Hemostatic Factors in Bacterial Virulence and Host Defense
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University of Cincinnati / OhioLINK
2012
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ndltd-OhioLink-oai-etd.ohiolink.edu-ucin13294951332021-08-03T06:15:19Z Hemostatic Factors in Bacterial Virulence and Host Defense Prasad, Joni M. Immunology Staphylococcus aureus is a re-emerging pathogen that is one of the most frequent causes of human disease, especially within the healthcare setting. With mortality rates around 25% even with antibiotic treatment and the increasing prevalence of antibiotic resistant strains, the need for new treatments options outside of traditional antibiotics has been highlighted. Like a number of other microbial pathogens, S. aureus has evolved the means to engage host hemostatic factors, including an impressive repertoire of products that control fibrin deposition (the prothrombin activators coagulase (Coa) and von Willebrand Factor binding protein (vWbp), dissolution (the plasminogen activator staphylokinase), and binding (the fibrinogen receptor clumping factor A (ClfA)). These observations suggest a hypothesis that hemostatic factors, in general, and fibrinogen, in particular, are likely to be important determinants of bacterial virulence and host defense in S. aureus infection. In order to test this hypothesis, we directly infected control (Fib+) and fibrinogen-deficient (Fib-) mice using a model of S. aureus-induced acute peritonitis.Control mice infected with 10^9 CFUs of S. aureus efficiently eliminated ~99.5% of bacterial CFUs within 15 minutes, whereas fibrinogen-deficient mice infected in parallel exhibited little to no capacity to clear the microbe, even after several hours. Consistent with these findings, fibrinogen-deficient mice challenged with S. aureus peritonitis exhibited a poor survival profile relative to control animals. More detailed studies to define the mechanism(s) underlying the efficient, fibrinogen-dependent clearance of S. aureus from the peritoneal cavity have excluded a critical contribution of a number of immune system components, including T and B cells, immunoglobulins, mast cells, NK cells, neutrophils, complement, toll-like receptor signaling pathways, and the bacterial fibrinogen receptor ClfA. Effective bacterial clearance was found to depend, however, on peritoneal macrophages. While the precise details of the inflammatory response mediating fibrinogen-dependent bacterial clearance remain to be defined, using three independent genetically engineered mice carrying either extremely low levels of prothrombin, a mutant form of prothrombin largely lacking procoagulant function, or mice carrying a mutant form of fibrinogen that cannot be converted into fibrin, we have demonstrated that bacterial clearance depends on fibrin polymer formation, and not on soluble fibrinogen. While the formation of fibrin polymer was determined to be critical for host success following intraperitoneal infection with S. aureus, thrombin generation via the initiator of host hemostasis, tissue factor, was apparently irrelevant for bacterial clearance, suggesting that bacterial prothrombin activators were likely to drive fibrin deposition, and thus bacterial clearance in this model. Studies of S. aureus mutants with single and combined deficits in the bacterial procoagulants confirmed this hypothesis and revealed that vWbp, but not Coa, is a fundamental determinant of bacterial clearance, supporting the concept that catalytically active vWbp- prothrombin complexes drive fibrin polymer formation and bacterial clearance from the peritoneal cavity. Our research reveals that a better understanding of the complex interactions between bacterial proteins, the hemostatic, and the inflammatory systems may reveal novel therapeutic approaches for the treatment of microbial infections. 2012-04-20 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1329495133 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1329495133 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Immunology |
| spellingShingle |
Immunology Prasad, Joni M. Hemostatic Factors in Bacterial Virulence and Host Defense |
| author |
Prasad, Joni M. |
| author_facet |
Prasad, Joni M. |
| author_sort |
Prasad, Joni M. |
| title |
Hemostatic Factors in Bacterial Virulence and Host Defense |
| title_short |
Hemostatic Factors in Bacterial Virulence and Host Defense |
| title_full |
Hemostatic Factors in Bacterial Virulence and Host Defense |
| title_fullStr |
Hemostatic Factors in Bacterial Virulence and Host Defense |
| title_full_unstemmed |
Hemostatic Factors in Bacterial Virulence and Host Defense |
| title_sort |
hemostatic factors in bacterial virulence and host defense |
| publisher |
University of Cincinnati / OhioLINK |
| publishDate |
2012 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1329495133 |
| work_keys_str_mv |
AT prasadjonim hemostaticfactorsinbacterialvirulenceandhostdefense |
| _version_ |
1719433517979402240 |