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Fibrin(ogen): friend and foe
Microbial infections and allergic reactions
Fibrin(ogen) is implicated in defense against pathogen invasion,112 for example in peritonitis. Recent findings from experiments in vitro and in vivo show that at the air-liquid interface formed following a skin wound fibrin can accu- mulate perpendicularly to generate a protective biofilm.14 These structures, which are an end product of clotting and fibrin formation, prevent blood cell loss from the wound but also block the entry and early proliferation of bacteria at the injury site. However, in other settings fibrin(ogen) enhances bacterial virulence15 or contributes to the develop- ment and perpetuation of allergic reactions.113
Certain bacteria express virulence factors that appropri- ate fibrin(ogen) to facilitate their entry into the host, lim- iting the antimicrobial role of fibrinogen and protecting the organisms from pharmacological treatments. Virulence factors can also enhance bacterial proliferation and dissemination.112
The anti- or pro-invasion effects of fibrin(ogen) reflect the activity of bacterial virulence factors (Table 1) which have adapted to unique host microenvironments. For example, different murine models of Staphylococcus aureus endocarditis require distinct factors for valve colonization. Microbial adhesion and colonization in mice with mechanically damaged valves involve fibrin(ogen), where- as in a model of cardiac valve inflammation, fibrin(ogen) depletion with ancrod did not impair bacterial coloniza- tion. Bacterial volume increased in ancrod-treated mice compared to that in controls.114 Further comprehension of the roles of coagulation factors on bacterial virulence may lead to therapeutic strategies for the treatment of infec- tious diseases, particularly given the increasing demand to find a solution to antibiotic resistance.115
In fungal infections, proteases contribute to inflamma- tion through interactions with the kinin system as well as the coagulation and fibrinolytic cascades.116 In this context, the fibrin(ogen) interaction with αMβ2 is implicated, as it
Table 1. Factors associated with fibrinogen-induced virulence.15,112
may further react with toll-like receptor 4 (TLR4) in immune cells, resulting in a highly efficient signaling com- plex that regulates the development of antifungal reac- tions, but also allergic airway disease.113 Fungal proteinases cleave fibrinogen into cleavage products (FCP) which, together with αMβ2 and TLR4, were found to be essential for fungal elimination by T and B lymphocytes, dendritic cells and macrophages. The fibrinogen hexamer can also inhibit fungal growth, perhaps due to low affinity fibrino- gen-target receptor interactions. However, the putative αMβ2/TLR4/FCP complex also triggered innate fungistatic immunity, modest allergic airway hyper-responsiveness and neutrophilia.113 Interestingly, this αMβ2/TLR4/FCP association has been described in unrelated settings, including endotoxemia and malaria.117,118 Thus, FCP that play a role in infection-mediated inflammatory responses have a pivotal role in the clinical outcome of patients with fungi-induced autoimmunity.113
Finally, fibrin(ogen) also seems to be implicated in bac- teria-driven hypersensitivity reactions. Pharmacological or genetic depletion of fibrinogen in mice improved the ani- mals’ survival when they were challenged with high con- centrations of lipopolysaccharide, and impeded the devel- opment of a variety of inflammatory conditions.15 In humans, afibrinogenemic patients have reduced responses in a delayed-type hypersensitivity reaction induced by exposure to bacterial antigens.119
Obesity and diabetes
Nutrient excess leads to imbalances in cellular and molecular mediators of immunity and inflammation.120 These may drive metabolic dysfunction while triggering a hypercoagulable state, with elevated circulating levels of fibrinogen being among key coagulation components.121 Initial risk, severe morbidity and mortality outcomes for vessel-occlusive disorders correlate positively with the
Factor
Clumping factor A
Fibronectin binding proteins A and B
Bone sialoprotein–binding protein
Extracellular fibrinogen–binding protein
Endocarditis- and biofilm-associated pilus-A
Coagulase and von Willebrand factor–binding protein
Staphylokinase
Virulence mechanisms
• Mediates the binding of bacteria to fibrin(ogen) immobilized on a surface
• Forms an abscess that prevents or inhibits platelet aggregation, complement activation and
opsonophagocytosis
• Contribute to biofilm formation
• Bind plasminogen to facilitate staphylokinase activity (see below)
• Prevents thrombin-mediated cleavage of fibrinogen
• Formation of a protective shield of fibrin(ogen) that prevents phagocytosis and innate immune cell recognition
• Sequestration of fibrinogen preventing its interaction with neutrophils
• Mediation of bacterial attachment to host fibrinogen, which permits building biofilms that o shield bacteria from immune cell recognition, antibiotics, and urine flow (if applicable) o contribute to nutrient acquisition
• Coagulase mediates formation of a fibrin(ogen)-containing inner pseudocapsule that envelopes bacterial microcolonies
• vWbp contributes to an extended outer dense protective layer
• Both induce thrombin activation to form a fibrin(ogen) protective shield around the bacteria
against phagocytosis and innate immune cell recognition
• Contributes to the activation of plasminogen, which readily degrades fibrin to prevent microbial entrapment or permit bacterial detachment and dispersion throughout the host
• Neutralizes the bactericidal effects of α-defensins secreted from polymorphonuclear cells
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