Activation of Heme Oxygenase Expression by Cobalt Protoporphyrin Treatment Prevents Pneumonic Plague Caused by Inhalation of Yersinia pestis

Abstract

Pneumonic plague, caused by the Gram-negative bacteria Yersinia pestis, is an invasive, rapidly progressing disease with poor survival rates. Following inhalation of Y. pestis, bacterial invasion of the lungs and a tissue-damaging inflammatory response allows vascular spread of the infection. Consequently, primary pneumonic plague is a multiorgan disease involving sepsis and necrosis of immune tissues and the liver, as well as bronchopneumonia and rampant bacterial growth. Given the likely role of the hyperinflammatory response in accelerating the destruction of tissue, in this work we evaluated the therapeutic potential of the inducible cytoprotective enzyme heme oxygenase 1 (HO-1) against primary pneumonic plague. On its own, the HO-1 inducer cobalt protoporphyrin IX (CoPP) provided mice protection from lethal challenge with Y. pestis CO92 with improved pulmonary bacterial clearance and a dampened inflammatory response compared to vehicle-treated mice. Furthermore, CoPP treatment combined with doxycycline strongly enhanced protection in a rat aerosol challenge model. Compared to doxycycline alone, CoPP treatment increased survival, with a 3-log decrease in median bacterial titer recovered from the lungs and the general absence of a systemic hyperinflammatory response. In contrast, treatment with the HO-1 inhibitor SnPP had no detectable impact on doxycycline efficacy. The combined data indicate that countering inflammatory toxicity by therapeutically inducing HO-1 is effective in reducing the rampant growth of Y. pestis and preventing pneumonic plague.

Sex differences in immune protection in mice conferred by heterologous vaccines for pneumonic plague

“…Sex differences in intrinsic Y. pestis resistance have rarely been observed, with most studies showing similar susceptibility between sexes. Several research groups have combined males and females in pneumonic plague experiments without noting any difference in outcomes, using BALB/c mice ( 78 ), C57BL/6 mice ( 49 , 90 ), rats ( 91 ), and NHPs ( 92 ). In some studies females even fare worse, as assessed by mortality in rats ( 90 ) or other markers, such as earlier time to bacteremia in Swiss Webster mice ( 93 ).…”

“…Several research groups have combined males and females in pneumonic plague experiments without noting any difference in outcomes, using BALB/c mice ( 78 ), C57BL/6 mice ( 49 , 90 ), rats ( 91 ), and NHPs ( 92 ). In some studies females even fare worse, as assessed by mortality in rats ( 90 ) or other markers, such as earlier time to bacteremia in Swiss Webster mice ( 93 ). One group looked at Brown Norway rats and saw no difference in mortality but reported minor differences in vital signs as monitored by telemetry ( 94 ).…”

Treatment with Fluticasone Propionate Increases Antibiotic Efficacy during Treatment of Late-Stage Primary Pneumonic Plague

“…These results indicate that host inflammatory responses complicate treatment of late-stage pneumonic plague, suggesting that coupling anti-inflammatory treatment with aggressive antibiotic therapy may improve survival outcomes of pneumonic plague. Little research has been performed to identify adjunctive therapies to overcome the host response during Y. pestis infection ( 61 – 64 ), and research is warranted to identify and evaluate additional supportive therapies in clinical cases. Further, these results may be relevant to other types of pneumonia for which host inflammatory responses complicate treatment of late and/or severe disease.…”