Chemokine receptors as important regulators of pathogenesis during arboviral encephalitis

Abstract

The central nervous system (CNS) is a highly complex network comprising long-lived neurons and glial cells. Accordingly, numerous mechanisms have evolved to tightly regulate the initiation of inflammatory responses within the brain. Under neuroinflammatory conditions, as in the case of viral encephalitides, the infiltration of leukocytes is often required for efficient viral clearance and recovery. The orchestration of leukocyte migration into the inflamed CNS is largely coordinated by a large family of chemotactic cytokines and their receptors. In this review, we will summarize our current understanding of how chemokines promote protection or pathogenesis during arbovirus induced encephalitis, focusing on neurotropic flaviviruses and alphaviruses. Furthermore, we will highlight the latest developments in chemokine and chemokine receptor based drugs that could have potential as therapeutics and have been shown to play a pivotal role in shaping the outcome of disease.

Keywords: alphaviruses; antagonists; chemokine receptors; flaviviruses; leukocyte infiltration.

FIGURE 1

The dual role of CCR2-expressing monocytes during West Nile virus (WNV) infection. The function of CCR2 on monocytes may involve two distinct steps: egress from the bone marrow induced early following WNV infection, and their migration into the WNV-infected central nervous system (CNS). However, the role of CCR2-expressing monocytes is highly dependent on the mode of infection utilized in mouse models. With peripheral infection (A), WNV induces a monocytosis within several days post infection. Genetic deficiency or pharmacological blockade of CCR2 in mice (red arrow) results in monocytopenia and leads to decreased monocyte infiltration into the CNS, enhanced viral titers in the brain and increased mortality. Therefore, CCR2-mediated monocytosis and the subsequent migration of monocytes into the inflamed CNS are protective (green arrows). In contrast using an intranasal infection model of WNV infection (B), the migration of CCR2-expressing monocytes into the CNS has also been shown to promote pathogenesis (red arrow) in mice. Thus, blocking CCR2 using anti-CCL2 antibodies in this model prolongs survival (green) in mice.

FIGURE 2

The role of CCR5 during flavivirus-induced encephalitis. During WNV and Japanese encephalitis virus (JEV) infection in mice, the migration of CD4⁺ T-cells, CD8⁺ T-cells, NK-cells and monocytes from the blood into CNS is required for efficient control of viral replication and recovery (upper). In the absence of CCR5 in mice, the migration of these leukocytes into the CNS is delayed and/or severely impaired (lower). During JEV infection, the absence of CCR5 also results in inefficient NK and CD8⁺ T-cell effector functions as well. Although the function of CCR5 has not been evaluated during WNV infection in humans, homozygosity for the complete loss-of-function mutation, CCR5Δ32, has been correlated with increased severity of WNV and tick borne encephalitis virus infections. It is anticipated that blockade of CCR5, either in mice or humans, may increase susceptibility to neurotropic flaviviruses.

FIGURE 3

The role of CXCR3 and CXCR4 during arbovirus-induced encephalitis in mice. (1a) CXCR3⁺CD8⁺ T-cells migrate into the CNS in response to high levels of neuronal CXCL10. Loss of CXCR3 or its ligand CXCL10, or antagonizing this interaction (1b) prevents the migration of CD8⁺ T-cells into the CNS during WNV in mice. (2a) Virally infected neurons are the predominant source of CXCL10 in the CNS during WNV infection. (2b) Neuronal CXCL10 can engage CXCR3 that is upregulated on infected neurons and induce apoptosis. (2c) Blockade of CXCR3 with antagonists or CXCL10 neutralizing antibodies leads to the reduced binding of neuronal CXCL10 to neuronal CXCR3 and result in reduction of apoptosis and increased neuronal survival. (3a) During WNV infection, CXCR4⁺CD8⁺ T-cells migrate toward endothelial CXCL12, expressed on the inflamed cerebral endothelium. (3b) The interaction of CXCL12 and CXCR4 causes the CD8⁺ T-cells to be retained within the perivascular space. (3c,d) After blockade with the CXCR4 antagonist, AMD3100, the CD8⁺ T-cells are released and can migrate into the brain parenchyma where they promote clearance of WNV. Pathological steps are depicted in red; beneficial steps involved in increasing survival and improving disease outcome in the host are depicted in green. Gray arrows signify functions that are neither beneficial nor pathogenic.