Correlation Between Early Plasma Interleukin 37 Responses With Low Inflammatory Cytokine Levels and Benign Clinical Outcomes in Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

BACKGROUND: The immune protective mechanisms during severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection remain to be deciphered for the development of an effective intervention approach. METHODS: We examined early responses of interleukin 37 (IL-37), a powerful anti-inflammatory cytokine, in 254 SARS-CoV-2-infected patients before any clinical intervention and determined its correlation with clinical prognosis. RESULTS: Our results demonstrated that SARS-CoV-2 infection causes elevation of plasma IL-37. Higher early IL-37 responses were correlated with earlier viral RNA negative conversion, chest computed tomographic improvement, and cough relief, consequently resulted in earlier hospital discharge. Further assays showed that higher IL-37 was associated with lower interleukin 6 and interleukin 8 (IL-8) and higher interferon α responses and facilitated biochemical homeostasis. Low IL-37 responses predicted severe clinical prognosis in combination with IL-8 and C-reactive protein. In addition, we observed that IL-37 administration was able to attenuate lung inflammation and alleviate respiratory tissue damage in human angiotensin-converting enzyme 2-transgenic mice infected with SARS-CoV-2. CONCLUSIONS: Overall, we found that IL-37 plays a protective role by antagonizing inflammatory responses while retaining type I interferon, thereby maintaining the functionalities of vital organs. IL-37, IL-8, and C-reactive protein might be formulated as a precise prediction model for screening severe clinical cases and have good value in clinical practice.

Virtual Screening of Potential AEC2 Inhibitors for COVID-19 from Traditional Chinese Medicine (preprint)

Background: Angiotensin-converting enzyme 2 (ACE2), a negative regulator of the renin-angiotensin system and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor, plays an important role in viral genome replication and immune response. ACE2 has been proposed as a potential therapeutic target. Traditional Chinese medicine (TCM) could be considered as a promising complementary therapeutic option in the management of COVID-19. However, the active components and action mechanisms that account for its therapeutic effects remain controversial. Methods: ACE2 was employed as a target related to COVID-19 to explore the active ingredients from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. And the PharmMapper database and TCMSP database were used to predict the targets of the compounds. Moreover, the potential therapeutic targets of COVID-19 were acquired by intersection among genes differentially expressed in COVID-19 patients, genes screened from five public databases and genes targeted by active compounds. Finally, molecular docking verification and function analysis were performed.Results: In this study, puerarin, the common active compound for targeting ACE2 across the five TCMs (Radix Cyathulae, Flos Puerariac, Radix Bupleuri, Radix Puerariac and Radix Hemerocallis), was found. Due to the comprehensive analysis, we revealed that puerarin might prevent the entrance of SARS-CoV-2 entry into cells by blocking ACE2, chiefly modulated the T cell immunity and regulate pro-inflammatory cytokine response by affecting TNF, STAT1 and RNASE3. Conclusion: Taken together, the present study found that puerarin might have a therapeutic effect on COVID-19 through regulation of the immune system, inhibition of inflammation and prevention of virus entry into cells.

Integrative Bioinformatics Analysis Provides Insight into the Molecular Mechanisms of 2019-nCoV (preprint)

The 2019-nCoV is reported to share the same entry (ACE2) as SARS-CoV according to the updated findings. Analyzing the distribution and expression level of the route of coronavirus may help reveal underlying mechanisms of viral susceptibility and post-infection modulation. In this study, we found that the expression of ACE2 in healthy populations and patients with underlying diseases was not significantly different, suggesting relatively similar susceptibility, which was consistent with current clinical observations. Moreover, based on the expression of ACE2 in smoking individuals, we inferred that long-term smoking might be a risk factor for 2019-nCoV. Analyzing the ACE2 in SARS-CoV infected cells suggested that ACE2 was more than just a receptor but also participated in post-infection regulation, including immune response, cytokine secretion, and viral genome replication. We also constructed Protein-protein interaction (PPI) networks and identified hub genes in viral activity and cytokine secretion. Our findings could explain the clinical symptoms so far and help clinicians and researchers understand the pathogenesis and design therapeutic strategies for 2019-nCoV.