Role of Diabetes in MERS Coronavirus Pathogenesis

糖尿病在 MERS 冠状病毒发病机制中的作用

• 批准号: 10649491
• 负责人: Matthew Bryan Frieman
• 金额: $ 55.08万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-16 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10649491
• 关键词: Alveolar; Alveolar Cell; Alveolus; Animal Model; Antiviral Agents; Antiviral Therapy; Architecture; Carbohydrates; Case Fatality Rates; Case Study; Cell surface; Cells; Cessation of life; Clinical; Complex Mixtures; Coronavirus; Coronavirus Infections; Data; Diabetes Mellitus; Diabetic mouse; Diet; Disease; Disease Outbreaks; Disease Outcome; Effectiveness; Exhibits; Future; Goals; Health Personnel; Heart Diseases; High Fat Diet; Human; Immune; Immune response; Immunosuppression; Infection; Infiltration; Inflammatory; Innate Immune Response; Kidney Failure; Kinetics; Knowledge; Lead; Link; Lung; Lung diseases; Middle East Respiratory Syndrome; Middle East Respiratory Syndrome Coronavirus; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mucous Membrane; Mucous body substance; Mus; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Persons; Poly I-C; Predisposition; Production; Proteins; Public Health; Pulmonary Inflammation; Respiratory System; Respiratory Tract Infections; Risk; Role; Saudi Arabia; South Korea; Structure; Surface; Therapeutic; Treatment Efficacy; Vaccines; Virus; Virus Diseases; Work; anti-viral efficacy; chemokine; comorbidity; comparative; cytokine; diabetic; diabetic patient; effective therapy; experimental study; in vivo; influenza virus vaccine; microbial; mortality; mouse model; novel; novel coronavirus; particle; pathogen; permissiveness; receptor; respiratory infection virus; respiratory virus; response; targeted treatment; therapeutically effective

Project summary: Here we seek to identify the role of diabetes in Middle East Respiratory Syndrome Coronavirus (MERS-CoV) pathogenesis. MERS-CoV emerged in 2012 in Saudi Arabia leading to over 2200 infections with a ~35% case fatality rate. The majority of lethal MERS-CoV infections are associated with a comorbidity, with diabetes as the top comorbidity. We have found that MERS-CoV pathogenesis is exacerbated in a mouse with pre-existing diabetes. We will determine the mechanism for this enhanced disease by determining the role of the changes in lung architecture, and immune response. In Aim1 we will determine whether accessibility of the Type 2 alveolar cells, the target cells for MERS-CoV in the alveoli, is increased in diabetic mice compared to normal mice. Our data suggests that at the earliest points of infection, the alveoli are highly susceptible to MERS- CoV but normal mouse Type 2 alveolar cells are not. We will evaluate the mucus and architecture of the lungs to determine if there is a difference that could explain the differential infection. In Aim 2, we will determine if the immune response in diabetic mice is different than normal mice. A difference in the immune response, especially innate immune response, could explain the susceptibility differences in diabetic and normal mice. In Aim 3 we will determine whether therapeutics that are effective in normal mice are deficient in diabetic mice with the goal of altering those therapeutics in the future for more effective therapies for comorbid patients. Together this proposal will determine why diabetic mice and potentially humans are highly susceptible to MERS-CoV.

项目概要： 在这里，我们试图确定糖尿病在中东呼吸综合征冠状病毒中的作用 （MERS-CoV）发病机制。中东呼吸综合征冠状病毒出现在2012年在沙特阿拉伯导致超过2200 感染，病死率约为35%。大多数致命的MERS-CoV感染与 糖尿病是最常见的合并症。我们发现中东呼吸综合征病毒 发病机制在预先存在糖尿病的小鼠中加剧。康贝特人将以 通过确定肺结构变化的作用， 和免疫反应。在目标1中，我们将确定2型肺泡细胞的可及性， 与正常小鼠相比，糖尿病小鼠肺泡中MERS-CoV的靶细胞增加。 我们的数据表明，在感染的最早阶段，肺泡对MERS非常敏感- 但正常小鼠2型肺泡细胞不是。我们将评估其粘液和结构， 以确定是否有差异可以解释差异性感染。在目标2中， 将确定糖尿病小鼠的免疫反应是否与正常小鼠不同。的差异 免疫反应，特别是先天免疫反应，可以解释易感性差异 在糖尿病和正常小鼠中。在目标3中，我们将确定是否有效的治疗方法， 正常小鼠在糖尿病小鼠中缺乏，目的是在未来改变这些治疗方法， 更有效的治疗方法。这一建议将共同确定为什么糖尿病 小鼠和潜在的人类对MERS-CoV高度易感。

项目成果

CNP blocks mitochondrial depolarization and inhibits SARS-CoV-2 replication in vitro and in vivo.

CNP 可阻断线粒体去极化，并在体外和体内抑制 SARS-CoV-2 复制。

• DOI: 10.1101/2023.06.09.544327
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Logue,James;Melville,VictoriaM;Ardanuy,Jeremy;Frieman,MatthewB
• 通讯作者: Frieman,MatthewB

An aluminum hydroxide:CpG adjuvant enhances protection elicited by a SARS-CoV-2 receptor binding domain vaccine in aged mice.

• DOI: 10.1126/scitranslmed.abj5305
• 发表时间: 2022-01-26
• 期刊: Science translational medicine
• 影响因子: 17.1

mRNA booster vaccination protects aged mice against the SARS-CoV-2 Omicron variant.

• DOI: 10.1038/s42003-022-03765-3
• 发表时间: 2022-08-06
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Nanishi, Etsuro;McGrath, Marisa E.;O'Meara, Timothy R.;Barman, Soumik;Yu, Jingyou;Wan, Huahua;Dillen, Carly A.;Menon, Manisha;Seo, Hyuk-Soo;Song, Kijun;Xu, Andrew Z.;Sebastian, Luke;Brook, Byron;Bosco, Anna-Nicole;Borriello, Francesco;Ernst, Robert K.;Barouch, Dan H.;Dhe-Paganon, Sirano;Levy, Ofer;Frieman, Matthew B.;Dowling, David J.
• 通讯作者: Dowling, David J.