Aging Dampens the Intestinal Innate Immune Response during Severe Clostridioides difficile Infection and Is Associated with Altered Cytokine Levels and Granulocyte Mobilization
Aging Dampens the Intestinal Innate Immune Response during Severe Clostridioides difficile Infection and Is Associated with Altered Cytokine Levels and Granulocyte Mobilization
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DOI：
10.1128/iai.00960-19
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发表时间：
2020-05-01
影响因子：
3.1
通讯作者：
Young, Vincent B.
中科院分区：
文献类型：
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作者：
Abernathy-Close, Lisa;Dieterle, Michael G.;Young, Vincent B.
艰难梭菌（以前称为艰难梭菌）是医院获得性感染的最常见原因，而高龄是艰难梭菌感染的危险因素。肠道微生物群和免疫反应的破坏会导致宿主对艰难梭菌感染的易感性和严重程度。然而，衰老对艰难梭菌感染期间免疫反应的具体影响仍有待详细描述。本研究探讨了年龄对艰难梭菌感染期间细胞和细胞因子免疫反应的影响。用抗生素头孢哌酮使幼小小鼠（2至3个月大）和老年小鼠（22至28个月大）对艰难梭菌感染敏感，然后用具有不同致病潜力的艰难梭菌菌株进行感染。我们观察到宿主年龄和感染的艰难梭菌菌株影响与感染相关的疾病的严重程度。在所有感染艰难梭菌高毒力菌株的小鼠的盲肠和结肠中，在疾病严重程度达到顶峰时，发生了组织特异性 CD45(+) 免疫细胞反应；然而，在老年小鼠中检测到肠道中性粒细胞和嗜酸性粒细胞显着缺乏，循环中的CXCL1（一种重要的中性粒细胞募集剂和激活剂）相应减少。有趣的是，在严重艰难梭菌感染期间，老年小鼠肠道粒细胞反应的缺乏伴随着循环白细胞、粒细胞和白细胞介素 17A (IL-17A) 的同时增加。这些发现表明，中性粒细胞和嗜酸性粒细胞的年龄相关变化以及全身细胞因子和趋化因子反应与严重的艰难梭菌感染有关，并支持肠道嗜酸性粒细胞在减轻艰难梭菌介导的疾病严重程度方面的关键作用。
Clostridioides (formerly Clostridium) difficile is the most common cause of hospital-acquired infection, and advanced age is a risk factor for C. difficile infection. Disruption of the intestinal microbiota and immune responses contribute to host susceptibility and severity of C. difficile infection. However, the specific impact of aging on immune responses during C. difficile infection remains to be well described. This study explores the effect of age on cellular and cytokine immune responses during C. difficile infection. Young mice (2 to 3 months old) and aged mice (22 to 28 months old) were rendered susceptible to C. difficile infection with the antibiotic cefoperazone and then infected with C. difficile strains with varied disease-causing potentials. We observe that the host age and the infecting C. difficile strain influenced the severity of disease associated with infection. Tissue-specific CD45(+) immune cell responses occurred at the time of peak disease severity in the ceca and colons of all mice infected with a high-virulence strain of C. difficile; however, significant deficits in intestinal neutrophils and eosinophils were detected in aged mice, with a corresponding decrease in circulating CXCL1, an important neutrophil recruiter and activator. Interestingly, this lack of intestinal granulocyte response in aged mice during severe C. difficile infection was accompanied by a simultaneous increase in circulating white blood cells, granulocytes, and interleukin 17A (IL-17A). These findings demonstrate that age-related alterations in neutrophils and eosinophils and systemic cytokine and chemokine responses are associated with severe C. difficile infection and support a key role for intestinal eosinophils in mitigating C. difficile-mediated disease severity.