing blood profiles in the LC and MC groups, along with samples from ‘normal’ subjects (UHC) and those infected with other human coronaviruses (HCoV), is encapsulated in the title of the paper, Immunological dysfunction persists for eight months following initial mild to moderateSARS-CoV-2 infection. A summary sentence tell us that: “Patients with LC had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-β) and type III IFN (IFN-λ1) that remained persistently high at eight months after infection.” The type I and type III interferons (IFNs) are classically associated with virus infections and with the protection of mucosal surfaces. Then, they also found that: “six proinflammatory cytokines (IFN-β, IFN-λ1, IFN-γ, CXCL9, CXCL10, interleukin-8 (IL-8) and soluble T cell immunoglobulin mucin domain 3 (sTIM-3)) were elevated in the LC and MC groups compared to the HCoV and UHC individuals”. And there were also “expanded subsets of memory CD8+ T cells expressing TIM-3 and PD-1, indicating chronic T cell activation and potentially exhaustion”.

The chronic production of ‘inflammatory mediator’ molecules described here indeed provides some explanation for the enduring clinical compromise of LC, while also being generally consistent with the idea (but by no means proving) that this results from a continuing (perhaps low level) confrontation between immune cells and virus (or viral protein) production ( #34 #51 #87 #94 ). The presence of expanded CD8+ memory populations showing evidence of ‘exhaustion’ might also suggest that these immune cells are simply unable to do the job of eliminating the virus-producing factory cells ( #34 ). At this stage, though, all that can be said definitively is that there is clear evidence of persistent immune activation in the type of LC that develops after a relative mild initial infection. What’s going on will be clarified as investigators ‘drill down’ to better define the roles of specific elements in this complex story. We will return to these themes.