Gazeau Sonia T, Deng Xiaoyan, Brunet-Ratnasingham Elsa, Kaufmann Daniel E, Larochelle Catherine, Morel Penelope A, Heffernan Jane M, Davis Courtney L, Smith Amber M, Jenner Adrianne L, Craig Morgan
Sainte-Justine University Hospital Research Centre, Montréal, Québec, Canada.
Department of Mathematics and Statistics, Université de Montréal, Montréal, Québec, Canada.
PLoS Comput Biol. 2025 Jun 9;21(6):e1013170. doi: 10.1371/journal.pcbi.1013170.
The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulted in millions of deaths globally. Adults with immunosuppression (e.g., solid organ transplant recipients) and those undergoing active cancer treatments experience worse infections and more severe COVID-19. It is difficult to conduct clinical studies in these populations, resulting in a restricted amount of data that can be used to relate mechanisms of immune dysfunction to COVID-19 outcomes in these vulnerable groups. To study immune dynamics after infection with SARS-CoV-2 and to investigate drivers of COVID-19 severity in individuals with cancer and immunosuppression, we adapted our mathematical model of the immune response during COVID-19 and generated virtual patient cohorts of cancer and immunosuppressed patients. The cohorts of plausible patients recapitulated available longitudinal clinical data collected from patients in Montréal, Canada area hospitals. Our model predicted that both cancer and immunosuppressed virtual patients with severe COVID-19 had decreased CD8 + T cells, elevated interleukin-6 concentrations, and delayed type I interferon peaks compared to those with mild COVID-19 outcomes. Additionally, our results suggest that cancer patients experience higher viral loads (however, with no direct relation with severity), likely because of decreased initial neutrophil counts (i.e., neutropenia), a frequent toxic side effect of anti-cancer therapy. Furthermore, severe cancer and immunosuppressed virtual patients suffered a high degree of tissue damage associated with elevated neutrophils. Lastly, parameter values associated with monocyte recruitment by infected cells were found to be elevated in severe cancer and immunosuppressed patients with respect to the COVID-19 reference group. Together, our study highlights that dysfunctions in type I interferon and CD8 + T cells are key drivers of immune dysregulation in COVID-19, particularly in cancer patients and immunosuppressed individuals.
由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的新冠疫情在全球导致了数百万人死亡。免疫功能低下的成年人（如实体器官移植受者）以及正在接受积极癌症治疗的人群感染情况更糟，新冠病情也更严重。在这些人群中开展临床研究很困难，导致可用于将免疫功能障碍机制与这些弱势群体的新冠病情转归相关联的数据量有限。为了研究感染SARS-CoV-2后的免疫动态，并调查癌症患者和免疫功能低下个体中新冠病情严重程度的驱动因素，我们调整了新冠疫情期间免疫反应的数学模型，并生成了癌症患者和免疫功能低下患者的虚拟队列。这些似是而非的患者队列概括了从加拿大蒙特利尔地区医院患者收集的现有纵向临床数据。我们的模型预测，与新冠病情较轻的患者相比，患有严重新冠的癌症和免疫功能低下虚拟患者的CD8 + T细胞减少、白细胞介素-6浓度升高，且I型干扰素峰值延迟。此外，我们的结果表明，癌症患者的病毒载量更高（然而，与严重程度无直接关系），可能是因为初始中性粒细胞计数减少（即中性粒细胞减少症），这是抗癌治疗常见的毒性副作用。此外，严重癌症和免疫功能低下的虚拟患者遭受了与中性粒细胞升高相关的高度组织损伤。最后，发现与感染细胞募集单核细胞相关的参数值在严重癌症和免疫功能低下患者中相对于新冠参考组有所升高。总之，我们的研究强调，I型干扰素和CD8 + T细胞功能障碍是新冠疫情中免疫失调的关键驱动因素，尤其是在癌症患者和免疫功能低下的个体中。
