Immunophenotyping and machine learning identify distinct immunotypes that predict COVID-19 clinical severity (preprint)

Quantitative or qualitative differences in immunity may drive and predict clinical severity in COVID-19. We therefore measured modules of serum pro-inflammatory, anti-inflammatory and anti-viral cytokines in combination with the anti-SARS-CoV-2 antibody response in COVID-19 patients admitted to tertiary care. Using machine learning and employing unsupervised hierarchical clustering, agnostic to severity, we identified three distinct immunotypes that were shown post-clustering to predict very different clinical courses such as clinical improvement or clinical deterioration. Immunotypes did not associate chronologically with disease duration but rather reflect variations in the nature and kinetics of individual patient’s immune response. Here we demonstrate that immunophenotyping can stratify patients to high and low risk clinical subtypes, with distinct cytokine and antibody profiles, that can predict severity progression and guide personalized therapy.

A path towards SARS-CoV-2 attenuation: metabolic pressure on CTP synthesis rules the virus evolution (preprint)

Fighting the COVID-19 epidemic summons deep understanding of the way SARS-CoV-2 taps into its host cell metabolic resources. We describe here the singular metabolic background that creates a bottleneck constraining coronaviruses to evolve towards likely attenuation in the long term. Cytidine triphosphate (CTP) is at the crossroad of the biosynthetic processes that allow the virus to multiply. This is because CTP is in demand for three essential steps. It is a building block of the virus genome, it is required for synthesis of the cytosine-based liponucleotide precursors of the viral envelope and, finally, it is a critical building block of the host transfer RNAs synthesis. The CCA 3-end of all the transfer RNAs required to translate the RNA genome and further transcripts into the proteins used to build active virus copies is not coded in the human genome. It must be synthesized de novo from CTP and ATP. Furthermore, intermediary metabolism is built on compulsory steps of synthesis and salvage of cytosine-based metabolites via uridine triphosphate (UTP) that keep limiting CTP availability. As a consequence, accidental replication errors tend to replace cytosine by uracil in the genome, unless recombination events allow the sequence to return to its ancestral sequences. We document some of the consequences of this situation in the function of viral proteins. We also highlight and provide a raison detre to viperin, an enzyme of innate antiviral immunity, which synthesizes 3-deoxy-3',4-didehydro-CTP (ddhCTP) as an extremely efficient antiviral nucleotide.