STREPTOCOCCUS PNEUMONIAE-INDUCED HOST RESPONSES & DISEASE

Abstract

STREPTOCOCCUS PNEUMONIAE IS A LEADING CAUSE OF PNEUMONIA AND ONE OF THE MOST COMMON CAUSES OF DEATH GLOBALLY. NEVERTHELESS, THE IMPACT OF S. PNEUMONIAE ON HOST MOLECULAR PROCESSES THAT LEAD TO DETRIMENTAL PULMONARY CONSEQUENCES ARE NOT FULLY UNDERSTOOD. HERE, WE SHOW THAT S. PNEUMONIAE INDUCES TOXIC DNA DOUBLE STRAND BREAKS (DSBS) IN HUMAN ALVEOLAR EPITHELIAL CELLS, AS INDICATED BY ATAXIA TELANGIECTASIA MUTATED (ATM) KINASE-DEPENDENT PHOSPHORYLATION OF HISTONE H2AX AND CO-LOCALIZATION WITH 53BP1. S. PNEUMONIAE IS ABLE TO INDUCE GENOTOXICITY VIA STREPTOCOCCAL PYRUVATE OXIDASE (SPXB)-MEDIATED PRODUCTION OF H2O2 AND DNA DAMAGE CAN OCCUR IN A BACTERIAL CONTACTIN DEPENDENT FASHION. THE EXTENT OF S. PNEUMONIAE-INDUCED DNA DAMAGE CORRELATES WITH THE EXTENT OF APOPTOSIS AND PRECEDES IT. FURTHER, BOTH ADDITION OF CATALASE, WHICH NEUTRALIZES H2O2, DURING IN VITRO INFECTION AND KNOCKOUT OF THE SPXB GENE IN S. PNEUMONIAE, GREATLY SUPPRESS PNEUMOCOCCI-INDUCED DNA DAMAGE AND APOPTOSIS. IMPORTANTLY,