Animal models of SARS-CoV-2 bacterial Coinfection

截至2月4日，新冠肺炎疫情已感染2600多万美国人，导致至少450,000美国人死亡 2021年。早期报告显示，混合感染可能是疾病严重程度的最大预测因素。混合病毒/细菌 肺炎是出了名的难治。研究最广泛的呼吸道混合感染是流感。 和肺炎链球菌，它们在正常呼吸过程中造成了显著的发病率和死亡率 感染季节。尽管接种了近20年的高效肺炎球菌结合物 疫苗(PCV)、肺炎链球菌(Spn或肺炎球菌)仍然是社区获得性肺炎的重要原因 肺炎、败血症和脑膜炎。许多肺炎球菌的发病率和死亡率发生在季节性和 流感大流行。尽管进行了广泛的研究，但其生理原因尚不完全清楚。 肺炎球菌致病机制的这一关键方面。抗病毒免疫变化，“激活”信号， 粘附素的促炎性上调和唾液酸的可获得性都与此有关。一般的主人 流感期间观察到的反应(发烧、强烈的炎性细胞因子谱和湿气释放)是 新冠肺炎期间重述了这一点。SPN是人类鼻咽的正常定殖者，发烧状态下 已被证明通过“激活”肺炎球菌而导致侵袭性肺炎球菌疾病。这种情况也会发生在 流感以外的呼吸道病毒，很可能在新冠肺炎相关发热期间发生，促进 继发性细菌性肺炎的发展。最近的一项单一地点研究发现，肺炎链球菌是最多的 SARS-CoV-2混合感染在SARS-CoV-2感染者中很常见，也是老年人死亡的重要来源。 尽管针对流感/Spn混合感染已经进行了很多工作，但基本上对此一无所知 SARS-CoV-2/Spn混合感染。在世界准备迎接SARS-CoV-2多波疫情之际，这一点至关重要 了解这些病原体如何相互作用促进严重疾病的重要性。 这项研究计划的长期目标是了解SARS-CoV-2与 本研究的目的是探讨SARS-CoV-2+肺炎球菌病的发病机制。 在混合感染期间的发病机制以及在适当的动物模型中建立疾病模型。最重要的是 假设是宿主对SARS-CoV-2的反应促进了侵袭性肺炎球菌病(IPD)， 最终导致疾病严重性增加，包括混合性肺炎。更具体地说，我们 假设SARS-CoV-2感染造成的炎症环境上调pIGR、PAFR、LamininR和 K-10，Spn利用粘附素促进IPD。我们进一步假设，常见的新冠肺炎疗法 可能会影响混合感染的严重程度。

The COVID-19 pandemic has infected over 26 million and killed at least 450,000 Americans as of 4 February 2021. Early reports show coinfections are possibly the greatest predictor of disease severity. Mixed viral/bacterial pneumonias are notoriously difficult to treat. The most extensively researched respiratory coinfection is influenza and Streptococcus pneumoniae, which contribute significant morbidity and mortality during normal respiratory infection seasons. Despite nearly two decades of vaccination with the highly effective pneumococcal conjugate vaccine (PCV), S. pneumoniae (Spn or the pneumococcus) remains a significant cause of community acquired pneumonia, sepsis, and meningitis. Much pneumococcal morbidity and mortality occurs during seasonal and pandemic flus. The physiological reasons for this are incompletely understood despite extensive investigation into this critical aspect of pneumococcal pathogenesis. Anti-viral immunological shifts, “activation” signals, proinflammatory upregulation of adhesins, and sialic acid availability have all been implicated. The general host responses observed during flu (fever, strong inflammatory cytokine profile, and release of DAMPS) are recapitulated during COVID-19. Spn is a normal colonizer of the human nasopharynx and a febrile state has been shown to lead to invasive pneumococcal disease by “activating” pneumococci. This also occurs with respiratory viruses other than flu and is likely to occur during COVID-19-associated fever, promoting the development of secondary bacterial pneumonia. A recent single-site study found S. pneumoniae to be the most common coinfection in SARS-CoV-2 infected individuals and a significant source of mortality in the aged. Although much work has been conducted with influenza/Spn coinfections, essentially nothing is known about SARS-CoV-2/Spn coinfections. As the world braces for multiple waves of SARS-CoV-2, it is of paramount importance to understand how these pathogens interact to promote severe disease. The long-term goal of this research program is to understand the interaction between SARS-CoV-2 and the pneumococcus; the objective here is to investigate the mechanisms of SARS-CoV-2 + pneumococcal disease pathogenesis during mixed infections and to model disease in appropriate animal models. The overarching hypothesis is that the host response to SARS-CoV-2 promotes invasive pneumococcal disease (IPD), ultimately resulting in increased disease severity including mixed pneumonia. More specifically, we hypothesize the inflammatory milieu created by SARS-CoV-2 infection upregulates pIGr, PafR, LamininR, and K-10, adhesins utilized by Spn to facilitate IPD. We further hypothesize that common COVID-19 treatments could impact the severity of coinfection.