Factors contributing to Pseudomonas aeruginosa pathogenesisPublic Deposited
Pseudomonas aeruginosa is a Gram-negative pathogen that frequently causes severe nosocomial infections through expression of virulence factors, evasion of immune clearance and resistance to therapeutic antimicrobial agents. These factors have led the US Centers for Disease Control and Prevention (CDC) and Infectious Disease Society of America (IDSA) to identify P. aeruginosa as a severe threat to public health. Thus, understanding P. aeruginosa pathogenesis is of interest and concern to the medical and scientific communities. In the current study, we examined factors that contribute to pathogenesis, including the host immune response and antimicrobial resistance. Using mice deficient in components of the inflammasome, an important component of the host innate immune defense to infection, we demonstrated that the inflammasome adaptor protein apoptosis speck-like protein containing a CARD (ASC) is associated with severe pre-lethal illness in a mouse model of pneumonia. In the absence of ASC, infected mice exhibited improved survival and bacterial clearance from the lungs compared to mice lacking the inflammasome effector protein caspase-1/11 and C57BL/6 (B6) mice. Interestingly, we found that ASC is required for activation of caspase-3 in addition to caspase-1. Furthermore, activation of ASC-dependent caspase-3 activity was dependent on P. aeruginosa possessing a functional type III secretion system. Collectively, these findings may provide an alternate strategy for P. aeruginosa to promote severe infection in vivo by activating caspase-3 through ASC, independent of caspase-1 activation. Next, we utilized a pre-existing library of P. aeruginosa isolates to analyze relationships between antimicrobial resistance and bacterial virulence using statistical models. We found that strains with higher bacterial virulence had a lower odds ratio of exhibiting an antibiotic-resistant or MDR phenotype by logistic regression. Interestingly, P. aeruginosa strains that secrete the T3SS effector protein ExoU had higher odds ratio of antibiotic resistance. We also found a correlation between resistance to a greater number of antimicrobial classes and lower virulence scores by linear regression. Collectively, these models demonstrate an inverse relationship between antimicrobial resistance and bacterial virulence. In summary, we describe how P. aeruginosa exacerbates the ASC-mediated immune response to promote severe illness in a mouse model of pneumonia and how strains of increased virulence are more likely to be antibiotic susceptible or exhibit resistance to fewer antimicrobial classes. These results further our understanding of the various strategies that P. aeruginosa employs to overcome clearance mechanisms in promoting disease.