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Biofilm-Innate Immune Interface: Contribution to Chronic Wound Formation

Versey, Zoya, da Cruz Nizer, Waleska Stephanie, Russell, Emily, Zigic, Sandra, DeZeeuw, Katrina G., Marek, Jonah E., Overhage, Joerg, Cassol, Edana·2021·Frontiers in Immunology
DOI 10.3389/fimmu.2021.648554PMC PMC8062706
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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.

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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 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).CC BY · PubMed Central
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 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.CC BY · PubMed Central
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.
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.CC BY · PubMed Central

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Metadata

Authors
Versey, Z., da Cruz Nizer, W. S., Russell, E., Zigic, S., DeZeeuw, K. G., Marek, J. E., Overhage, J., & Cassol, E.
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2021-04-09
Volume
12
ISSN
1664-3224
DOI
10.3389/fimmu.2021.648554
PMC
PMC8062706
Cited by
253
References
35
Licence
creativecommons.org/licenses/by/4.0/ (vor)

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CoChat. (2026). Citation check: Biofilm-Innate Immune Interface: Contribution to Chronic Wound Formation. https://app.cochat.ai/papers/10.3389/fimmu.2021.648554
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Versey, Z., da Cruz Nizer, W. S., Russell, E., Zigic, S., DeZeeuw, K. G., Marek, J. E., Overhage, J., & Cassol, E. (2021). Biofilm-Innate Immune Interface: Contribution to Chronic Wound Formation. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2021.648554