Molecular machinations: chemokine signals in host-pathogen interactions

Abstract

Chemokines and their G-protein-coupled receptors represent an ancient and complex system of cellular communication participating in growth, development, homeostasis and immunity. Chemokine production has been detected in virtually every microbial infection examined; however, the precise role of chemokines is still far from clear. In most cases they appear to promote host resistance by mobilizing leukocytes and activating immune functions that kill, expel, or sequester pathogens. In other cases, the chemokine system has been pirated by pathogens, especially protozoa and viruses, which have exploited host chemokine receptors as modes of cellular invasion or developed chemokine mimics and binding proteins that act as antagonists or inappropriate agonists. Understanding microbial mechanisms of chemokine evasion will potentially lead to novel antimicrobial and anti-inflammatory therapeutic agents.

FIG. 1

Chemokine receptor ligation and activation events. (Top) The GPCR with its seven transmembrane hydrophobic domains and the G-protein α-β/γ complex in the nonactivated GDP-bound state. (Bottom) After ligation with chemokine (CK), GTP replaces GDP and the Gα-β/γ complex subunits dissociate. This leads to activation of phospholipase C (PLC), which generates DAG and IP₃ from the phosphotidylinositol diphosphate membrane substrate (PIP₂). The DAG activates protein kinase C, while IP₃ initiates calcium (Ca++) flux. The Gα subunit also activates protein tyrosine kinase (PTK). These transduction events initiate cellular functions such as chemotaxis, degranulation, respiratory burst, and cell adhesion, as well as activating regulatory protiens that uncouple the chemokine receptor, leading to desensitization.

FIG. 2

Stage-specific Th-cell chemokine receptor expression. Sallusto et al. (151) propose that after antigen priming, naïve T cells differentiate into Th1 and Th2 cells that display different patterns of chemokine receptors, allowing selective recruitment to sites of inflammation and secondary lymphoid tissues.

FIG. 3

Chemokine evolution. Based on sequence analysis, the different chemokine classes appear to have diverged from a primordial chemokine gene before the divergence of mammalian orders.

FIG. 4

Cascade model of cytokine-chemokine networks. (Top) When an epithelial surface is compromised by microbial invasion, chemokines can be derived from the damaged cells and subepithelial tissue macrophages (MP), which initially respond to microbial components. The macrophages also produce cytokines (e.g., TNF-α and IL-1) that can activate tissue mesenchymal cells such as myofibroblasts (MF), which likewise contribute to the first wave of chemokines. Cytokines also activate local endothelium to express addressins in preparation for leukocyte recruitment. (Middle) After initiation, leukocytes begin to be locally recruited from the blood. The recruited cells, neutrophils and NK cells, responding in an innate fashion provide a further source of amplifying cytokines (e.g., IFN-γ) as well as chemokines. (Bottom) If the initial innate mechanisms are unable to quickly clear the infection, recruited Th cells reactive with microbe-specific antigens will produce cytokines that further amplify the local production of chemokines. Hatched arrows indicate produced factors. Solid arrows indicate amplifying signals.