Illness during the last pandemic may have been even more immune-driven than we thought.
“Cytokine storm”.
If you read and/or wrote as much about covid in the dark days of early 2020 as we at TMR did, that phrase will have triggered an unwelcome flashback just as surely as if we’d said “social distancing”, “flatten the curve” or “toilet paper”. Apologies.
The Back Page writes it only as a reminder that we knew very early on how much overreactions by our immune systems contributed to covid pathology and severity.
Now a mouse study (yes, your scribe is again exploiting our exemption from TMR’s hallowed no-mice rule) hints just how great a contribution the adaptive side of immunity may have made.
In the study, published in Science Advances, the team out of Cornell University used a mouse model of covid – a non-lethal one that causes mild disease and whose chief clinical symptom is weight loss – to infect wild-type and rag-/- mice lacking B and T lymphocytes.
The team expected the immune-depleted mice to be knocked sideways by the infection, but they were shocked by their own results.
They measured the mice’s weight daily until the animals (sigh) went to live on the farm at three, seven or 14 days post infection (dpi), at which point their lungs were examined.
Wild-type mice began losing weight at 2dpi and eventually lose about 10% of their baseline weight before recovering after a week.
But the immune-depleted rag-/- mice did not lose any weight in that time. In some versions of the experiment they even gained about 1% of their baseline weight.
Adaptive immunity is known to play a role in viral clearance. When they looked at the mice’s lungs, the rag-/- mice had lower loads than wild-type mice three days post infection. However, while wild-type mice had significantly reduced their viral loads after a fortnight, the rag-/- mice’s loads didn’t change much at 7dpi and 14dpi.
Histology showed more pathology – more infected cells and perivascular infiltrates – in the wild-type mice’s lungs than in those of the immune-depleted mice.
Flow cytometry showed the rag−/− mice also had a significantly lower presence of neutrophils and monocyte-derived macrophages at 3dpi, but by 14dpi they had more monocyte-derived macrophages than the wild types, presumably helping to clear their elevated viral loads.
The team also collected bronchial alveolar lavage fluid to assess cytokine levels and found the wild-types had 10 times as much IL-6, seven times as much TNF-α and twice as much IL-2 as rag−/− mice at the peak of disease.
“Altogether, these data indicate that while rag−/− mice have less viral replication early during infection and do not clear the virus up to 30dpi, they do not develop the severity of disease and pathology as compared to SARS-CoV-2 MA10-infected WT animals,” the authors write.
“These findings suggest that adaptive immune cells play an important role in reducing SARS-CoV-2 levels, but that this benefit may come at the expense of increased inflammation and pathology.”
The results are in complete contrast to those of a previous experiment using flu.
“Unlike the main other respiratory viruses that circulate, without the adaptive immune response, on its own, SARS-CoV-2 doesn’t seem to cause the damage that leads to significant pathology,” said immunologist and co-author Professor Avery August.
“It means that we can explore therapeutics that modulate the immune response, so that we can dampen those parts that are causing inflammation while leaving those parts alone that are important for clearing the virus.”
Tales of immune betrayal are nothing new, but the Back Page feels somewhat astonished to think (assuming the aptness of the model) how much pandemic morbidity and mortality may have been a massive immune own goal.
Here’s hoping we can act on these results before the next one comes along.
Send classic thrillers to penny@medicalrepublic.com.au, no remakes please.
