Mycoplasma pneumoniae CARDS toxin is a unique virulence factor targeting the Th1/Th2 response for persistent infection

Abstract

Abstract Mycoplasma pneumoniae is a leading cause of bacterial community-acquired pneumonia and is implicated in the initiation and exacerbation of asthma. Over 2 million cases of M. pneumoniae infection occur in the United States each year. However, with no surveillance system in place for reporting infections, the true scope of the problem may be vastly underestimated. One of the hallmark immunological effects of M. pneumoniae infection is an imbalanced Th1/Th2 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 provoking a Th2 cytokine phenotype in mice. We hypothesize that CARDS toxin is utilized by M. pneumoniae in vivo to dampen the Th1 response and influence the Th2 response in order to establish a strong, persistent infection. The clinical isolate strain M. pneumoniae S1 abundantly produces CARDS toxin during infection and causes severe pathology. We utilized S1 as a template to generate a CARDS-deficient mutant we designated M7. M7 and S1 were used in vitro and in vivo to identify Th1- and Th2-specific cytokine changes during active infection. We observed significant differences in pathology between M7- and S1-infected mice, indicating that CARDS toxin directly impacted M. pneumoniae disease and persistence. Our findings provide insights to understand the elusive pathological mechanisms behind M. pneumoniae infection and implicate CARDS toxin as a potentially important target for therapeutic intervention during M. pneumoniae infection.