Research Description

Characterization of Polymicrobial Sepsis-Induced Immune Suppression after Infection with Pseudomonas aeruginosa or Listeria monocytogenes

Polymicrobial sepsis carries an overall mortality rate of 30-50%. A successful response to sepsis requires an appropriate early innate immune response that is not overly exaggerated contributing to shock and subsequent death. However, the early innate immune response required to address the initial infective challenge may also predispose the host to a subsequent state of immune dysfunction/suppression that contributes to late sepsis mortality. We believe that a better understanding of sepsis-induced immune suppression will help guide therapy and reduce late sepsis mortality.

Pseudomonas aeruginosa and Listeria monocytogenes are microbial pathogens that commonly cause infections in critically ill patients. In order to determine whether these infections are the result of post-sepsis immune dysfunction, we developed a two hit mouse model of polymicrobial sepsis, by first performing a cecal ligation and puncture (CLP), followed by pseudomonal pneumonia or listeriosis. Following these secondary bacterial assaults, the spleen, liver, and lungs from infected animals were harvested and the colony forming units of each microorganism determined. We found that animals infected by P. aeruginosa at day 3 after CLP-sepsis exhibit increased mortality compared to sham and healthy control animals however that difference in mortality had disappeared by 10 days after CLP-sepsis. Conversely, animals treated at 3 and 10 days post CLP-sepsis with Listeria monocytogenes demonstrated improved survival, compared to sham-treated mice and healthy controls. Furthermore, by infecting mice with a Listeria monocytogenes that expresses OVA-peptide on its surface, we were able to demonstrate that septic mice exhibit five-fold greater levels of OVA-specific IgM antibodies after listerial infection than do sham-treated mice or healthy controls.

The data demonstrate that mice display an elevated mortality rate to Pseudomonas infection early after sepsis, but improved survival to Listeria challenge throughout sepsis. Moreover, septic mice demonstrate elevated levels of IgM antibodies toward Listeria which may explain their enhanced survival.