Sepsis is not only the leading cause of death in non-coronary intensive care units (ICUs) but also one of the most common causes of morbidity and mortality for all hospitalised patients. Globally, 20 to 30 million patients are estimated to be afflicted every year with an astonishing hospital mortality rates between 30 and 60%. There is no current therapy for sepsis other than anti-infectives and supportive care. These approaches only give the body time to recover, but do not treat the cause of the problem. In this study we seek to discover the effects of the virulence factor from a bacterium, Yersinia pestis V antigen on LPS-induced responses. Y. pestis, the causative agent of the three main plague pandemics has been responsible for over 200 million deaths. The bacterium has been so successful because it encodes several virulence factors, one of which is V antigen. Our results demonstrate a modulatory role of Y. pestis V antigen on bacterial infections. Using monocytic and macrophage cells we have shown that V antigen can reduce the expression of pattern recognition receptors (PRRs) of the innate immune system, causing the modulation of the cellular response directed towards LPS bacterial pathogen-associated molecular patterns (PAMPs). We also tested different fractions of Y. pestis in order to identify the functional domain of responsible for this immunomodulation. Our results demonstrated that this functional domain in found within the amino acids 135-275 of V antigen. Of a greater magnitude, our in vivo data show an impressive 80% reduction in mortality in a mouse model of sepsis when mice are treated with V antigen in comparison to those that were not. This protein should unquestionably be further investigated as a possible therapeutic intervention for sepsis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:649412 |
| Date | January 2014 |
| Creators | Olden, Robin |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/73439/ |
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