Issue #115: Persistence of SARS-CoV-2 and Long COVID, 3 - The inside/outside of us

Written by Nobel Laureate Professor Peter Doherty

We’re all very aware that our experience of COVID-19 begins when we breathe in finely dispersed droplets of somebody else’s coughed or sneezed out mucous containing the SARS-CoV-2 virus, or when such material is conveyed to our nasopharyngeal area (or possibly eyes) via hand-to-face contact (#11, #82). Health care workers helping very sick patients are also at high risk of an ‘eye splash’, which is why they sport a similar type of face shields that welders wear.

And the fact that a good N95 mask, plus hand hygiene protects most of us, most of the time tells us that this virus is not invading via the largest organ of our body, the skin. Comedian Alan Sherman’s summary that ‘you gotta have skin,…you got it outside, and it helps keep your insides in’ may not be anatomically precise, but it is true that the skin keeps most viruses out. Exceptions are, of course, when we are ‘jabbed’ with the ‘needle’ proboscis of an arbovirus-infected mosquito (#99), or are bitten by a rabid dog, bat or raccoon.

While skin is definitely on the outside of us, the ACE2+ mucosal epithelial cells that are initially infected with SARS-CoV-2 in our nasopharynx or our eyes are, in a sense, ‘inside/outside’. The mucosal epithelia (#38) that line our respiratory, gastrointestinal (GI) and urogenital tracts all surround an ‘inside/outside’ space (the lumen) that contains a mix of inspired and expired air (respiratory), ingested food and digestion products (GI) and fluid containing molecules extracted by our kidneys as they ‘clean’ the blood (urine). Connected to the mother by the placenta, the foetus is wrapped in a highly vascularised chorioallantoic membrane that confers ‘fully inside’ status. The placenta and foetus are on the list of immunologically privileged sites we mentioned last week (#114).

Our ‘strictly inside’ organs, like the heart and brain, are bathed constantly in the blood that, if we are immune due to prior infection or vaccination, carries the antibodies (especially IgG) and immune T cells (#21, #34) that will protect us from any antigenically stable (unlike SARS-CoV-2) virus that gains access to our circulation. The half-life (t1/2) of a circulating human IgG molecule made within us is 10-25 days, though some ‘engineered’ monoclonal antibodies generated in the laboratory can still be detected out to 12 months after infusion.

Maintaining long-term immunity at a mucosal surface (#38) is more fraught, and less reliable. Though antibody-secreting plasma cells may potentially localize to the mucosal associated lymphoid tissue (MALT) – such as the adenoids, tonsils, Peyer’s patches, BALT (bronchus) and NALT (nasal) – the IgG and secreted IgA that enters the lumen of, for instance, the respiratory tract or the gut, is essentially inside/outside and will soon depart permanently in our body secretions and excretions. The same is true for immune T cells that have exited the blood and, though they may be found transiently in nasal mucus (#10) or in deep lung samples obtained by bronchoscopy, are swept up, out and away by retrograde mucus flow.

Evidence of long-term SARS-CoV-2 persistence (detected by PCR) in the respiratory tract (50 to 150 days) has been found for patients who are immunosuppressed, either as a consequence of their underlying clinical condition or by some therapeutic intervention. When it comes to sampling recovered individuals, it seems that SARS-CoV-2 may tend to ‘hide out’ longer in the GI tract than in other mucosal sites. For example, in an Iranian patient series analysed from time of hospital admission through subsequent discharge, SARS-CoV-2 RNA was found in nasal swabs and (less consistently) in blood, urine and stool samples, for a mean intervals of  8, 7, 6 and 13 days, with the latest recovery being at 25, 17, 11 and 42 days.

A US study focused on the GI tract found that, for a series of asymptomatic adults with PCR negative nasal swabs who were sampled at an average of four months (2.8 to 5.7) after an initial COVID-19 diagnosis, analysis of high and low GI tract biopsies showed scattered, sporadic viral nucleoprotein (NP) staining (by immunofluorescence) in gut enterocytes from 5 of 14 individuals, while viral RNA was found in 3/14 by PCR of tissue samples. 

Gastrointestinal problems can be a common feature of Long COVID. For example, a survey of 1,783 COVID-19 survivors at six months elicited 749 responses, with 220 patients (29%) self-reporting gastrointestinal symptoms that included diarrhoea (10%), constipation (11%), abdominal pain (9%), nausea and/or vomiting (7%) and heartburn (16%).

A detailed molecular diagnostic analysis of 113 individuals who experienced a mild to moderate initial disease found that 49.2% showed evidence of faecal SARS-CoV-2 RNA shedding during the first week after diagnosis, with that declining to 12.7% at four months (when nasal swabs were universally negative), 3.8% at seven months and zero at ten months. Of the four different SARS-CoV-2 RNAs analysed, the one coding for the N1 nucleocapsid (nucleoprotein) was the most readily detected. Furthermore, being positive for RNA shedding correlated with GI tract symptoms of abdominal pain, nausea and vomiting. Such individuals may not be producing any infectious virus (#113), but they could be suffering from the consequences of a continued, active immune response (#77).

Next week we’ll look further at the issue of SARS-CoV-2 persistence in our ‘inside/inside’ body organs.