Infections of the central nervous system (CNS) can occur in two anatomically distinct tissue compartments: the subarachnoid and leptomeningeal spaces (meningitis) and the parenchyma of the brain and spinal cord (encephalomyelitis). While an intact blood–brain barrier (BBB) ordinarily deters microorganisms from invading either tissue compartment, it also excludes most circulating components of the immune system, making the CNS susceptible to infection once such invasion does occur. Cells of the immune system can extravasate into the CNS in response to infection, but they appear to do so in a tightly regulated manner. Within the brain, neural cells have restricted immunological function, and the local microenvironment of the CNS can also down-modulate various effector responses of recruited inflammatory cells. In general, a successful host immune response against a CNS infection must overcome these structural and functional barriers to eradicate infectious organisms without causing excessive damage to non-renewable neural cell populations. In some cases, however, the host response is not fully controlled and actually contributes to the neurologic deficits associated with CNS infection. This chapter will review these concepts by citing examples from both human disease states and laboratory-based experimental systems.
There are several anatomical features of the nervous system that influence how local and systemic immune responses are mounted in response to CNS infection. These include: (i) the BBB which stands as a physical barrier against the passage of immune elements from the periphery into the CNS, (ii) the Virchow–Robin spaces immediately surrounding blood vessels that penetrate into the brain where important immunologic reactions can take place, and (iii) cerebrospinal fluid (CSF) recirculation pathways, which may disseminate microorganisms throughout the neuraxis and cause infectious antigens to be carried out of the CNS via particular routes, therefore influencing how they are detected by the immune system in the periphery.
Under normal circumstances, structures that comprise the BBB generally prevent the entry of infectious pathogens, inflammatory cells, and circulating proteins such as antibodies and cytokines into the CNS. Cerebrovascular endothelial cells maintain tight intercellular junctions and very low rates of vesicular transport that differentiate them from the more permeable endothelium found in other tissues. A dense basement membrane ensheathes the cerebrovascular endothelium which is itself surrounded by a network of pericytes and astrocytic foot processes that collectively maintain the integrity of the BBB.