What do organs reveal during autopsies?

The COVID-19 pandemic has caused the death of almost 2 million people across the world. In hospitals and research laboratories, knowledge about the illness has increased and certain treatments as well as vaccines have been developed. Autopsies have provided morphological information allowing us to see which organ failure has led to death. However, little molecular data is available to help explain this information. This inhibits optimal clinical management of patients since we don’t know enough about which biological molecules our medicines should target.

In order to improve our knowledge on this question, Chinese University teams in Hangzhou and Wuhan studied the entire range of proteins expressed in the various organs of 19 patients who died from respiratory distress linked to COVID-19 (proteomic analysis). Amongst these patients, 7 had multiple organ failure and 14 had signs of sepsis (generalized inflammation following serious infection). The study concentrated on 7 organs (lungs, kidneys, liver, heart, spleen, thyroid and testicles) and the results were compared to those of 56 other patients not infected with COVID-19, but having undergone surgery for other illnesses. In total, 144 COVID-19 organs and 74 negative organs were analyzed. Using this methodology (Tandem Mass Tagging) the expression patterns of 11 394 proteins were observed and comparisons were made with other data bases and with scientific literature. In order to compensate for potential errors, samples were chosen at random, analyses were reproduced numerous times, the results were subjected to stringent statistical analysis and certain observations were checked through supplementary in vitro experiments.

In total, 5336 proteins were clearly dysregulated (with greater or lesser expression than in normal circumstances) in at least one organ of COVID-19 patients. Except for the testicles, only 27 identical proteins were dysregulated in 6 other organs, suggesting that each organ reacts differently to a SARS-CoV-2 infection. The C-Reactive (CRP) inflammatory protein and the CD163 receptor (a highly expressed receptor in M2 macrophage immune cells) were the most over-expressed proteins following infection, which indicates the patients’ states of hyper-inflammation. Numerous other proteins were dysregulated following infection, including the following examples:

• The ACE2 viral receptor was not dysregulated in the lungs. However, five proteins potentially involved in the virus’ entry were overexpressed. Amongst them, CTSL (an endosomal system protein) was over-present in the lungs, the spleen, the kidneys and the thyroid, making it a better therapeutical target than ACE2 to block infection.
• Numerous proteins involved in the process of coagulation were dysregulated, reflecting the microthrombosis (obstruction of the circulatory system) frequently seen in severe cases. The VWF protein, which regulates the aggregation of platelets following a lesion, was present in greater than usual quantities in the kidneys, indicating an elevated risk of thrombosis in this organ. Certain fibrin precursors (FGA, FGG FGB) were too much in evidence in the lungs, promoting the formation of blood clots and fibrosis.
• Certain proteins regulating immunity (CEACAM1, CD274 and CD276,…) were over-abundant only in the lungs and the spleen, indicating that the functioning of adaptive immunity could be altered in these organs.
• Numerous proteins linked to the response to hypoxia were found to be dysregulated in the liver or the heart, reflecting the failure of the pulmonary functions, causing these organs to suffer from a lack of oxygenation. This sets in process a supplementary stimulus of the inflammatory response (GSEA proteins and cytokines) by the activation of the NF-kB channel, contributing to hyper-inflammation.
• A total of 139 proteins linked to angiogenesis (formation of new blood vessels) had abnormal expression. This shows that in response to thromboses and hypoxia, the body tries to optimise blood flow.
• In the thyroid, the CXCL12 chemokine (a protein that regulates the mobility of immune cells) was over-present, indicating an infiltration of lymphocytes and of macrophages in this organ.

In this study, the number of samples was relatively limited, the negative patients were suffering from various illnesses and it was difficult to evaluate the influence of pre-existing conditions. But this systematic analysis provides a rich source of molecular information to help us better understand the pathophysiology of COVID-19. Several pertinent biological processes emerge from this work, including the immune response, hypoxia, coagulation and fibrosis.

However certain proteins were found to be involved in less expected processes (dysregulation of glucose and fat metabolism, dysregulation in the testicles and in the production of hormones) and remain to be explored. This “proteomic atlas” offers up numerous therapeutic avenues to explore.