RUI: Mathematical Modeling of Immune Response to SARS-CoV-2

这项研究调查了人类对SARS-CoV-2病毒的免疫反应，以阐明一些新冠肺炎患者表现出的导致疾病严重程度的关键机制。尽管对SARS-CoV-2病毒的详细机制进行了大量的临床和实验研究，但对宿主对该病毒的免疫反应缺乏了解，这在很大程度上导致了疾病严重程度的变化。为了加速和补充我们对免疫应答中关键靶途径的理解，本项目将开发和分析一个基本的、全面的SARS-CoV-2宿主免疫动力学模型。鉴于我们作为一个在大流行条件下继续出现新变种和推出疫苗接种的国家，通过数学建模进行的理论探索将作为基于实验室和基于数据的方法的补充。这项工作的其他特点包括学生参与这项研究，在三个机构建立一个合作伙伴网络，制定课程，从代表性较低的群体中招收学生，以及努力将研究新冠肺炎宿主免疫动力学的广泛研究人员社区聚集在一起，以增进我们对免疫系统和SARS-CoV-2之间相互作用的理解。本项目旨在完成两个具体的研究目标：(I)建立新冠肺炎宿主免疫动力学的数学模型；(Ii)探索该模型以解决与新冠肺炎治疗相关的重要问题。对于第一个目标，PI将开发和分析一个明确表示病毒、免疫细胞、细胞因子及其相互作用的数学模型，该模型在一个耦合的常微分方程组和延迟微分方程组中表达。主要目的是为了更好地了解SARS-CoV-2免疫反应的关键方面，特别是其敏感途径。对于第二个目标，PI将调查特定免疫反应的时机在疾病严重程度和不同结果中的重要性，以及所谓的细胞因子风暴的出现，即免疫系统中促炎症细胞因子的过度产生。其目的是确定导致疾病严重程度的关键机制，这可能有助于确定其他治疗靶向的途径。这个项目使用的主要工具是使用一系列临床和实验数据的模型参数化、敏感性分析和数值模拟。主要的数学贡献是发展了分析高维非线性动力系统的计算技术。此外，这项关于新冠肺炎病理机制和几个治疗靶点确定的研究结果将提供有待临床测试的假设，从而为开发循证治疗方案以应对全球挑战奠定基础。该奖项反映了美国国家科学基金会的法定使命，并已通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This research investigates the human immune response to SARS-CoV-2 virus to elucidate the key mechanisms responsible for disease severity exhibited by some COVID-19 patients. Despite a significant volume of clinical and experimental studies for the detailed mechanisms of SARS-CoV-2 virus, there is a lack of understanding about the host immune response to the virus, which is largely responsible for the variability in disease severity. To accelerate and supplement our understanding of key target pathways in the immune response, this project will develop and analyze a fundamental, comprehensive model for the host immune dynamics of SARS-CoV-2. Given we continue as a nation under pandemic conditions with new variants emerging and vaccination rollouts, the theoretical explorations through mathematical modeling will serve as a complement to lab-based and data-based approaches. Other features of this work include student involvement in this research, development of a network of collaborators across three institutions, curricula development, recruitment of students from underrepresented groups, and efforts to bring a broad community of researchers studying the host immune dynamics of COVID-19 together to advance our understanding of the interactions between the immune system and SARS-CoV-2. This project aims to accomplish two specific research goals: (i) development of a mathematical model of the host immune dynamics of COVID-19; and (ii) exploration of the model to address important COVID-19 treatment-related questions. For the first goal, the PI will develop and analyze a mathematical model that explicitly represents the virus, immune cells, cytokines, and their interactions, formulated in a system of coupled ordinary and delay differential equations. The main objective is to obtain a better understanding of key aspects of immune response to SARS-CoV-2, specifically its sensitive pathways. For the second goal, the PI will investigate the importance of timing of specific immune responses in disease severity and divergent outcomes, and the emergence of the so-called cytokine storm, excessive production of proinflammatory cytokines in the immune system. The aim is to identify the key mechanisms responsible for disease severity, which could help to identify other pathways to target therapeutically. The primary tools to be used for this project are model parameterization using a series of clinical and experimental data, sensitivity analysis, and numerical simulations. The primary mathematical contribution is the development of computational techniques to analyze high-dimensional nonlinear dynamical systems. In addition, the results from this study on the mechanisms involved in COVID-19 pathology and identification of several therapeutic targets would provide hypotheses to be clinically tested, thus, serving as a foundation for the development of evidence-based treatment protocols to address the global challenge.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.