CARDS toxin is critical for mediating the early inflammatory response during Mycoplasma pneumoniae infection

Abstract

Abstract Mycoplasma pneumoniae is a leading cause of bacterial community-acquired pneumonia and is implicated in initiation and exacerbation of asthma. One of the characteristic signs of M. pneumoniae infection in humans is an imbalanced proinflammatory immune response. A recently identified M. pneumoniae virulence factor is the Community-Acquired Respiratory Distress Syndrome (CARDS) toxin, an ADP-ribosylating and vacuolating protein produced abundantly during infection that is capable of displaying inflammation and pathology similar to infection with live M. pneumoniae. Our prior studies have focused heavily on the potent inflammatory effects of CARDS toxin in vitro, however its exact role during infection is unclear. We hypothesized that an M. pneumoniae strain lacking CARDS toxin expression would be unable to trigger the robust inflammatory response in vivo that is necessary for M. pneumoniae pathogenesis. We genetically modified the clinical isolate M. pneumoniae S1 strain to generate a CARDS-deficient mutant we designated M7. M7 and S1 were used in vivo to identify changes in the proinflammatory response. Interestingly, we observed a drastic difference in the dynamics of M. pneumoniae infection during the early course of infection. Secretion of the cytokines TNF-α and CXCL1 were both significantly altered early during infection in M7-infected mice. The effects of this response led to a significant impact on Mycoplasma survival. By utilizing a novel CARDS toxin-deficient mutant of M. pneumoniae, our findings provide valuable insight into our understanding of the innate immune response against M. pneumoniae and implicate CARDS toxin as a potentially important target for therapeutic intervention during M. pneumoniae infection.