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

FK506 reduces abnormal prion protein through the activation of autolysosomal degradation and prolongs survival in prion-infected mice

“…Following exposure to PRNP Sc , microglia produce neurotoxins that exacerbate neurodegeneration. 40,41 In contrast, it is reported elsewhere that activated microglia may afford protection to neurons through phagocytosis and digestion of aggregated PRNP Sc . 42,43 It is possible that the balance between the two contrary effects of microglial activation may proceed in a time-dependent manner.…”

The brain parenchyma has a type I interferon response that can limit virus spread

“…In addition, we analyzed the response of microglia to VSV infection in vivo. Microglia are believed to be the major resident cell type to mediate innate immune responses within the brain (5,10,12,21). We found that infected microglia produce type I IFN and that uninfected microglia are primed for a full type I IFN response in the context of brain infection.…”

“…A similar study with LACV found nearly no type I IFN-expressing neurons but rather that glia expressed type I IFN (9). In addition, other innate immune pathways, such as the type II and III IFN responses (10,11), and inflammation (12), are activated by viral infection. These observations suggest a great deal of complexity in the brain's response to viral infection and raise several issues in need of clarification.…”

Extensive fusion of haematopoietic cells with Purkinje neurons in response to chronic inflammation

“…We postulated that factors that caused an increase and activation of macrophages/microglia would lead to increased numbers of cerebellar heterokaryons. To test this hypothesis, we performed experiments using a well characterized compound, lipopolysaccharide (LPS), an endotoxin with a strong immunogenic response associated with leukocyte extravasation in vivo and activation of microglia leading to secretion of cytokines, chemokines, and prostaglandins 26 . Three 20-week-old BMT mice were chronically exposed to LPS before being sacrificed.…”