Molecular signature of postmortem lung tissue from COVID-19 patients suggests distinct trajectories driving mortality

Abstract

The precise molecular mechanisms behind severe life-threatening lung abnormalities during severe SARS-CoV-2 infections are still unclear. To address this challenge, we performed whole transcriptome sequencing of lung autopsies from 31 patients suffering from severe COVID-19 related complications and 10 uninfected controls. Using a metatranscriptome analysis of lung tissue samples we identified the existence of two distinct molecular signatures of lethal COVID-19. The dominant “classical” signature (n=23) showed upregulation of unfolded protein response, steroid biosynthesis and complement activation supported by massive metabolic reprogramming leading to characteristic lung damage. The rarer signature (n=8) potentially representing “Cytokine Release Syndrome” (CRS) showed upregulation of IL1 cytokines such CCL19 but absence of complement activation and muted inflammation. Further, dissecting expression of individual genes within enriched pathways for patient signature suggests heterogeneity in host response to the primary infection. We found that the majority of patients cleared the SARS-CoV-2 infection, but all suffered from acute dysbiosis with characteristic enrichment of opportunistic pathogens such as Gordonia bronchialis in “classical” patients and Staphylococcus warneri in CRS patients. Our results suggest two distinct models of lung pathology in severe COVID-19 patients that can be identified through the status of the complement activation, presence of specific cytokines and characteristic microbiome. This information can be used to design personalized therapy to treat COVID-19 related complications corresponding to patient signature such as using the identified drug molecules or mitigating specific secondary infections.

ACE2 protein expression in lung tissues of severe COVID-19 infection

“…These findings regarding the immunopathology and expression of ACE2 in relation to SARS-CoV-2 suggest an abnormal macrophage infiltration and microthrombi response, primarily in the lung, that is not clearly topologically associated with viral presence. The evidence we present suggests that virus-independent immunopathology may be a primary mechanism underlying the fatal COVID-19 infection, supporting personalised therapeutic interventions as a therapeutic strategy 24 . Our results are in line with previous research demonstrating an abnormal macrophage response and plasma-cell abnormalities that are detrimental to the host in COVID-19 11 , 25 – 28 and, more importantly, establish a potential biologic and mechanistic link for future investigation of therapeutic targets underlying fatal COVID-19.…”

Uncovering common pathobiological processes between COVID‐19 and pulmonary arterial hypertension by integrating Omics data

“…In the transcriptomes of lung tissue from COVID‐19 patients, 29 we identified 3470 differentially expressed genes, among which 1581 are upregulated and 1889 are downregulated. We then identified differentially expressed genes in PAH using the microarray data from lung tissues 32 (Figure S2 ).…”

“… 28 We also retrieved the RNA‐seq whole transcriptomes of lung biopsies from 31 deceased COVID‐19 patients and 10 healthy individuals (GSE183533). 29 An R package, EdgeR, was used to identify differentially expressed genes in COVID‐19. 30 A gene is said to be significantly differentially expressed if the corresponding false discovery rate (FDR) is less than 0.05 and the fold change is greater than 2.…”

Systems pharmacology approaches in herbal medicine research: a brief review

“…The advantage of such large-scale data is that we can rapidly utilize them to repurpose existing drugs in urgent situations. For example, several approved drugs have been proposed as candidates for clinical intervention to combat rapidly emerging diseases such as COVID-19 through in silico screening using CMap data (114,115). Accordingly, the establishment of a well-organized drug-related database (e.g., drug-induced transcriptome data) for standardized herbs or herbal medicines should pave the way for advancement of herbal medicine research.…”