Mice expressing a mutant form of fibrinogen that cannot support fibrin formation exhibit compromised antimicrobial host defense

Prasad, Joni M.; Gorkun, Oleg V.; Raghu, Harini; Thornton, Sherry; Mullins, Eric S.; Palumbo, Joseph S.; Ko, Ya Ping; Höök, Magnus; David, Tovo; Coughlin, Shaun R.; Degen, Jay L.; Flick, Matthew J.

doi:10.1182/blood-2015-04-639849

Cited by 83 publications

(92 citation statements)

References 63 publications

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“…However, as illustrated by the case of fibrin-dependent killing of S. aureus in the peritoneal cavity (Prasad et al, 2015), in some instances it is beneficial for the pathogen to escape from clumps, and thus avoid entrapment by the immune system and freely disseminate to other infection sites. Therefore S. aureus may have evolved mechanisms for leaving clumps and fibrin aggregates.…”

Section: Anti-clumping Mechanismsmentioning

confidence: 99%

Staphylococcus aureus Aggregation and Coagulation Mechanisms, and Their Function in Host–Pathogen Interactions

Crosby

Kwieciński

Horswill

2016

Advances in Applied Microbiology

117

100

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The human commensal bacterium Staphylococcus aureus can cause a wide range of infections ranging from skin and soft tissue infections to invasive diseases like septicemia, endocarditis, and pneumonia. Muticellular organization almost certainly contributes to S. aureus pathogenesis mechanisms. While there has been considerable focus on biofilm formation and its role in colonizing prosthetic joints and indwelling devices, less attention has been paid to non-surface attached group behavior like aggregation and clumping. S. aureus is unique in its ability to coagulate blood, and it also produces multiple fibrinogen-binding proteins that facilitate clumping. Formation of clumps, which are large, tightly-packed groups of cells held together by fibrin(ogen), has been demonstrated to be important for S. aureus virulence and immune evasion. Clumps of cells are able to avoid detection by the host’s immune system due to a fibrin(ogen) coat that acts as a shield, and the size of the clumps facilitates evasion of phagocytosis. In addition, clumping could be an important early step in establishing infections that involve tight clusters of cells embedded in host matrix proteins, such as soft tissue abscesses and endocarditis. In this review we discuss clumping mechanisms and regulation, as well as what is known about how clumping contributes to immune evasion.

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Section: Anti-clumping Mechanismsmentioning

confidence: 99%

Staphylococcus aureus Aggregation and Coagulation Mechanisms, and Their Function in Host–Pathogen Interactions

Crosby

Kwieciński

Horswill

2016

Advances in Applied Microbiology

117

100

View full text Add to dashboard Cite

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“…To confirm the association between increased fibrin clotting and increased S. aureus virulence and infection severity, a heterozygous plasminogen activator inhibitor-1 (PAI-1) transgenic mouse was utilized. This mouse is modestly hypercoagulable and has no known immune defects (36), in contrast to strains with either ablated or overexpressed fibrinogen that have immunologic impairments that are likely to confound results (37). This mouse model is also relevant because PAI-1 levels are known to be increased in diabetic patients (33).…”

Section: Figmentioning

confidence: 99%

Adaptive Upregulation of Clumping Factor A (ClfA) by Staphylococcus aureus in the Obese, Type 2 Diabetic Host Mediates Increased Virulence

et al. 2017

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Obesity and associated type 2 diabetes (T2D) are important risk factors for infection following orthopedic implant surgery. Staphylococcus aureus, the most common pathogen in bone infections, adapts to multiple environments to survive and evade host immune responses. Whether adaptation of S. aureus to the unique environment of the obese/T2D host accounts for its increased virulence and persistence in this population is unknown. Thus, we assessed implant-associated osteomyelitis in normal versus high-fat-diet obese/T2D mice and found that S. aureus infection was more severe, including increases in bone abscesses relative to nondiabetic controls. S. aureus isolated from bone of obese/T2D mice displayed marked upregulation of four adhesion genes (clfA, clfB, bbp, and sdrC), all with binding affinity for fibrin(ogen). Immunostaining of infected bone revealed increased fibrin deposition surrounding bacterial abscesses in obese/T2D mice. In vitro coagulation assays demonstrated a hypercoagulable state in obese/T2D mice that was comparable to that of diabetic patients. S. aureus with an inactivating mutation in clumping factor A (clfA) showed a reduction in bone infection severity that eliminated the effect of obesity/T2D, while infections in control mice were unchanged. In infected mice that overexpress plasminogen activator inhibitor-1 (PAI-1), S. aureus clfA expression and fibrin-encapsulated abscess communities in bone were also increased, further linking fibrin deposition to S. aureus expression of clfA and infection severity. Together, these results demonstrate an adaptation by S. aureus to obesity/T2D with increased expression of clfA that is associated with the hypercoagulable state of the host and increased virulence of S. aureus.

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“…Fib AEK mice demonstrated partial cessation of bleeding in a standard tail amputation bleeding time. 39 This suggests that, although inadequate fibrin polymerization contributes to abnormal hemostasis in fII MZ mice, positive feedback for selfactivation also likely participates in the failure to achieve hemostasis.…”

Section: Discussionmentioning

confidence: 99%

Limiting prothrombin activation to meizothrombin is compatible with survival but significantly alters hemostasis in mice

Shaw¹,

Kombrinck

McElhinney³

et al. 2016

Blood

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• Mice expressing a form of prothrombin with limited activation potential to meizothrombin are viable and are reproductively successful.• Meizothrombin directly activates platelets but has diminished positive regulation of hemostatic factor activation.Thrombin-mediated proteolysis is central to hemostatic function but also plays a prominent role in multiple disease processes. The proteolytic conversion of fII to a-thrombin (fIIa) by the prothrombinase complex occurs through 2 parallel pathways: (1)

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Mice expressing a mutant form of fibrinogen that cannot support fibrin formation exhibit compromised antimicrobial host defense

Abstract: Key Points Mutation of the fibrinogen Aα chain in mice to selectively eliminate thrombin cleavage prevents fibrin polymer formation in vivo. Fibrin polymer formation drives antimicrobial function and supports host survival following S aureus peritoneal infection.

Cited by 83 publications

References 63 publications

Staphylococcus aureus Aggregation and Coagulation Mechanisms, and Their Function in Host–Pathogen Interactions

Staphylococcus aureus Aggregation and Coagulation Mechanisms, and Their Function in Host–Pathogen Interactions

Adaptive Upregulation of Clumping Factor A (ClfA) by Staphylococcus aureus in the Obese, Type 2 Diabetic Host Mediates Increased Virulence

Limiting prothrombin activation to meizothrombin is compatible with survival but significantly alters hemostasis in mice

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