Animal models of SARS-CoV-2 bacterial Coinfection

截至2月4日，COVID-19大流行已感染超过2600万美国人，并造成至少45万美国人死亡 2021.早期报告显示，合并感染可能是疾病严重程度的最大预测因素。混合病毒/细菌 众所周知，肺炎很难治疗。研究最广泛的呼吸道合并感染是流感 和肺炎链球菌，其在正常呼吸道疾病中造成显著的发病率和死亡率。 感染季节尽管使用高效肺炎球菌结合物进行了近二十年的疫苗接种， 疫苗（PCV）、S.肺炎球菌（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 流行性流感尽管进行了广泛的调查，但其生理原因仍不完全清楚 肺炎球菌发病机制的关键方面。抗病毒免疫转变，“激活”信号， 粘附素的促炎性上调和唾液酸可用性都与此有关。一般主持人 流感期间观察到的反应（发热、强烈的炎性细胞因子谱和DAMPS的释放）是 在COVID-19期间重演。Spn是人鼻咽部的正常定植者， 已被证明通过“激活”肺炎球菌而导致侵袭性肺炎球菌疾病。这也发生在 流感以外的呼吸道病毒，并可能在COVID-19相关发热期间发生，促进 继发性细菌性肺炎。最近的一项单点研究发现，S。肺炎是最 在SARS-CoV-2感染者中常见合并感染，是老年人死亡的重要来源。 虽然已经对流感/Spn合并感染进行了大量工作，但基本上对 SARS-CoV-2/Spn合并感染。随着世界为SARS-CoV-2的多波浪潮做好准备， 重要的是要了解这些病原体如何相互作用，以促进严重的疾病。 这项研究计划的长期目标是了解SARS-CoV-2与 肺炎球菌;这里的目的是研究SARS-CoV-2 +肺炎球菌疾病的机制 在混合感染期间的发病机制和在适当的动物模型中对疾病建模。总体 假设宿主对SARS-CoV-2的反应促进了侵袭性肺炎球菌病（IPD）， 最终导致包括混合性肺炎在内的疾病严重程度增加。更具体地说，我们 假设SARS-CoV-2感染产生的炎症环境上调pIGr、PafR、层粘连蛋白R和 K-10，由Spn利用以促进IPD的粘附素。我们进一步假设，常见的COVID-19治疗 可能会影响合并感染的严重程度

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.