COVID-19: role of co-infections, and drug repurposing for treament

临床研究报告了至少20%的Covid-19患者合并感染。这一数字可能被低估，因为ICU机械通气导致高达75%的患者发生院内肺炎。此外，对死于严重COVID-19的患者的尸检肺活检的病理学分析显示，一些患者的组织病理学发现与叠加的细菌性肺炎一致。令人担忧的是，这种情况发生在针对这些感染的抗生素有限的情况下，对SARS-CoV-2诱导的病理生理学中合并感染的影响一无所知。SARS-CoV-2感染是否会影响医院感染的病理生理也是未知的。如果我们要开发治疗方法，解决这一知识差距至关重要;否则，治疗可能会从一种感染到另一种感染。这种情况发生在针对医院感染的抗生素有限的情况下。我们将通过利用相关的转化研究模型来研究SARS-CoV-2和细菌感染（肺炎克雷伯氏菌、铜绿假单胞菌、鲍曼不动杆菌和金黄色葡萄球菌）之间的界面：良好分化的原代人气道上皮细胞培养物（WD-PAECs）、体内人气道上皮的优秀替代物和PBMC，反映了人类免疫系统的复杂性。单细胞RNA测序和多路单细胞质谱仪（CyTOF）将揭示与感染相关的细胞类型特异性免疫途径。这些反应可能适用于治疗操作。细胞病变、合并感染中的病毒和细菌复制以及细胞因子/趋化因子将是额外的读数。SARS-CoV-2和细菌对彼此毒力的影响将通过确定暴露细菌的转录组，并研究感染WD-PAEC和PMBC后的病毒和细菌感染参数来分析。我们将筛选一组FDA批准的影响宿主-病原体相互作用的药物，以确定在合并感染界面中针对SARS-CoV-2的药物。这些药物应被视为进入临床试验的新疗法。

Clinical studies have reported co-infections in at least 20% of Covid-19 patients. This figure is likely underestimated because ICU mechanical ventilation results in up to 75% of patients developing nosocomial pneumonia. Moreover, pathological analysis of post-mortem biopsies of lung from patients who died of severe COVID-19 revealed histopathologic findings consistent with superimposed bacterial pneumonia in some patients. Alarmingly, this occurs in a scenario of a limited arsenal of antibiotics to target these infections.Nothing is known on the effect of co-infections in SARS-CoV-2-induced pathophysiology. It is also unknown whether SARS-CoV-2 infection may affect the pathophysiology of nosocomial infections. Addressing this knowledge gap is critical if we are to develop therapeutics; otherwise, treatments may tip the balance from one infection to the other. This happens in a scenario of a limited arsenal of antibiotics to target nosocomial infections. We will investigate the interface between SARS-CoV-2 and bacterial infections (Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii and Staphylococcus aureus) by exploiting relevant translational research models: well-differentiated primary human airway epithelial cell cultures (WD-PAECs), excellent surrogates of human airway epithelium in vivo, and PBMCs, reflecting the complexity of the human immune system. Single-cell RNA seq and multiplexed single-cell mass cytometry (CyTOF) will reveal cell-type specific immune pathways associated with the infections. These responses might be suitable for therapeutic manipulation. Cytopathogenesis, viral and bacterial replication in co-infection, and cytokines/chemokines will be additional read-outs. The effect of SARS-CoV-2 and bacteria on each other's virulence will be analysed by determining the transcriptome of exposed bacteria, and investigating viral and bacterial infection parameters upon infection of WD-PAECs and PMBCs. We will screen a panel of FDA-approved drugs affecting host-pathogen interactions to identify drugs against SARS-CoV-2 in the co-infection interface. These drugs shall be considered as new therapeutics entering clinical trials.