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

COVID-19：合并感染的作用以及重新利用药物进行治疗

• 批准号: BB/V006576/1
• 负责人: Jose Bengoechea
• 金额: $ 61.9万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV006576%2F1
• 关键词: COVID; 19; role; co; infections

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.

临床研究报告称，至少 20% 的 Covid-19 患者存在双重感染。这个数字可能被低估，因为 ICU 机械通气导致高达 75% 的患者发展为院内肺炎。此外，对死于重症 COVID-19 的患者进行尸检肺活检的病理分析显示，组织病理学结果与某些患者合并细菌性肺炎一致。令人担忧的是，这种情况发生在针对这些感染的抗生素库有限的情况下。对于共同感染对 SARS-CoV-2 诱导的病理生理学的影响尚不清楚。目前尚不清楚 SARS-CoV-2 感染是否可能影响医院感染的病理生理学。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库有限的情况下。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）之间的相互作用：分化良好的原代人气道上皮细胞培养物 (WD-PAEC)、人类气道上皮的优秀替代物 体内和PBMCs，反映了人体免疫系统的复杂性。单细胞 RNA seq 和多重单细胞质谱流式分析 (CyTOF) 将揭示与感染相关的细胞类型特异性免疫途径。这些反应可能适合治疗操作。细胞发病机制、共同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。通过确定暴露细菌的转录组，并研究 WD-PAEC 和 PMBC 感染后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 批准的影响宿主与病原体相互作用的药物，以识别在共感染界面中针对 SARS-CoV-2 的药物。这些药物应被视为进入临床试验的新疗法。