Role of CNS-associated macrophages in mycobacterial meningoencephalitis

Prof. Dr. Philipp Henneke

• B04

Dr. Anne Kathrin Lößlein

• B04

Project Summary

Mycobacterial infections are particularly dangerous early in life, with disseminati on leading to the life-threatening tuberculous (TB) meningitis. Even if treated early, TB meningitis can cause permanent disability in many cases. Overall, mycobacterial infections of the central nervous system (CNS) involve complex immune processes including chronic granulomatous tissue inflammation with macrophages as key players. However, cellular and molecular mechanisms underlying the disease, e.g. related to the role of resident versus recruited immune cells, are largely unclear. A particular complexity arises from the variety of macrophages populating the meninges at the CNS borders, which are of mixed primitive and postnatal bone marrow origin. In mycobacterial infecti ons affecting other organs (lung and liver), we previously found that macrophage progenitors, in particular common monocyte progenitors (cMoP), which reside in the bone marrow, and their inducible circulating progeny (iMoP) are transformed into distinct granuloma macrophage species. These processes essentially involve cholesterol metabolism and the DNA damage response. However, the role
of meningeal macrophage-intrinsic and heterocellular processes in the course and consequences of mycobacterial meningitis, and thus in chronic bacterial infection, are essentially unresolved. In order to break new ground in these areas, we will combine both adult and neonatal mycobacterial meningitis models with high dimensional transcriptional and metabolic analysis, cellular immunophenotyping, fate-mapping and multi modular imaging (Aim 1 and 2). Meningeal macrophages and microglia will be in the focus for deciphering the impact of age, cellular origin and metabolic changes on infection outcome (Aim 1 and 2). Furthermore, we will study the contribution of heterocellular interactions between CNS border macrophages and nociceptors and meningeal fi broblasts to host defense, susceptibility, and resulting immunopathology (Aim 3). Thus, we envision to identify targets for adjunctive therapy for a devastating early-life CNS disease.