Agrawal Sudhanshu, Tran Michelle Thu, Jennings Tara Sinta Kartika, Soliman Marlaine Maged Hosny, Heo Sally, Sasson Bobby, Rahmatpanah Farah, Agrawal Anshu
Division of Basic and Clinical Immunology, Department of Medicine, University of California Irvine, Irvine, CA, 92697, USA.
Department of Pathology, University of California Irvine, Irvine, CA, 92697, USA.
Immun Ageing. 2024 Mar 21;21(1):21. doi: 10.1186/s12979-024-00426-3.
Advancing age is a major risk factor for respiratory viral infections. The infections are often prolonged and difficult to resolve resulting hospitalizations and mortality. The recent COVID-19 pandemic has highlighted this as elderly subjects have emerged as vulnerable populations that display increased susceptibility and severity to SARS-CoV-2. There is an urgent need to identify the probable mechanisms underlying this to protect against future outbreaks of such nature. Innate immunity is the first line of defense against viruses and its decline impacts downstream immune responses. This is because dendritic cells (DCs) and macrophages are key cellular elements of the innate immune system that can sense and respond to viruses by producing inflammatory mediators and priming CD4 and CD8 T-cell responses.
We investigated the changes in innate immune responses to SARS-CoV-2 as a function of age. Our results using human PBMCs from aged, middle-aged, and young subjects indicate that the activation of DCs and monocytes in response to SARS-CoV-2 is compromised with age. The impairment is most apparent in pDCs where both aged and middle-aged display reduced responses. The secretion of IL-29 that confers protection against respiratory viruses is also decreased in both aged and middle-aged subjects. In contrast, inflammatory mediators associated with severe COVID-19 including CXCL-8, TREM-1 are increased with age. This is also apparent in the gene expression data where pathways related host defense display an age dependent decrease with a concomitant increase in inflammatory pathways. Not only are the inflammatory pathways and mediators increased after stimulation with SARS-CoV-2 but also at homeostasis. In keeping with reduced DC activation, the induction of cytotoxic CD8 T cells is also impaired in aged subjects. However, the CD8 T cells from aged subjects display increased baseline activation in accordance with the enhanced baseline inflammation.
Our results demonstrate a decline in protective anti-viral immune responses and increase in damaging inflammatory responses with age indicating that dysregulated innate immune responses play a significant role in the increased susceptibility of aged subjects to COVID-19. Furthermore, the dysregulation in immune responses develops early on as middle-aged demonstrate several of these changes.
年龄增长是呼吸道病毒感染的主要风险因素。这些感染往往病程延长且难以治愈，从而导致住院和死亡。最近的新冠疫情凸显了这一点，因为老年人群已成为对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）易感性增加且病情严重的脆弱群体。迫切需要确定其潜在机制，以防范未来此类疫情的爆发。固有免疫是抵御病毒的第一道防线，其功能衰退会影响下游免疫反应。这是因为树突状细胞（DC）和巨噬细胞是固有免疫系统的关键细胞成分，它们能够通过产生炎症介质以及启动CD4和CD8 T细胞反应来感知并应对病毒。
我们研究了固有免疫对SARS-CoV-2的反应随年龄的变化。我们使用来自老年、中年和青年受试者的人外周血单核细胞（PBMC）得出的结果表明，DC和单核细胞对SARS-CoV-2的反应激活能力会随着年龄增长而受损。这种损害在浆细胞样DC中最为明显，老年和中年受试者的反应均降低。在老年和中年受试者中，具有抗呼吸道病毒保护作用 的白细胞介素-29（IL-29）的分泌也减少。相比之下，与严重新冠相关的炎症介质，包括趋化因子配体8（CXCL-8）、触发受体表达于髓系细胞-1（TREM-1），会随着年龄增长而增加 在基因表达数据中也很明显，与宿主防御相关的通路显示出随年龄增长而下降，同时炎症通路增加。不仅在受到SARS-CoV-2刺激后炎症通路和介质会增加，在稳态时也是如此。与DC激活减少一致，老年受试者中细胞毒性CD8 T细胞的诱导也受损。然而，老年受试者的CD8 T细胞根据增强的基线炎症表现出基线激活增加。
我们的结果表明，随着年龄增长，保护性抗病毒免疫反应下降，损伤性炎症反应增加，这表明固有免疫反应失调在老年受试者对新冠易感性增加中起重要作用。此外，免疫反应失调在中年时就已出现，因为中年受试者也表现出其中的一些变化。
