Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19, 2023, Harish Narasimhan et al

Mostly University of Virginia work

This paper is about 'respiratory PASC'. They appear to be suggesting that the compromise to lung function can last a long time whereas PASC impacts elsewhere do not.

Despite the paper being focused on lungs, maybe it can tell us something about Long covid more generally, maybe it can't.

So, Type 2 epithelial cells in the furthest reaches of the lungs differentiate into new epithelial cells when there is injury. Differentiating cells express high levels of cytokeratin 8 (Krt8hi).

If there is severe damage of the alveoli (distal lung is just the part of the lung at the end of the branching tubes, where the alveoli are), then Krt5+ basal cells are recruited to the distal lung. Some of these just stay there and some differentiate into the airway tubes (bronchiolisation). Essentially, the repaired tissue gets messed up and doesn't work properly. They talk about these 'ectopic' pods of the Krt5+ cells - I'm imagining it's a bit like endometriosis, where cells of one type migrate and settle in places where they shouldn't be. This 'cells in the wrong place' seems to result in lung fibrosis.

In this study, they did a lot of things, including looking at the lungs that had been removed from people who needed a lung transplant as a result of a Covid-19 infection.

They seem to be suggesting that the normal cell replacement process in the alveoli wasn't happening so well, with more cells in the stage between AT1 and AT2 cells which don't function so well and also more of those upper airway cells down further in the lungs where they shouldn't be. I don't yet know what they mean by the 'expression of alpha smooth muscle actin, indicative of myofibrobalst activity' that they found in the lungs, along with pockets of aberrant basaloid cells.

 

They seem to be suggesting that increased levels of CD8+ T cells and areas where the tissue repair wasn't happening properly was a feature of post-viral pulmonary fibrosis.

The researchers tried to recreate this situation in mice by exposing them to a SARS-CoV-2 but they couldn't. However, when they infected mice with a flu virus, they could. There was immune cell infiltration and collagen deposition and persistent lung dysfunction.

"Exuberant tissue CD8+ T cell responses impair alveolar regeneration and promote dysplastic lung repair following viral pneumonia"
(I'm wondering if there is similar damage to the micro-vascular system in muscles and that some dysfunctional healing might result in in the cardiovascular dysfunction that has been reported by people like Systrom, where there is inadequate oxygen extraction. Of course, there is the issue of how people who seem very mildly affected by an infection would sustain such damage. Anyway, onwards.)

Depleting the CD8+ T cells (after they had done their job in the acute disease) seemed to stop the faulty tissue repair, but primarily in aged mice as opposed to the young mice.

They say they achieved the removal of circulating T cells with a low dose of an antiCD8 treatment, and the removal of lung-resident T cells with a high dose of the antiCD8 treatment. What I take away from that, is that you could apply a treatment that removes T cells from the blood, but that they could still be hanging out in the tissues, potentially causing problems. So, if you are testing an anti-T cell treatment and you think the T cells are causing a problem in tissues, then you need to test for the removal of the T cells from the tissue, not just the blood.

 

Analysis of gene expression seemed to point to highly active inflammatory responses in the areas of dysfunctional repair. There were a whole range of immune cells active in the areas of dysfunctional repair, including macrophages.

A CD8+ T cell-macrophage axis induces IL-1β release to arrest AT2 trans-differentiation in the transitional cell state

They are proposing that the CD8+ T cells persisting in tissue makes macrophages release IL-1B, which promotes the expansion of the cells that cause fibrosis.

They did a number of studies showing that the CD8+ T cells are having these effects by releasing IFN-y and TNF. Knocking out the T cells or the IFN-y and TNF stopped the pathology.

They found that the relationship between the macrophages and the CD8+ T cells required an infection to prime the cells.

 

I haven't looked at the figures, but my impression is that these researchers did a lot of work, checking their assumptions in several ways. It seems like good work that should move the understanding of post-infectious lung fibrosis forward. I think it might possibly have some relevance to ME/CFS too.

The researchers say that depletion of CD8+ T cells isn't clinically feasible, so they blocked IFN-y and TNF, and that worked. They say that neutralising the IL-1B worked too.

They found higher levels of IL-1B in people with persistent abnormal pulmonary function. I did check that out - here it is:


I think we've seen variable reports on blood IL-1B in people with ME/CFS. I think if levels were consistently higher, we would know by now. But, that said, the chart does show overlap in the levels with healthy controls

 

What I like about this idea in terms of it being useful for thinking about ME/CFS is that it is the process of healing following infection-induced injury that causes the harm.
From the discussion:

The authors mention two drugs that they think could stop the pathological process they have set out:

(Alternatively, they could just tell the people to join a choir and work on their disordered breathing...)

 

Those references that are given to support the claim that 'excessive infiltration and accumulation of profibrotic monocyte derived macrophages have been reported in ..PASC'?
12. Phetsouphanh C, Darley DR, Wilson DB, Howe A, Munier CML, Patel SK, et al. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nature Immunology. 2022;23(2):210-6.

53. Joseph IB, Connor HP, Karolina JS, Nikolay SM, Estefani D, Emmy J, et al. Expansion of profibrotic monocyte-derived alveolar macrophages in patients with persistent respiratory symptoms and radiographic abnormalities after COVID-19. bioRxiv. 2023:2023.07.30.551145.

57. Wendisch D, Dietrich O, Mari T, von Stillfried S, Ibarra IL, Mittermaier M, et al. SARS-CoV-2 infection triggers profibrotic macrophage responses and lung fibrosis. Cell. 2021;184(26):6243-61.e27.

58. Misharin AV, Morales-Nebreda L, Reyfman PA, Cuda CM, Walter JM, McQuattie-Pimentel AC, et al. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. Journal of Experimental Medicine. 2017;214(8):2387-404.

So, mostly very lung focused. I think we have seen similar reports for other parts of the body, both in Long covid and PASC.

 

On baricitinib for Long Covid: