ZBP1-dependent inflammatory cell death, PANoptosis, and cytokine storm disrupt IFN therapeutic efficacy during coronavirus infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), continues to cause substantial morbidity and mortality in the ongoing global pandemic. Understanding the fundamental mechanisms that govern innate immune and inflammatory responses during SARS-CoV-2 infection is critical for developing effective therapeutic strategies. Whereas interferon (IFN)-based therapies are generally expected to be beneficial during viral infection, clinical trials in COVID-19 have shown limited efficacy and potential detrimental effects of IFN treatment during SARS-CoV-2 infection. However, the underlying mechanisms responsible for this failure remain unknown. In this study, we found that IFN induced Z-DNA-binding protein 1 (ZBP1)-mediated inflammatory cell death, PANoptosis, in human and murine macrophages and in the lungs of mice infected with ß-coronaviruses, including SARS-CoV-2 and mouse hepatitis virus (MHV). In patients with COVID-19, expression of the innate immune sensor ZBP1 was increased in immune cells from those who succumbed to the disease compared with those who recovered, further suggesting a link between ZBP1 and pathology. In mice, IFN-ß treatment after ß-coronavirus infection increased lethality, and genetic deletion of Zbp1 or its Zα domain suppressed cell death and protected the mice from IFN-mediated lethality during ß-coronavirus infection. Overall, our results identify that ZBP1 induced during coronavirus infection limits the efficacy of IFN therapy by driving inflammatory cell death and lethality. Therefore, inhibiting ZBP1 activity may improve the efficacy of IFN therapy, paving the way for the development of new and critically needed therapeutics for COVID-19 as well as other infections and inflammatory conditions where IFN-mediated cell death and pathology occur.

Post-COVID-19 symptoms are not uncommon among recovered patients-A cross-sectional online survey among the Indian population. (preprint)

Background: Coronavirus disease-2019 (COVID-19) can have a myriad of symptoms. However, it is now known that most patients recovered from COVID-19 have symptoms related to COVID-19. There is a paucity of literature on post-COVID-19 symptoms from India. Hence we aimed to assess the incidence of post-COVID-19 symptoms in patients recovered from COVID-19. Methods: An online Microsoft forms survey was conducted through multiple social media platforms. Results: Of the 5,347 individuals who received and clicked the link, a total of 2038 infected patients responded (Supplementary figure). Approximately 48% (967/2038) had recovered from COVID-19 within 1-3 months (short-term recovered), 34.2% (375/2038) had recovered from COVID-19 >3 months ago (long recovered), and 18.4% (375) were recovered within the last one month (recently recovered). Nearly 38% (770/2038) had a history of hospitalization for COVID-19. Of them, 34.28% (264/770) required oxygen therapy during the hospital stay. Most patients were discharged within 5-10 days of hospital stay (54%, 415/770). Only 5.58% (43/770) required a stay of more than 20 days. Seventy-five percent (575/770) of the hospitalized patients received steroid therapy. Of those who received steroid therapy, 56.5% (325/575) had not required oxygen therapy. Forty percent (233/575) of patients received steroid therapy for two weeks, 24% (138/575) for one week, 33.73% received steroids only during the hospital stay, and 1.73% were still on steroid therapy during the survey. Most importantly, of the 2038 respondents, 41.8% (851/2038) still had persistent symptoms related to COVID-19. Most common symptom was fatigue (64.15%), followed by body pain (31%) and gastrointestinal symptoms (25%) (Figure). Six percent (49/851) of them required hospitalization for post-COVID-19 symptoms. Forty-six percent (449/967) in the short term recovered group (1-3 months), 40.1% (279/696) in the long-recovered group, and 32.8% (123/375) in the recently recovered group had persistent symptoms related to COVID-19 (P=0.001). Forty-eight percent (374/770) of the hospitalized patients developed post-COVID-19 symptoms, while only 37.6% (477/1268) developed post-COVID-19 symptoms among the non-hospitalized patients (P<0.001). Fifty-three percent (303/575) of those who received steroids developed post-COVID-19 symptoms, while only 36.41% (71/195) of those who did not receive steroids developed post-COVID-19 symptoms (P<0.001). 49% (159/325) of patients who received steroids despite being not requiring oxygen developed post-COVID-19 symptoms compared to only 37.5% (543/1449) who did not receive steroids and were not on oxygen therapy (P<0.001). Nearly 40% (336/851) of respondents felt that post-COVID-19 symptoms are not being appropriately treated or taken care of seriously. Conclusions: Post-COVID-19 symptoms are common in patients who recovered from COVID-19. These symptoms are more often noted in patients who received steroid therapy. Post-COVID-19 symptomatology is present in a significant number of patients and requires to be addressed seriously.