Changes in the innate immune response to SARS-CoV-2 with advancing age in humans.

IF 5.2 2区 医学 Q1 GERIATRICS & GERONTOLOGY Immunity & Ageing Pub Date : 2024-03-21 DOI:10.1186/s12979-024-00426-3
Sudhanshu Agrawal, Michelle Thu Tran, Tara Sinta Kartika Jennings, Marlaine Maged Hosny Soliman, Sally Heo, Bobby Sasson, Farah Rahmatpanah, Anshu Agrawal
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Abstract

Background: 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.

Results: 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.

Conclusions: 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.

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人类对 SARS-CoV-2 的先天免疫反应随年龄增长而发生的变化。
背景:年龄增长是呼吸道病毒感染的主要风险因素。这种感染通常持续时间较长,难以治愈,导致住院和死亡。最近的 COVID-19 大流行凸显了这一点,因为老年人已成为易感人群,对 SARS-CoV-2 的易感性和严重程度都有所增加。目前迫切需要确定造成这种情况的可能机制,以防止今后爆发此类疾病。先天免疫是抵御病毒的第一道防线,它的衰退会影响下游免疫反应。这是因为树突状细胞(DC)和巨噬细胞是先天性免疫系统的关键细胞元素,它们可以通过产生炎症介质和启动 CD4 和 CD8 T 细胞反应来感知病毒并做出反应:我们研究了先天免疫系统对 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 PBMCs 得出的结果表明,随着年龄的增长,DCs 和单核细胞对 SARS-CoV-2 的活化会受到影响。这种损伤在 pDCs 中最为明显,老年和中年的 pDCs 都显示出反应减弱。对呼吸道病毒有保护作用的 IL-29 的分泌也在老年和中年受试者中减少。相反,与严重 COVID-19 相关的炎症介质(包括 CXCL-8、TREM-1)则随着年龄的增长而增加。这一点在基因表达数据中也很明显,与宿主防御相关的通路随年龄增长而减少,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,在平衡状态下也是如此。与直流电活化减少相一致的是,高龄受试者诱导细胞毒性 CD8 T 细胞的能力也会减弱。然而,老年受试者的 CD8 T 细胞显示基线活化增加,与基线炎症增强相一致:结论:我们的研究结果表明,随着年龄的增长,保护性抗病毒免疫反应会下降,而破坏性炎症反应会增加,这表明先天性免疫反应失调是导致老年受试者对 COVID-19 易感性增加的重要原因。此外,免疫反应失调很早就出现了,因为中年人表现出了其中的一些变化。
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来源期刊
Immunity & Ageing
Immunity & Ageing GERIATRICS & GERONTOLOGY-IMMUNOLOGY
CiteScore
10.20
自引率
3.80%
发文量
55
期刊介绍: Immunity & Ageing is a specialist open access journal that was first published in 2004. The journal focuses on the impact of ageing on immune systems, the influence of aged immune systems on organismal well-being and longevity, age-associated diseases with immune etiology, and potential immune interventions to increase health span. All articles published in Immunity & Ageing are indexed in the following databases: Biological Abstracts, BIOSIS, CAS, Citebase, DOAJ, Embase, Google Scholar, Journal Citation Reports/Science Edition, OAIster, PubMed, PubMed Central, Science Citation Index Expanded, SCImago, Scopus, SOCOLAR, and Zetoc.
期刊最新文献
Age-dependent immune profile in healthy individuals: an original study, systematic review and meta-analysis. Biologically informed machine learning modeling of immune cells to reveal physiological and pathological aging process. Review of evidence linking exposure to environmental stressors and associated alterations in the dynamics of immunosenescence (ISC) with the global increase in multiple sclerosis (MS). Distinct immunomodulation elicited by young versus aged extracellular vesicles in bone marrow-derived macrophages. Inhibiting IL11: a novel approach to turning back the clock.
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