Human keratinocytes infected with Actinomadura madurae responded by producing antimicrobial peptides LL-37 and beta-defensins, upregulating TLR2 and TLR6, and eventually controlling the intracellular bacterial infection.
3 antimicrobial peptides deployed by infected skin cellsKeratinocytes produced LL-37, hBD-1, and hBD-2 in response to A. madurae infection, eventually controlling intracellular bacterial replication.
What the researchers found
A. madurae achieved intracellular replication in HaCaT keratinocytes early in infection, but the cells eventually controlled the bacterial growth. In response to infection, keratinocytes overexpressed Toll-like receptors TLR2 and TLR6, and produced high concentrations of the antimicrobial peptides LL-37, human beta-defensin-1 (hBD-1), and human beta-defensin-2 (hBD-2).
The infected cells also released inflammatory chemokines and cytokines including monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8), which recruit immune cells to the infection site. Tumor necrosis factor alpha (TNFα) was produced at lower levels. These findings demonstrate that keratinocytes are active participants in the immune defense against actinomycetoma, not just passive barriers.
Why it matters
Actinomycetoma is a neglected tropical disease that causes chronic, disfiguring skin infections primarily affecting people in developing countries. Understanding how the body's first line of defense — skin cells — responds to this infection could inform new treatment strategies. The finding that keratinocytes produce multiple antimicrobial peptides against A. madurae suggests these natural peptides could potentially be harnessed or boosted as therapeutic agents.
How the study worked
HaCaT keratinocyte cell lines were infected with A. madurae at a multiplicity of infection of 20:1 for 2 hours. Samples were collected from 2 to 72 hours post-infection. Intracellular bacterial replication was measured by colony-forming unit counts. TLR expression and antimicrobial peptide production were assessed by confocal microscopy. Chemokine and cytokine levels were quantified by ELISA.
What this study cannot tell us
This is an in vitro study using a single keratinocyte cell line (HaCaT), which may not fully represent the complex immune environment of living skin tissue with its multiple cell types and systemic immune connections. The study tested only one bacterial strain at one multiplicity of infection. Whether the antimicrobial peptides produced are sufficient to control infection in vivo remains unclear.
How to read the evidence
This is an in vitro cell culture study using a single keratinocyte cell line. While it provides clear mechanistic evidence of antimicrobial peptide responses, it represents the most basic level of experimental evidence — far from clinical validation in human patients.
When this study was published
Published in 2019, this study addresses a neglected tropical disease where research progress is generally slow. The fundamental immunological findings about antimicrobial peptide responses remain relevant to ongoing efforts to develop better treatments for actinomycetoma.
The bigger picture
This study adds to the understanding of antimicrobial peptides as a fundamental component of innate skin immunity. LL-37 and beta-defensins are produced by keratinocytes against many different pathogens, and understanding their role in neglected tropical diseases like actinomycetoma could help develop peptide-based treatments for infections that currently have limited therapeutic options.
Questions still open
- Could boosting antimicrobial peptide production in skin cells improve treatment outcomes for actinomycetoma patients?
- How does the immune response in full-thickness skin tissue compare to this single-cell-type model?
- Do patients with actinomycetoma have deficient antimicrobial peptide production that allows the infection to become chronic?
Common questions
What are antimicrobial peptides and how do they fight infection?
What is actinomycetoma and why is it hard to treat?
Read the original research
Keratinocyte infection by Actinomadura madurae triggers an inflammatory response.
Transactions of the Royal Society of Tropical Medicine and Hygiene, 113(7), 392-398
Citation
Santiago-Téllez, Alfonso; Castrillón-Rivera, Laura Estela; Palma-Ramos, Alejandro; Bello-López, Juan Manuel; Sainz-Espuñes, Teresita; Contreras-Paredes, Adriana; Luna-Herrera, Julieta; Castañeda-Sánchez, Jorge Ismael. (2019). Keratinocyte infection by Actinomadura madurae triggers an inflammatory response.. Transactions of the Royal Society of Tropical Medicine and Hygiene, 113(7), 392-398. https://doi.org/10.1093/trstmh/trz022