Thread by @HowellJollyBody

Thrilled to finally share the pre-print of our study in which we propose a mechanism underlying progression to severe #COVID19 medrxiv.org/content/10.110… Here is our tweetorial! A🧵 (1/9)

Hugely important landmark studies by @VirusesImmunity, @EJohnWherry, @SetteLab, @ScottBudinger and others have proposed that immune system dysregulation is implicated in disease progression and severity. (2/9)

To look for a mechanism of immune dysregulation, we performed multiparameter immune monitoring in a tightly controlled cohort of 128 COVID–19 patients, and used the ratio of SpO2:FiO2 as a dynamic and physiologic measure of disease severity. (3/9)

Machine learning algorithms integrating 139 parameters identified IL–6 and CCL2 as two factors predictive of severe disease, consistent with the therapeutic benefit observed with anti–IL6–R antibody treatment. (4/9)

But we couldn’t find transcripts for these cytokines in circulating immune cells. Instead, in situ analysis of lung specimens using RNAscope and immunofluorescent staining revealed that elevated IL–6 and CCL2 were dominantly produced by infected lung type II pneumocytes! (5/9)

Here you have TTF1 (red), CD45 (green), IL6 RNA (yellow), SARSCoV2 RNA (light blue), and nuclear DAPI in (blue). Zoom in and you can see yellow IL-6 in these 3 red staining type 2 pneumocytes, who are also light blue for SARS-CoV-2 RNA. More pretty pix in the manuscript! (6/9)

In our cohort of immune competent patients who were not treated with steroids (pre-#RECOVERY era study), severe disease was not associated with higher viral load, deficient antibody responses, or dysfunctional T cell responses. (7/9)

We propose aberrant cytokine production by infected lung epithelial cells is a major driver of pathology and may cause local immune regulation towards the benefit of the virus. Perhaps steroids, including inhaled #budesonide, disrupt these pathways. More work to be done! (8/9)

Huge thx to my co-first authors Drs. Sherin Rouhani @srouhani1 and Jon Trujillo @JonTrujilloNM, our PI Dr. Tom Gajewski, and the entire team. Most of all, thx to the patients who gave their time, samples and trust during those frightening early days in 2020. #TeamScience (fin)

@UChicagoHemOnc @UChicagoMed @jovianyu