McMahan Rachel H, Hulsebus Holly J, Najarro Kevin M, Giesy Lauren E, Frank Daniel N, Orlicky David J, Kovacs Elizabeth J
Department of Surgery, Division of GI, Trauma and Endocrine Surgery, and Alcohol Research Program, Burn Research Program, University of Colorado Denver, Aurora, CO, United States.
GI and Liver Innate Immune Program, University of Colorado Denver, Aurora, CO, United States.
Front Aging. 2022;3. doi: 10.3389/fragi.2022.859991. Epub 2022 Mar 18.
The portion of the global population that is over the age of 65 is growing rapidly and this presents a number of clinical complications, as the aged population is at higher risk for various diseases, including infection. For example, advanced age is a risk factor for heightened morbidity and mortality following infection with . This increased vulnerability is due, at least in part, to age-related dysregulation of the immune response, a phenomenon termed immunosenescence. However, our understanding of the mechanisms influencing the immunosenescent state and its effects on the innate immune response to pneumonia remain incomplete. Recently, a role for the gut microbiome in age-specific alterations in immunity has been described. Here, we utilized a murine model of intranasal infection to investigate the effects of age on both the innate immune response and the intestinal microbial populations after infection. In aged mice, compared to their younger counterparts, infection with led to increased mortality, impaired lung function and inadequate bacterial control. This poor response to infection was associated with increased influx of neutrophils into the lungs of aged mice 24 h after infection. The exacerbated pulmonary immune response was not associated with increased pro-inflammatory cytokines in the lung compared to young mice but instead heightened expression of immune cell recruiting chemokines by lung neutrophils. Bacterial 16S-rRNA gene sequencing of the fecal microbiome of aged and young-infected mice revealed expansion of in the feces of aged, but not young mice, after infection. We also saw elevated levels of gut-derived bacteria in the lung of aged-infected mice, including the potentially pathogenic symbiote . Taken together, these results reveal that, when compared to young mice, infection in age leads to increased lung neutrophilia along with potentially pathogenic alterations in commensal bacteria and highlight potential mechanistic targets contributing to the increased morbidity and mortality observed in infections in age.
全球65岁以上人口比例正在迅速增长，这带来了许多临床并发症，因为老年人群患包括感染在内的各种疾病的风险更高。例如，高龄是感染后发病率和死亡率升高的一个风险因素。这种易感性增加至少部分归因于与年龄相关的免疫反应失调，这一现象被称为免疫衰老。然而，我们对影响免疫衰老状态的机制及其对肺炎固有免疫反应的影响的理解仍不完整。最近，肠道微生物群在年龄特异性免疫改变中的作用已被描述。在这里，我们利用鼻内感染的小鼠模型来研究年龄对感染后固有免疫反应和肠道微生物群的影响。与年轻小鼠相比，老年小鼠感染后死亡率增加、肺功能受损且细菌控制不足。这种对感染的不良反应与感染后24小时老年小鼠肺部中性粒细胞流入增加有关。与年轻小鼠相比，老年小鼠肺部加剧的免疫反应与促炎细胞因子增加无关，而是与肺部中性粒细胞免疫细胞募集趋化因子的表达升高有关。对老年和年轻感染小鼠粪便微生物群进行细菌16S-rRNA基因测序发现，感染后老年小鼠粪便中 扩张，而年轻小鼠则没有。我们还在老年感染小鼠的肺部发现肠道来源细菌水平升高，包括潜在致病性共生菌 。综上所述，这些结果表明，与年轻小鼠相比，老年小鼠感染后肺部中性粒细胞增多，同时共生细菌出现潜在致病性改变，并突出了导致老年感染中观察到的发病率和死亡率增加的潜在机制靶点。
