Protection from pneumonic plague by the induction of heme oxygenase-1
Yersinia pestis is the etiological agent of the disease known as plague. The pathology of this disease is characterized by organ failure due to necrosis and hyperinflammation towards the end of the disease. However, Y. pestis has a type 3 secretion system (T3SS) with effector Yops that stifle inflammation, a pgm locus that enables better survival within the mammalian host, and a tetraacylated LPS that renders innate immune sensing by TLR4 anti-stimulatory. Based on the evidence of these virulence factors, added with the lack of inflammation that is present at the beginning of the infection we made the hypothesis that the inflammation may not be related to the pathogen, but to the damage the pathogen creates. This led our laboratory to investigate the damage to the host as the potential source of this hyperinflammation response. We found that the production of yersiniabactin was necessary to induce damage and establish Y. pestis colonies in the lung. This lung damage induced the cytoprotective enzyme heme oxygenase-1, which is an enzyme that catalyzes heme degradation into CO, biliverdin, and Fe2+. We show that by upregulating HO-1 activity by administering a compound, cobalt protoporphyrin IX, we were able to ameliorate the hyperinflammation, lessen tissue damage, and increase survival in animals infected with Y. pestis.
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