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.
