Systemic Listeria monocytogenes infection in aged mice induces long-term neuroinflammation: the role of miR-155

Abstract

Background: Understanding mechanisms of pathologic neuroinflammation is essential for improving outcomes after central nervous system infections. Brain tissue-resident memory T cells (bT_RM) 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_RM 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_RM in aged mice infected with Lm.

Methods: 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.

Results: Aged mice had significantly more homeostatic CD8⁺ bT_RM 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 10⁷ CFU ΔactA Lm. This mutant caused no mortality and significantly increased CD8⁺ bT_RM 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_RM were unaffected.

Conclusions: Systemic infection with Lm ΔactA is a novel model for studying infection-induced brain inflammation in aged mice without excessive mortality. CD8⁺ bT_RM 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_RM. 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.

Keywords: Bacterial meningitis; Listeria; Neuroinflammation; Tissue-resident memory T cells; miR-155; sepsis.