Impacts of SARS-CoV-2 Infection and Age on Musculoskeletal Health

SARS-CoV-2 感染和年龄对肌肉骨骼健康的影响

• 批准号: 10707001
• 负责人: Olatundun Dupe Awosanya
• 金额: $ 4.02万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707001
• 关键词: 2019-nCoV; Age; Age Months; Area; Autopsy; Blood Platelets; Body Weight; Bone Marrow; Bone Resorption; Brain; COVID-19; COVID-19 complications; COVID-19 impact; COVID-19 pandemic; COVID-19 patient; COVID-19 severity; CXCL10 gene; Cardiac; Cells; Cessation of life; Clinical; Conditioned Culture Media; Contracts; Data; Disease; Disease model; Dose; Elderly; Epidemic; Euthanasia; Exhibits; Femur; General Population; Goals; Growth Factor; Health; Heart; Histologic; Homeostasis; Human body; IL17 gene; Infection; Inflammatory; Interleukin-1 beta; Interleukin-6; K-18 conjugate; Laboratories; Lead; Light; Lung; Megakaryocytes; Monitor; Mus; Musculoskeletal; Musculoskeletal System; OSTF1 gene; Organ; Osteitis; Osteoclasts; Osteoporosis; Patients; Platelet Count measurement; Population; Posture; Predisposition; Reporting; SARS-CoV-2 infection; SARS-CoV-2 negative; Serum; Severities; Severity of illness; Skeleton; Surface; System; TNF gene; TNFSF11 gene; Testing; Thrombophilia; Thrombopoietin; Thrombus; Time; Titrations; Transgenic Mice; Vaccines; Viral Load result; aged; aging population; body system; bone; bone loss; bone mass; bone metabolism; bone turnover; cohort; combat; cytokine; cytokine release syndrome; experience; high risk; mortality; mouse model; osteoclast progenitor; post SARS-CoV-2 infection; severe COVID-19; skeletal; substantia spongiosa; treatment strategy

PROJECT SUMMARY/ABSTRACT The Coronavirus Disease 2019 (COVID-19) pandemic as of June 14, 2021, has totaled 176.02 million cases, 3.80 million deaths, and 2.37 billion vaccine doses have been administered globally. However, many have suffered prior to the vaccine and have survived or will still suffer without the vaccine. Therefore, determining the possible long-term health ramifications post-infection, how they vary based on age at the time of infection, and whether disease severity differentially impacts long-term health is imperative. Information on how COVID-19 affects bone metabolism and homeostasis is limited. This is of crucial concern because the aging population generally has higher bone loss and are at the highest risk of developing severe COVID-19 infection. The objective of the current application is to determine whether long-term deficits in bone mass are experienced following SARS-CoV-2 infection. The long-term goal is to develop potential treatment strategies to combat COVID-19 related bone loss. Preliminary studies showed that in a K18-hACE2 mouse model of COVID-19, surviving mice infected with 1x103 or 1x104 PFU exhibited up to a 24% reduction in trabecular bone volume fraction just 2 weeks post infection (p<0.001). Infected mice had a 63% increase in osteoclast numbers (p<0.0002) and a 30% increase in surface occupied by osteoclasts (p<0.02) compared to non-infected controls. Additionally, mice infected with any dose of SARS-CoV-2 had a 40% increase in megakaryocytes (MKs) within their femoral bone marrow compared to that observed in mock-infected controls (p<0.008). Further, previously conducted studies showed that MKs regulate bone mass and osteoclast (OC) formation (aged MKs increase OCs and have increased RANKL expression). Moreover, patients with severe forms of COVID-19 have upregulated expression of numerous cytokines and growth factors which is known as an inflammatory cytokine storm. Many of these cytokines, including IL-6 and TNF-α, are known to regulate OCs and/or MKs and may be responsible for the bone loss observed in the preliminary studies. Based on these observations it is hypothesized that i) SARS-CoV-2 infection results in long-term health complications in the musculoskeletal system, and ii) SARS-CoV-2 infection and the associated cytokine storm increases MK- stimulated OC formation. To test this hypothesis, two specific aims will be pursued: 1- determine whether following SARS-CoV-2 infection the bone loss observed remains over time and whether age at the time of infection impacts the severity of bone loss induced by SARS-CoV-2 infection, and: 2- investigate the mechanisms by which OC formation and bone resorption are increased as a consequence of SARS-CoV-2 infection and age, including the extent to which MKs from infected mice induce OC formation and bone resorption. The successful completion of these studies will deepen the understanding of the health implications post-infection with SARS-COV-2 and will demonstrate how disease severity, age, and MKs influence skeletal homeostasis as well as OC formation and resorption.

项目总结/摘要 截至2021年6月14日，2019年冠状病毒病（COVID-19）大流行已累计17602万人 在全球范围内，有380万例死亡，23.7亿剂疫苗接种。但不少 在接种疫苗之前已经遭受痛苦，并且在没有接种疫苗的情况下幸存或仍然会遭受痛苦。因此，我们认为， 确定感染后可能的长期健康后果，以及它们如何根据当时的年龄变化 感染的风险，以及疾病的严重程度是否对长期健康产生不同的影响，都是至关重要的。信息 COVID-19如何影响骨代谢和体内平衡是有限的。这一点至关重要，因为 老龄化人口通常有更高的骨质流失，并且处于发展严重COVID-19的最高风险 感染本申请的目的是确定骨量的长期缺乏是否 在感染SARS-CoV-2后出现。长期目标是开发潜在的治疗方法 应对COVID-19相关骨质流失的策略。初步研究表明，在K18-hACE 2小鼠中， 在COVID-19模型中，感染1x 103或1x 104 PFU的存活小鼠表现出高达24%的减少， 感染后2周骨小梁体积分数（p<0.001）。受感染的小鼠的免疫力增加了63%， 破骨细胞数量（p<0.0002）和破骨细胞占据的表面增加30%（p<0.02）， 未感染的对照组。此外，感染任何剂量SARS-CoV-2的小鼠， 与模拟感染对照组中观察到的相比， （p<0.008）。此外，先前进行的研究表明，MK调节骨量和破骨细胞（OC） 形成（老化的MK增加OC并增加RANKL表达）。此外，严重的 COVID-19的形式上调了许多细胞因子和生长因子的表达， 炎症细胞因子风暴已知许多这些细胞因子，包括IL-6和TNF-α， OC和/或MK，可能导致初步研究中观察到的骨丢失。基于 根据这些观察，假设i）SARS-CoV-2感染导致长期健康并发症， 肌肉骨骼系统，和ii）SARS-CoV-2感染和相关的细胞因子风暴增加MK- 刺激OC形成。为了检验这一假设，将追求两个具体目标：1-确定是否 在SARS-CoV-2感染后，观察到的骨丢失随着时间的推移而保持不变， 感染影响由SARS-CoV-2感染引起的骨丢失的严重程度，并且：2-研究 SARS-CoV-2导致OC形成和骨吸收增加的机制 感染和年龄，包括感染小鼠的MK诱导OC形成和骨形成的程度。 再吸收这些研究的成功完成将加深对健康影响的理解 并将展示疾病的严重程度，年龄和MK如何影响骨骼 体内平衡以及OC形成和再吸收。