Role of microglia in central nervous system infections

Abstract

The nature of microglia fascinated many prominent researchers in the 19th and early 20th centuries, and in a classic treatise in 1932, Pio del Rio-Hortega formulated a number of concepts regarding the function of these resident macrophages of the brain parenchyma that remain relevant to this day. However, a renaissance of interest in microglia occurred toward the end of the 20th century, fueled by the recognition of their role in neuropathogenesis of infectious agents, such as human immunodeficiency virus type 1, and by what appears to be their participation in other neurodegenerative and neuroinflammatory disorders. During the same period, insights into the physiological and pathological properties of microglia were gained from in vivo and in vitro studies of neurotropic viruses, bacteria, fungi, parasites, and prions, which are reviewed in this article. New concepts that have emerged from these studies include the importance of cytokines and chemokines produced by activated microglia in neurodegenerative and neuroprotective processes and the elegant but astonishingly complex interactions between microglia, astrocytes, lymphocytes, and neurons that underlie these processes. It is proposed that an enhanced understanding of microglia will yield improved therapies of central nervous system infections, since such therapies are, by and large, sorely needed.

FIG.1.

Human microglia. (A) Microglial cells in fetal brain tissue at 11 weeks' gestation are predominantly amoeboid in shape (left panel), whereas by 18 weeks they have assumed a ramified morphology (right panel) (stained with anti-CD68 antibodies, a macrophage marker). (B and C) Microglia in cell cultures isolated from 18-week fetal brain tissue have assumed an amoeboid morphology (CD68 antibody positive) (B) and up-regulate CD14 antigen (a marker not seen in nonactivated ramified microglia) (C). (D) A double-stained mixed culture of microglia (anti-CD68 antibody positive, dark blue) and astrocytes (anti-GFAP antibody positive, red) from 18-week fetal brain tissue shows differences in morphology and size. (E) Microglial cell cultures infected for 14 days with HIV-1 assume a multinucleated giant cell morphology (stained with anti-p24 antigen antibodies, green). (F and G) LPS (100 ng/ml)-stimulated microglial cell cultures express intracellular CXCL8/IL-8 (green) (F) and intracellular CXCL10/IP10 (green) (G). (H) Microglial cell cultures are shown after 18 h of incubation with nonopsonized M. tuberculosis H37Rv (tubercle-to-cell ratio, 10:1) (auramine-rhodamine stain).