Pattern recognition receptor-associated immuno-thrombotic transcript changes in platelets and leukocytes with COVID19

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Respiratory infections are characterized by an increased risk of thrombosis, likely involving platelet-leukocyte crosstalk via pattern recognition receptors (PRRs). Here we characterized COVID19-mediated changes in PRR levels and their associations with thrombotic/coagulation-related transcriptional programs across platelets and leukocytes and assessed their correlation with COVID19 outcomes. Amplicon RNAseq of platelets and leukocytes from COVID19 patients (n = 10) and non-infected donors (n = 15) showed distinct patterns of PRR-expression levels based on cell type. Platelets from non-infected donors expressed TLR9 > RIG-I> CGAS at the highest level while leukocytes expressed TLR4 > TLR8 > RIG-I. COVID19 resulted in increased levels of TLR9, RIG-I, CGAS, and TLR1 in platelets and decreased levels of TLR6 and TLR8 in leukocytes, while the levels of the highest expressed PRRs remained almost unchanged. In platelets from COVID19 patients, MDA5, RIG-I, and LGP2 showed the highest associations with thrombotic-, coagulation-, and thrombolysis-associated transcripts, while in non-infected donors, TLR9 showed the highest associations with those transcripts. In leukocytes, RIG-I and MDA5 also correlated with coagulation-related transcripts when derived from the non-infected donors, but those associations were almost lost with COVID19. Platelet-leukocyte aggregates increased with COVID19 as did extracellular vesicles detected by imaging cytometry, immunofluorescence, or electron microscopy. Platelet-TLR3 and leukocyte-TLR5 positively correlated with severity and survival of the COVID19 patients, while leukocyte-TLR7 showed an inverse correlation. Coagulopathy, measured by INR, was associated with platelet-TLR4 and leukocyte-TLR10. Liver inflammation, assessed by ALT levels, correlated with platelet- and leukocyte-LGP2, in addition to leukocyte-TLR3, -TLR6, -TLR7, and -RIG-I. Analysis of publicly available whole-blood-RNAseq, showed that COVID19 and tuberculosis were more similar than COVID19 and influenza with respect to associations between PRRs and thrombotic/coagulation-related transcripts. Overall, platelets and leukocytes exhibit distinct patterns of PRR expression and correlations with thrombotic/coagulation-related transcripts that change with COVID19, and there are distinct PRRs in each cell population that associate with COVID19 severity, coagulopathy, and liver damage.

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