Neuroimmunology of central nervous system viral infections: the cells, molecules and mechanisms involved

Abstract

Viral infections of the central nervous system (CNS) necessitate rapid, yet tightly controlled responses to contain viral spread while limiting tissue damage. All CNS resident cell types are equipped with pattern recognition receptors (PRRs) to respond to viruses. The resulting activation of IFN-alpha/beta, pro-inflammatory cytokines and chemokines is dependent on the virus replication strategy, tropism and PRR distribution. Although IFN-alpha/beta induced antiviral mediators are essential to restrict initial viral spread, adaptive immunity promoted by chemokines, cytokines and metalloproteinases is equally crucial in lowering viral burden. Recognition of viral antigen presented by MHC molecules is crucial for T cell retention and function. Non-lytic clearance mechanisms mediated by IFN-gamma and antibodies prevail in providing protection. Targeted intervention can be achieved by PRR stimulation, chemokine-receptor blockade and immune modulation of T cell function. However, owing to the extensive positive and negative feedback signaling cascades linking innate and adaptive immune responses, enhanced anti-viral functions will have to be counterbalanced to avoid pathology.

Figure 1. Regulation of innate and adaptive immune components during viral CNS infection

(A) Select activation of constitutively expressed PRRs by viral nucleic acids leads to cell type dependent induction of IFN-α/β, proinflammatory chemokines and cytokines. For simplicity, nuclear translocation of transcription factors activated by PRR signal transduction is magnified as a blue rectangle representative of all CNS cells. IFN-α/β amplifies PRR signaling and induces antiviral ISGs and class I expression, while chemokines and cytokines enhance leukocyte recruitment. MMP expression by CNS cells as well PMNs facilitate lymphocyte CNS entry, but also contribute to neurotoxicity. (B) CNS infiltrating T cells are attracted to infected cells. Their antiviral function depends on the ability of infected cells to present viral antigen. Target cell recognition results in viral control via targeted release of perforin and granzymes and IFN-γ production, which in turn amplifies MHC expression. However, cell type dependent regulation of T cell effector functions by immunomodulatory molecules may contribute to persistence. (C) Persistent, low level infections are associated with ongoing chemokine and cytokine expression, potentially mediated by PRRs. Their control by persisting T cells and/or local antibodies depends on continued antigen presentation and maintenance of ASC.

Figure 2. Diverse roles of chemokine-chemokine receptor expression during viral CNS infections

The dual roles of individual chemokines and chemokine receptors associated with viral infection in enhancing antiviral responses early, but sustaining pathogenic T cells and macrophages is outlined.