The SARS-CoV-2 pandemic poses an unprecedented public health crisis. Evidence suggests that SARS-CoV-2 infection causes dysregulation of the immune system. However, the unique signature of early immune responses remains elusive. We characterized the transcriptome of rhesus macaques and mice infected with SARS-CoV-2. Alarmin S100A8 was robustly induced in SARS-CoV-2 infected animal models as well as in COVID-19 patients. Paquinimod, a specific inhibitor of S100A8/A9, could rescue the pneumonia with substantial reduction of viral loads in SARS-CoV-2 infected mice. Remarkably, Paquinimod treatment resulted in almost 100% survival in a lethal model of mouse coronavirus infection using the mouse hepatitis virus (MHV). A group of neutrophils that contributes to the uncontrolled pathological damage and onset of COVID-19 were dramatically induced by coronavirus infection. Paquinimod treatment could reduce these neutrophils and regain antiviral responses, unveiling key roles of S100A8/A9 and aberrant neutrophils in the pathogenesis of COVID-19, highlighting new opportunities for therapeutic intervention.
Highlights d The nuclear matrix protein SAFA is required for antiviral immunity in cells and mice d SAFA directly senses viral RNA in the nucleus d SAFA facilitates antiviral immunity through interacting with chromatin remodelers d Oligomerized SAFA mediates IFNB1 transcription by activating its distal enhancers
Emerging and re-emerging zoonoses are a significant public health concern and cause considerable socioeconomic problems globally. The emergence of severe acute respiratory syndrome (SARS), highly pathogenic avian influenza (HPAI) H5N1, avian influenza H7N9, and severe fever with thrombocytopenia syndrome (SFTS), and the re-emergence of rabies, brucellosis, and other zoonoses have had a significant effect on the national economy and public health in China, and have affected other countries. Contributing factors that continue to affect emerging and re-emerging zoonoses in China include social and environmental factors and microbial evolution, such as population growth, urbanization, deforestation, livestock production, food safety, climate change, and pathogen mutation. The Chinese government has devised new strategies and has taken measures to deal with the challenges of these diseases, including the issuing of laws and regulations, establishment of disease reporting systems, implementation of special projects for major infectious diseases, interdisciplinary and international cooperation, exotic disease surveillance, and health education. These strategies and measures can serve as models for the surveillance and response to continuing threats from emerging and re-emerging zoonoses in other countries.
Combination therapy can be used for the treatment of fungal infections, especially for those caused by antifungal-resistant fungi. In the present study, in vitro interactions and mechanisms between fluconazole and minocycline against Candida albicans were evaluated. The nature of the interactions determined by spectrophotometric method in a checkerboard assay was interpreted using nonparametric models of fractional inhibitory concentration index (FICI) and percentages of growth difference (ΔE). In the mechanism study, we evaluated the potential activity of minocycline on fluconazole penetrating the C. albicans biofilm. Furthermore, the effect of fluconazole and minocycline alone and in combination on the cellular calcium balance, as well as on the uptake and efflux of fluconazole were evaluated. It was found that fluconazole can work synergistically with minocycline against fluconazole-resistant C. albicans; the minimum inhibitory concentration of fluconazole decreased from 512 to 2 microgmL(-1) when fluconazole and minocycline were given in combination, with an FICI of 0.035 and 0.064 and high-percentage synergistic interactions of 1250% and 988% for the two resistant strains. The mechanism of action was suggested to be the enhancement of minocycline on fluconazole penetrating biofilm, and inducing the intracellular calcium release, instead of impacting on the uptake and efflux of fluconazole. Our results suggest that the combination of fluconazole and minocycline can reduce the fluconazole resistance of C. albicans in vitro.
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