Biofilm-Innate Immune Interface: Contribution to Chronic Wound Formation

Zoya Versey, Waleska Stephanie da Cruz Nizer, Emily Russell, Sandra Zigic, Katrina G DeZeeuw, Jonah E Marek, Joerg Overhage, Edana Cassol, Zoya Versey, Waleska Stephanie da Cruz Nizer, Emily Russell, Sandra Zigic, Katrina G DeZeeuw, Jonah E Marek, Joerg Overhage, Edana Cassol

Abstract

Delayed wound healing can cause significant issues for immobile and ageing individuals as well as those living with co-morbid conditions such as diabetes, cardiovascular disease, and cancer. These delays increase a patient's risk for infection and, in severe cases, can result in the formation of chronic, non-healing ulcers (e.g., diabetic foot ulcers, surgical site infections, pressure ulcers and venous leg ulcers). Chronic wounds are very difficult and expensive to treat and there is an urgent need to develop more effective therapeutics that restore healing processes. Sustained innate immune activation and inflammation are common features observed across most chronic wound types. However, the factors driving this activation remain incompletely understood. Emerging evidence suggests that the composition and structure of the wound microbiome may play a central role in driving this dysregulated activation but the cellular and molecular mechanisms underlying these processes require further investigation. In this review, we will discuss the current literature on: 1) how bacterial populations and biofilms contribute to chronic wound formation, 2) the role of bacteria and biofilms in driving dysfunctional innate immune responses in chronic wounds, and 3) therapeutics currently available (or underdevelopment) that target bacteria-innate immune interactions to improve healing. We will also discuss potential issues in studying the complexity of immune-biofilm interactions in chronic wounds and explore future areas of investigation for the field.

Keywords: biofilm; chronic wound; delayed healing; host-pathogen interaction; inflammation; innate immune responses; skin microbiome.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Versey, da Cruz Nizer, Russell, Zigic, DeZeeuw, Marek, Overhage and Cassol.

Figures

Figure 1
Figure 1
Schematic of skin microbiota according to the physiological sites: dry (green): buttock, volar forearm, hypothenar palm; moist (yellow): plantar heel, popliteal fossa, toe web space, axillary vault, and nare; sebaceous (purple): back, occiput, retroauricular crease, and glabella. Developed using data from (27).
Figure 2
Figure 2
Contribution of innate immune cells and inflammation to timely and delayed wound healing. (A) Representation of the four phases of wound healing ([1] Hemostasis, [2] Inflammation, [3] Proliferation and [4] Tissue Remodeling). (B) Chronic wounds are stalled in the inflammatory stage. We hypothesize that this inflammation is sustained by chronic activation of the innate immune system, which is driven their interactions and responses to polymicrobial biofilms found in and on the wound bed. DAMPs, damage-associate molecular patterns; PAMPs, pathogen-associated molecular patterns; MMPs, matrix metalloproteinases; ROS, reactive oxygen species; AMPs, antimicrobial peptides; TIMPs, tissue inhibitor of metalloproteinases. Created with BioRender.com.
Figure 3
Figure 3
Targeting bacteria-innate immune interactions to restore healing in chronic wounds. Standard therapies such as debridement, NPWT, antiseptics, and antibiotics have been shown to reduce bacterial bioburden in the wound bed, but they do not always restore healing processes. New therapeutics that have both antimicrobial and immunomodulatory properties may be able to overcome the limitations of more traditional treatments. Here, we show novel therapeutics that target these interactions that can be used in early and late stages of healing to restore tissue homeostasis. LPS, lipopolysaccharide; EPS, extracellular polymeric substance; PGA, peptidoglycan; AMP, antimicrobial peptide; mAb, monoclonal antibody; miRNA, microRNA. Created with BioRender.com.

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