Cassidy Benjamin R, Sonntag William E, Leenen Pieter J M, Drevets Douglas A
Infectious Diseases, Department of Internal Medicine, 800 Stanton L. Young, Suite 7300, Oklahoma City, OK, 73104, USA.
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Immun Ageing. 2022 May 25;19(1):25. doi: 10.1186/s12979-022-00281-0.
Understanding mechanisms of pathologic neuroinflammation is essential for improving outcomes after central nervous system infections. Brain tissue-resident memory T cells (bT) are recruited during central nervous system infection and promote pathogen control as well as noxious inflammation. Our prior studies in young mice showed optimal recruitment of CD8 bT during neuroinvasive Listeria monocytogenes (Lm) infection required miR-155, and was significantly inhibited by anti-miR-155 oligonucleotides. Since Lm is an important pathogen in the elderly, we hypothesized anti-miR-155 would also inhibit accumulation of CD8 bT in aged mice infected with Lm.
Young (2 mo) and aged (> 18 mo) male C57BL/6 mice were infected intra-peritoneally with wild-type Lm, or avirulent Lm mutants lacking the genes required for intracellular motility (ΔactA) or phagosomal escape (Δhly), then were given antibiotics. Brain leukocytes and their intracellular cytokine production were quantified by flow cytometry >28d post-infection (p.i.). The role of miR-155 was tested by injecting mice with anti-miR-155 or control oligonucleotides along with antibiotics.
Aged mice had significantly more homeostatic CD8 bT than did young mice, which did not increase after infection with wild-type Lm despite 50% mortality, whereas young mice suffered no mortality after a larger inoculum. For direct comparison of post-infectious neuroinflammation after the same inoculum, young and aged mice were infected with 10 CFU ΔactA Lm. This mutant caused no mortality and significantly increased CD8 bT 28d p.i. in both groups, whereas bone marrow-derived myeloid cells, particularly neutrophils, increased only in aged mice. Notably, anti-miR-155 reduced accumulation of brain myeloid cells in aged mice after infection, whereas CD8 bT were unaffected.
Systemic infection with Lm ΔactA is a novel model for studying infection-induced brain inflammation in aged mice without excessive mortality. CD8 bT increase in both young and aged mice after infection, whereas only in aged mice bone marrow-derived myeloid cells increase long-term. In aged mice, anti-miR-155 inhibits brain accumulation of myeloid cells, but not CD8 bT. These results suggest young and aged mice differ in manifestations and mechanisms of infection-induced neuroinflammation and give insight for developing therapies to ameliorate brain inflammation following severe infection in the elderly.
了解病理性神经炎症的机制对于改善中枢神经系统感染后的预后至关重要。脑组织驻留记忆T细胞（bT）在中枢神经系统感染期间被招募，并促进病原体控制以及有害炎症。我们之前在幼鼠中的研究表明，在神经侵袭性单核细胞增生李斯特菌（Lm）感染期间，CD8 bT的最佳招募需要miR-155，并且被抗miR-155寡核苷酸显著抑制。由于Lm是老年人的重要病原体，我们假设抗miR-155也会抑制感染Lm的老年小鼠中CD8 bT的积累。
将年轻（2个月）和老年（>18个月）雄性C57BL/6小鼠腹腔注射野生型Lm，或缺乏细胞内运动所需基因（ΔactA）或吞噬体逃逸所需基因（Δhly）的无毒Lm突变体，然后给予抗生素。感染后>28天（p.i.）通过流式细胞术对脑白细胞及其细胞内细胞因子产生进行定量。通过给小鼠注射抗miR-155或对照寡核苷酸以及抗生素来测试miR-155的作用。
老年小鼠的稳态CD8 bT明显多于年轻小鼠，尽管野生型Lm感染后死亡率为50%，但老年小鼠的稳态CD8 bT并未增加，而年轻小鼠在接种更大剂量后未出现死亡。为了在相同接种量后直接比较感染后神经炎症，将年轻和老年小鼠感染10 CFU ΔactA Lm。该突变体未导致死亡，并且在感染后28天两组中CD8 bT均显著增加，而骨髓来源的髓样细胞，特别是中性粒细胞，仅在老年小鼠中增加。值得注意的是，抗miR-155减少了老年小鼠感染后脑髓样细胞的积累，而CD8 bT未受影响。
Lm ΔactA全身感染是一种用于研究老年小鼠感染诱导的脑炎症且无过高死亡率的新模型。感染后年轻和老年小鼠的CD8 bT均增加，而仅老年小鼠的骨髓来源髓样细胞长期增加。在老年小鼠中，抗miR-155抑制髓样细胞在脑中的积累，但不抑制CD8 bT。这些结果表明年轻和老年小鼠在感染诱导的神经炎症的表现和机制上存在差异，并为开发改善老年人严重感染后脑炎症的治疗方法提供了见解。
