Thread by @lumosbio, "Imbalanced host response to #SARSCoV2 drives development of #COVID19" Highlighting "We [...]

"Imbalanced host response to #SARSCoV2 drives development of #COVID19"

Highlighting

"We propose that reduced innate #antiviral defenses coupled with exuberant inflammatory #cytokine production are the defining and driving feature of COVID-19"

https://www.cell.com/pb-assets/products/coronavirus/CELL_CELL-D-20-00985.pdf

"The physiological response to

infection is generally initiated at the cellular level following replication. After virus entry, the infected cell detects the presence of virus replication through use of any one of a number of pattern recognition receptors (PRRs)"

#SARSCoV2

"Engagement of virus-specific RNA structures
culminates in the oligomerization of these receptors and the activation of downstream transcription factors, most notably the interferon regulator factors (IRFs) and Nuclear Factor (NF)."

#SARSCoV2

"The first is the engagement of cellular #antiviral defenses, which is mediated by the transcriptional induction of Type I and III interferons (IFN-I and IFN-III) and the subsequent upregulation of interferon stimulated genes (ISGs)"

#SARSCoV2

"The second arm of the #antiviral response involves the recruitment and coordination of specific subsets of leukocytes, which is orchestrated primarily by #chemokine secretion"

#SARSCoV2

"Despite virus replication, the host response to #SARSCoV2 fails to launch a robust IFN-I/-III response, while simultaneously inducing high levels of chemokines needed to recruit effector cells."

"The discrepancy between the levels of viral replicationand IFN production/signaling suggests that although #SARSCoV2 is capable of engaging the IFN-I and IFN-III systems, this response is prevented by an antagonist that is rendered ineffective under high MOI conditions."

"At three days post infection, virus replication peaks at 1.2% of the total sequencing reads before decreasing to 0.05% of total reads on day 7 and completely clearing the virus by day 14 (Figure 3A)."

#Ferrets #SARSCoV2 #infection

"As a comparison, a sublethal infection of IAV comprises less than 0.03% of total reads on day 7 from the same sample type (Figure S3A)."

(IAV) = influenza A virus /vs/ #SARS_COV_2

" #SARSCoV2 generates a unique gene signature enriched for cell death and leukocyte activation including transcripts such asIL1A and CXCL8 (GO: 0008219 and GO: 0045431, Table S3)."

"By day fourteen, we detect no viral reads for #SARSCoV2 and the observed cytokines return to baseline with the exception of IL-6 and IL1RN/IL1RA, which remain elevated similar to results observed with MERS."

"Intriguingly, unique gene signatures from #SARSCoV2 -infected trachea that were largely absent in response to IAV align with those of progenitor cells from the hematopoietic lineage, suggesting that infection may be inducing #hematopoiesis (Figure 3D and Figure S3C)."

"Significant elevation of CXCL9 and CXCL16, chemoattractants of T or NK cells, CCL8 and CCL2,
which recruit monocytes/macrophages, and CXCL8, a classic neutrophil chemoattractant, suggest that the presence of these cells may be a primary driver of the
signature #pathology...

...observed in #COVID19 patients."

"This is consistent with data showing elevated circulating neutrophil levels among COVID-19 patients (Chen et al., 2020; Qin et al., 2020), which may have prognostic value in identifying individuals at risk for developing severe disease."

"Given the moderate viral replication levels observed in vivo, one explanation for the low IFN expression could be that a small subset of cells are refractory to the antagonistic mechanism of #SARSCoV2 (similar to infected Calu-3 cells) ...

...producing sufficient amounts of IFN-I and/or IFN-III to
guide immune cell activation and ISG induction."

https://www.cell.com/pb-assets/products/coronavirus/CELL_CELL-D-20-00985.pdf

#SARSCoV2 #biochemistry #immune #response #COVID19

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