Infectious immunity in the central nervous system and brain function

Abstract

Inflammation is emerging as a critical mechanism underlying neurological disorders of various etiologies, yet its role in altering brain function as a consequence of neuroinfectious disease remains unclear. Although acute alterations in mental status due to inflammation are a hallmark of central nervous system (CNS) infections with neurotropic pathogens, post-infectious neurologic dysfunction has traditionally been attributed to irreversible damage caused by the pathogens themselves. More recently, studies indicate that pathogen eradication within the CNS may require immune responses that interfere with neural cell function and communication without affecting their survival. In this Review we explore inflammatory processes underlying neurological impairments caused by CNS infection and discuss their potential links to established mechanisms of psychiatric and neurodegenerative diseases.

Figure 1

Neuroinfectious diseases and cytokine modulation of brain functions. (a) Neurotropic pathogens gain access to the CNS parenchyma (bacteria, viruses and parasites) or CSF compartments (bacteria, viruses and fungi), the latter of which includes the subarachnoid space and the ventricular system. (b, c) Increased expression of cytokines and chemokines modulate brain function via effects on dopaminergic pathways (b) and glutamatergic pathways (c). Dopamine is manufactured in the substantia nigra (SN), which affects motor function, and in the ventral tegmental area (VTA), which is involved in memory, motivation and reward. Dopaminergic neurons of the SN project to the dorsal striatum, and those of the VTA project to the nucleus accumbens (NA) and the prefrontal cortex. Glutamatergic pathways are involved in learning and memory formation, which also require long-term potentiation, characterized by a persistent increase in synaptic strength following high-frequency stimulation, and genesis of new neurons within the dentate gyrus (adult neurogenesis). Molecules labeled in red have inhibitory effects; those labeled in blue have stimulatory effects.

Figure 2

Potential mechanisms of neurological sequelae subsequent to bacterial and fungal meningoencephalitis. (a) Perivascular or meningeal macrophages (PVM) recognize invading pathogens during meningoencephalitis and release a variety of chemoattractants, including CCL2, CCL3, CCL4 (CCL2/3/4), IL-8 and CXCL1, to recruit neutrophils and monocytes to the CSF compartment. Recruited neutrophils release proteolytic enzymes, which contribute to BBB breakdown through loss of tight junctions and degradation of the basement membrane. Reactive oxygen (ROS) and nitrogen (RN1) species can initiate apoptosis or necrosis in neurons. TNF, IL-1β and IL-6 can participate in BBB breakdown and neuronal death. These proinflammatory cytokines are increased in the hippocampus and cortex during experimental meningitis in mouse models and can cause learning and memory deficits in surviving animals. (b) Balance between IFN-γ and IL-4 produced by meningeal T cells is necessary for normal behavior. IFN-γ acts on inhibitory neurons to increase GABAergic current and maintain normal social behavior. IL-4 maintains normal learning and memory, potentially through inhibition of proinflammatory cytokine production by meningeal myeloid cells and/or increasing brain-derived neurotrophic factor (BDNF) production by astrocytes, which is crucial for adult neurogenesis. During infection, the balance is disrupted, which may cause behavioral alteration. Chronic infection by Mtb results in T_H1 cell recruitment to the CSF compartment, increasing IFN-γ production. Meningitis caused by S. pneumoniae and other acute bacterial pathogens results in the influx of IL-4 producing T_H2 cells, shifting the balance toward an IL-4-dominated cytokine milieu.

Figure 3

Mechanisms underlying neurological sequelae in a subset of viral encephalitis survivors. (a) Microglia are activated after WNV infection, leading to upregulation of complement receptor 3 (CR3) and expression of complement component C1qa. C1qa and the downstream complement cleavage protein C3d localize to presynaptic terminals in the hippocampus. Complement-mediated engulfment of tagged synapses by microglia leads to selective loss of presynaptic terminals in the CA3 region of the hippocampus and deficits in spatial learning. CD11b, cluster of differentiaton 11b. (b) B cells can produce autoantibodies to synaptic proteins, including NMDAR, after HSV-1 mediated encephalitis. Autoantibodies bind to NMDAR on the post-synaptic terminal, which leads to selective internalization of NMDAR, whereas other synaptic components, such as AMPAR and PSD-95, remain intact. Loss of NMDAR in the hippocampus leads to behavioral memory deficits and neuropsychiatric symptoms of depression and anhedonia.