Pro-Inflammatory Response of Human Monocyte-Derived Dendritic Cells to Bacterial Biofilms — ASN Events
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  3. Pro-Inflammatory Response of Human Monocyte-Derived Dendritic Cells to Bacterial Biofilms

Pro-Inflammatory Response of Human Monocyte-Derived Dendritic Cells to Bacterial Biofilms (#175)

Leah M Whiteman 1 , Guangnan Hu 1 , Emily Lowry 2 , Kaitlyn Grando 3 , Amir Mitchell 2 , Çagla Tükel 3 , Roberto Caricchio 4 , Stefania Gallucci 1
  1. Dept. of Medicine, Division of Innate Immunity, University of Massachusetts Chan Medical School, Worcester, MA, USA
  2. Dept System Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
  3. Center for Microbiology-Immunology, Temple University, Lewis Katz School of Medicine, Philadelphia, PA, US
  4. Dept of Medicine, Division of Rheumatology, University of Massachusetts Chan Medical School, Worcester, MA, USA

Many human bacterial pathogens form biofilms in response to hostile environments. Biofilms are multicellular bacterial communities embedded in an extracellular polymeric matrix that shield bacteria from external stressors such as antibiotics, antimicrobials and host immune responses, promoting persistence and chronic infection. The structure of many biofilms is strengthened by functional amyloids, such as curli, produced by the Enterobacteriaceae Salmonella and E. coli. Despite their clinical significance, the mechanisms by which biofilms are recognized by the innate immune cells remain under-investigated. We have previously shown that curli amyloid activates murine dendritic cells. Biofilms contain many other PAMPs, and it is pivotal to understand their roles in host defense.

In this study we investigated the response of human monocyte-derived dendritic cells (hu-moDCs) from healthy donors to biofilms generated in vitro by Gram-negative Uropathogenic E. coli (UPEC), the leading cause of urinary tract infections in humans. Using UPEC strain UTI-89 WT and its msbB mutant, which produces a pentacylated LPS that is not stimulatory for human TLR4, we analyzed hu-moDC responses to biofilms and individual biofilm components, including hexacylated LPS and curli, through transcriptomics, proteomics and Flow Cytometry.

We found that exposure to biofilms strongly activates hu-moDCs, inducing increased surface expression of MHC and costimulatory molecules, and secretion of pro-inflammatory cytokines, especially IL-23, as well as many chemokines that recruit neutrophils, monocytes and immature DCs. Both WT and msbB mutant biofilms elicited quantitatively, but not qualitatively different DC activations, indicating a redundant role for LPS. The response to curli mirrored the activation profile induced by msbB mutant biofilms, inducing a molecular program that promotes TH17 responses.

Our findings reveal that human DCs are strongly activated by biofilms through LPS-independent mechanisms and identify curli as a major biofilm-associated PAMP driving innate immune activation.

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