Preprint: Early immune pathology and persistent dysregulation characterise severe COVID-19, Bergamaschi et al, 2021

Andy · Jan 19, 2021

In a study of 207 SARS-CoV2-infected individuals with a range of severities followed over 12 weeks from symptom onset, we demonstrate that an early robust immune response, without systemic inflammation, is characteristic of asymptomatic or mild disease. Those presenting to hospital had delayed adaptive responses and systemic inflammation already evident at around symptom onset. Such early evidence of inflammation suggests immunopathology may be inevitable in some individuals, or that preventative intervention might be needed before symptom onset. Viral load does not correlate with the development of this pathological response, but does with its subsequent severity. Immune recovery is complex, with profound persistent cellular abnormalities correlating with a change in the nature of the inflammatory response, where signatures characteristic of increased oxidative phosphorylation and reactive-oxygen species-associated inflammation replace those driven by TNF and IL-6. These late immunometabolic inflammatory changes and unresolved immune cell defects, if persistent, may contribute to “long COVID”.
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https://www.medrxiv.org/content/10.1101/2021.01.11.20248765v1

Snow Leopard · Jan 20, 2021

Stuff in discussion relevant to "LongCovid"

Finally, some cell populations remain markedly abnormal, or show a limited recovery, even once CRP-associated inflammation has resolved, and indeed after patients have been discharged from hospital. These persistent changes may reflect a slow intrinsic regenerative capacity of the cell type concerned, but in other situations, such as the continued elevation of effector T and B cells, it is tempting to speculate that there is ongoing abnormal signalling driving such changes. For that reason, we explored late changes that are seen in the inflammatory response in COVID-19.

Interestingly, three transcriptional signatures arise late in those with severe COVID-19 and are not present in early severe, nor mild, disease. These include activation of OXPHOS-, ROS- and heme-related metabolic pathways (Figure 7E). Activation of immune cells results in metabolic reprogramming that supports cell growth, proliferation and differentiation. Disruption of metabolic pathways can result in bioenergetic, anabolic, epigenetic or redox cellular crises – culminating in immune dysfunction (Bantug et al., 2018). It is unlikely that the metabolic signatures observed here simply reflect heightened bioenergetic requirements of activated immune cells, as one would expect that similar requirements are present also at early stages in the disease. OXPHOS can drive inflammation (Mills et al., 2017), and it is intriguing to note COVID-19 patients treated with metformin, which inhibits Complex I of the respiratory chain, had lower amounts of circulating inflammatory cytokines (Cheng et al., 2020). The ROS transcriptional signature may relate to more abundant production of ROS-species inevitably accompanying increased OXPHOS. Alternatively, it may reflect specific mitochondrial pathology, and thus per se contribute to immune cell dysfunction (Nathan and Cunningham-Bussel, 2013). Mitochondria are also critically involved in heme biosynthesis. Heme serves as a prosthetic group for haemoglobin as well as many other proteins – including several that constitute the respiratory chain of mitochondria. While free heme can act as damage-associated molecular pattern and promote ROS formation, the role of heme biosynthesis vs. catabolism in balancing cellular sensitivity to oxidants is complex and context dependent (Prestes et al., 2020). Here, given correlated regulation of heme and OXPHOS pathways in the clinical categories C, D and E, activity of these modules may be interrelated and possibly jointly reflective of dysfunctional mitochondria. How heme and OXPHOS transcriptional programmes are linked on a molecular level cannot be inferred from our data. Erythroid cell activation has recently been detected in severe COVID-19 (Bernardes et al., 2020) and could also contributes to a heme transcriptional signature. However, the increase in heme metabolism in our cohort correlates strongly with a falling haemoglobin, and reticulocytes (Figure S7) in patients in groups C, D and E are low – suggesting suppression rather than activation of erythropoiesis in these individuals.
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The discussion about ROS certainly overlaps with ME/CFS. Also note that dysregulations of cellular iron metabolism is often associated with increased oxidative stress.
See:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496698/

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Preprint: Early immune pathology and persistent dysregulation characterise severe COVID-19, Bergamaschi et al, 2021

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Preprint: Early immune pathology and persistent dysregulation characterise severe COVID-19, Bergamaschi et al, 2021

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