RLR-mediated type I IFN production plays a pivotal role in elevating host immunity for viral clearance and cancer immune surveillance. Here, we report that glycolysis, which is inactivated during RLR activation, serves as a barrier to impede type I IFN production upon RLR activation. RLR-triggered MAVS-RIG-I recognition hijacks hexokinase binding to MAVS, leading to the impairment of hexokinase mitochondria localization and activation. Lactate serves as a key metabolite responsible for glycolysis-mediated RLR signaling inhibition by directly binding to MAVS transmembrane (TM) domain and preventing MAVS aggregation. Notably, lactate restoration reverses increased IFN production caused by lactate deficiency. Using pharmacological and genetic approaches, we show that lactate reduction by lactate dehydrogenase A (LDHA) inactivation heightens type I IFN production to protect mice from viral infection. Our study establishes a critical role of glycolysis-derived lactate in limiting RLR signaling and identifies MAVS as a direct sensor of lactate, which functions to connect energy metabolism and innate immunity.

The coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now spread to >200 countries posing a global public health concern. Patients with comorbidity, such as hypertension suffer more severe infection with elevated mortality. The development of effective antiviral drugs is in urgent need to treat COVID-19 patients. Here, we report that calcium channel blockers (CCBs), a type of antihypertensive drug that is widely used in clinics, inhibited the post-entry replication events of SARS-CoV-2 in vitro, while no in vitro anti-SARS-CoV-2 effect was observed for the two other major types of antihypertensive drugs, namely, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. CCB combined with chloroquine showed a significantly enhanced anti-SARS-CoV-2 efficacy. A retrospective clinical investigation on hospitalized COVID-19 patients with hypertension as the only comorbidity revealed that the CCB amlodipine besylate therapy was associated with a decreased case fatality rate. The results from this study suggest that CCB administration to COVID-19 patients with hypertension as the comorbidity might improve the disease outcome.

The variations and dynamics of essential and toxic metal(loid)s in patients with COVID-19 may associate with the progression and fatal outcome of the disease, which still remains to investigate. In the present study, a retrospective analysis was performed in a cohort of 306 confirmed COVID-19 patients admitted to Tongji hospital (Wuhan, China) from February 10 to March 15, 2020. Whole blood levels of essential and/or toxic metal(loid)s were analyzed, including magnesium, calcium, chromium, manganese, iron, copper, zinc, arsenic, cadmium, mercury, thallium, and lead according to the disease severity and outcome. Compared to the non-severe COVID-19 patients, severe cases showed significant higher levels of whole blood calcium, chromium, and copper, but lower levels of magnesium, manganese, iron, zinc, arsenic, thallium, and lead. These differences were further found consistently across the clinical course since the disease onset by longitudinal analysis. Among the severe patients, chromium and cadmium were higher in the deceased group compared to the recovered group, while arsenic was lower. Whole blood iron, age, and sex were determined to be independent factors associated with the disease severity, while chromium, cadmium, and the comorbidity of cardiovascular disease were determined to be independent factors associated with the mortality. These results suggest that variations of whole blood metal(loid)s may be associated with the severe illness and fatal outcome of COVID-19, which could be persistently monitored and would be helpful in the evaluation of the dynamic changes in patients with COVID-19.

Up to 10–20% of patients with coronavirus disease 2019 (COVID‐19) develop a severe pulmonary disease due to immune dysfunction and cytokine dysregulation. However, the extracellular proteomic characteristics in respiratory tract of these critical COVID‐19 patients still remain to be investigated. In the present study, we performed a quantitative proteomic analysis of the bronchoalveolar lavage fluid (BALF) from patients with critical COVID‐19 and from non‐COVID‐19 controls. Our study identified 358 differentially expressed BALF proteins (P < 0.05), among which 41 were significantly changed after using the Benjamini–Hochberg correction (q < 0.05). The up‐regulated signaling was found to be mainly involved in inflammatory signaling and response to oxidative stress. A series of increased extracellular factors including Tenascin‐C (TNC), Mucin‐1 (KL‐6 or MUC1), Lipocalin‐2 (LCN2), periostin (POSTN), Chitinase 3‐like 1 (CHI3L1 or YKL40), and S100A12, and the antigens including lymphocyte antigen 6D/E48 antigen (LY6D), CD9 antigen, CD177 antigen, and prostate stem cell antigen (PSCA) were identified, among which the proinflammatory factors TNC and KL‐6 were further validated in serum of another thirty‐nine COVID‐19 patients and healthy controls, showing high potentials of being biomarkers or therapeutic candidates for COVID‐19. This BALF proteome associated with COVID‐19 would also be a valuable resource for researches on anti‐inflammatory medication and understanding the molecular mechanisms of host response. Database Proteomic raw data are available in ProteomeXchange (http://proteomecentral.proteomexchange.org) under the accession number PXD022085, and in iProX (http://www.iprox.org) under the accession number IPX0002429000.

Antibody-dependent cellular cytotoxicity (ADCC) responses to viral infection are a form of antibody regulated immune responses mediated through the Fc fragment. Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered ADCC responses contributes to COVID-19 disease development is currently not well understood. To understand the potential correlation between ADCC responses and COVID-19 disease development, we analyzed the ADCC activity and neutralizing antibody response in 255 individuals ranging from asymptomatic to fatal infections over 1 year post disease. ADCC was elicited by 10 days post-infection, peaked by 11–20 days, and remained detectable until 400 days post-infection. In general, patients with severe disease had higher ADCC activities. Notably, patients who had severe disease and recovered had higher ADCC activities than patients who had severe disease and deceased. Importantly, ADCC activities were mediated by a diversity of epitopes in SARS-COV-2-infected mice and induced to comparable levels against SARS-CoV-2 variants of concern (VOCs) (B.1.1.7, B.1.351, and P.1) as that against the D614G mutant in human patients and vaccinated mice. Our study indicates anti-SARS-CoV-2 ADCC as a major trait of COVID-19 patients with various conditions, which can be applied to estimate the extra-neutralization level against COVID-19, especially lethal COVID-19.

Background The dynamics of urinary trace elements in patients with COVID-19 still remains to be investigated. Methods A retrospective study was performed on a cohort of 138 confirmed COVID-19 patients for their urinary levels of essential and/or toxic metals including chromium, manganese, copper, arsenic, selenium, cadmium, mercury, thallium and lead according to the different disease severity (severe or non-severe) and outcome (recovered or deceased). Results Urinary concentrations of chromium, manganese, copper, selenium, cadmium, mercury and lead after creatinine adjustment were found to be higher in severe patients than the non-severe cases with COVID-19. And among the severe cases, these elements were also higher in the deceased group than the recovered group. When the weeks of the post-symptom onset were taken in account, the changes of these urinary elements were existed across the clinical course since the disease onset. These urinary elements were found to be mostly positively inter-correlated, and further positively correlated with other laboratory inflammatory parameters including serum cytokines (IL-1B, IL2R, IL6, IL8, IL10, TNFα), ferritin, and neutrophil count and white blood cell count. As a independently predictive factor, urinary creatinine-adjusted copper of ≥ 25.57 μg/g and ≥ 99.32 μg/g were associated with significantly increased risk of severe illness and fatal outcome in COVID-19, respectively. Conclusions These results suggest abnormities in urinary levels of the trace metals were tightly associated with the severe illness and fatal outcome of COVID-19.

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There is ample evidence indicating that epicardial adipose tissue (EAT) volume and thickness is positively associated with coronary artery disease (CAD). However, the exact pathological changes in the human EAT after myocardial ischemia remains largely unclear. In the current study, we applied a comparative quantitative proteomics to elucidate the altered biological processes in the EAT of ischemic cardiomyopathy (ICM) patients. A total of 1649 proteins were successfully quantified in our study, among which 165 proteins were significantly changed (ratio <0.8 or >1.2 fold and p < 0.05 in both repetitions) in EAT of ICM individuals. Gene ontology (GO) enrichment analysis revealed that cardiac structure and cellular metabolism were over-represented among these regulated proteins. The hypertrophic cardiomyopathy, adrenergic signaling in cardiomyocytes, extracellular matrix (ECM)-receptor interaction, phagosome, Glycolysis/Gluconeogenesis, and PPAR signaling pathway were highlighted by the KEGG PATHWAY analysis. More importantly, we found that the proteins responsible for extracellular matrix organization were dramatically increased in EAT of ICM patients. In addition, the picrosirius red (PSR) staining results showed that the collagen fiber content was prominently increased, which indicated the EAT of ICM individuals underwent extracellular matrix remodeling and ERK1/2 activation maybe responsible for these pathological changes partially.