Mechanistic insights and therapeutic opportunities of antimicrobial chemokines

Abstract

Chemokines are a family of small proteins best known for their ability to orchestrate immune cell trafficking and recruitment to sites of infection. Their role in promoting host defense is multiplied by a number of additional receptor-dependent biological activities, and most, but not all, chemokines have been found to mediate direct antimicrobial effects against a broad range of microorganisms. The molecular mechanism(s) by which antimicrobial chemokines kill bacteria remains unknown; however, recent observations have expanded our fundamental understanding of chemokine-mediated bactericidal activity to reveal increasingly diverse and complex actions. In the current review, we present and consider mechanistic insights of chemokine-mediated antimicrobial activity against bacteria. We also discuss how contemporary advances are reshaping traditional paradigms and opening up new and innovative avenues of research with translational implications. Towards this end, we highlight a developing framework for leveraging chemokine-mediated bactericidal and immunomodulatory effects to advance pioneering therapeutic approaches for treating bacterial infections, including those caused by multidrug-resistant pathogens.

Switchable Membrane Remodeling and Antifungal Defense by Metamorphic Chemokine XCL1

“…Antimicrobial peptides (AMPs) are innate immune molecules that often exhibit a common antimicrobial mechanism of disrupting pathogen membranes, which leads to depolarization, leakage, and eventual cell death. , Examples of AMPs include cathelicidins, defensins, bacteriocins, histatins, protegrins, and, more recently, an increasing number of chemokines, which are more commonly thought of as signaling molecules. − Among the human chemokines that exhibit antibacterial, antifungal, or antiviral properties are CCL20, CXCL4, CCL28, CXCL17, and XCL1 . Chemokines are a family of ∼50 small, secreted proteins that direct cellular migration by binding to glycosaminoglycans (GAGs) to form concentration gradients, and by binding to G-protein coupled receptors (GPCRs) to induce pro-migratory cellular changes.…”

Recent sexual violence exposure is associated with immune biomarkers of HIV susceptibility in women

“…In the genital mucosa, significant reductions of chemokines MIP‐3α and MCP‐1 were observed in Exposed. Chemokines are critical in combating infection by their participation in the inflammatory process 46,47 . MIP‐3α chemo‐attracts T cells and has in vitro HIV inhibitory activity 48‐50 .…”

The Solution Structure of CCL28 Reveals Structural Lability that Does Not Constrain Antifungal Activity

“…It is becoming increasingly recognized that chemokines have functions beyond the direction of cell migration, and one such function is direct antimicrobial activity against invading pathogens. Indeed, the immunologic functions of both chemokines and antimicrobial peptides (AMPs) have considerable overlap, with members of each family acting as both chemoattractants and antimicrobial agents [25–27]. The physiologic significance of the antimicrobial functions of chemokines remains unclear, but it has been proposed that they may allow for a more robust immunologic response to microbial infection in vivo [27].…”

“…Indeed, the immunologic functions of both chemokines and antimicrobial peptides (AMPs) have considerable overlap, with members of each family acting as both chemoattractants and antimicrobial agents [25–27]. The physiologic significance of the antimicrobial functions of chemokines remains unclear, but it has been proposed that they may allow for a more robust immunologic response to microbial infection in vivo [27]. Additionally, it has been suggested that the antimicrobial activities of homeostatic chemokines may be important for controlling commensal microbial populations [5].…”