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

临床研究报告称，至少20%的Covid-19患者存在合并感染。这一数字可能被低估了，因为ICU机械通气导致高达75%的患者发生院内肺炎。此外，对COVID-19重症死亡患者的尸检活检病理分析显示，部分患者的组织病理学结果与叠加性细菌性肺炎一致。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。在sars - cov -2诱导的病理生理中，合并感染的影响尚不清楚。SARS-CoV-2感染是否会影响医院感染的病理生理尚不清楚。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，治疗可能会使平衡从一种感染转向另一种感染。这种情况发生在针对医院感染的抗生素有限的情况下。我们将研究SARS-CoV-2与细菌感染（肺炎克雷伯菌、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，通过相关的转化研究模型：高分化的原代人气道上皮细胞培养物（pd - paecs）、体内优秀的人气道上皮代物和PBMCs，反映了人类免疫系统的复杂性。单细胞RNA测序和多重单细胞细胞计数（CyTOF）将揭示与感染相关的细胞类型特异性免疫途径。这些反应可能适合于治疗性操作。细胞病变，病毒和细菌在共感染中的复制，细胞因子/趋化因子将是额外的读出。将通过测定暴露细菌的转录组，以及研究感染WD-PAECs和pmbc时的病毒和细菌感染参数，分析SARS-CoV-2和细菌对彼此毒力的影响。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，以确定在共感染界面中针对SARS-CoV-2的药物。这些药物应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.