Cardiac microlesion formation during invasive pneumococcal disease

University Of Alabama At Birmingham, Birmingham AL

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Abstract

One-in-five adults hospitalized for Streptococcus pneumoniae (Spn, the pneumococcus) pneumonia experience a major adverse cardiac event (MACE) with affected individuals four times more likely to die than those with pneumonia alone. Spn-associated MACE is the result of the physiological stress imposed on the heart as well as direct cardiac damage caused by harmful bacterial products. This competitive Multi-PI R01 renewal is focused on identifying the molecular mechanisms underlying the hyper-virulence of Global Pneumococcal Sequence Cluster 10 (GPSC10). GPSC10 is a globally distributed and expanding genetic lineage of Spn which causes MACE at 2.5-fold the rate of all other GPSC. Moreover, GPSC10 is multi-drug resistant and has member isolates carrying serotypes not covered by the newest 20-valent conjugate vaccine. Thus, current prophylactic and therapeutic approaches against GPSC10 are inadequate. Our goal is to identify the genetic determinants responsible for GPSC10 hyper-virulence and determine if the encoded proteins are viable targets for intervention. Our hypotheses are: 1) genes present in GPSC10 and absent in non-invasive / non-cardiotropic GPSC are responsible for its enhanced virulence, and 2) virulence determinants encoded by these genes can be blocked for protection against severe disease, cardiac damage, and MACE. Note, that in pilot studies we have already determined that a particular allele of zmpB, a gene encoding a zinc metalloprotease (Zmp), is disproportionately present among GPSC10 isolates; that an isogenic zmpB deficient mutant, i.e., ∆zmpB, had substantially reduced capacity to cause cardiac damage in mice versus wildtype Spn; and collected data that suggests immunization with recombinant (r)ZmpB is protective against cardiac damage following invasive disease. Thus, our chosen approach is strong. AIM 1: Identify the genetic determinants responsible for GPSC10 hyper-virulence and cardiac tropism. Using Spn whole genome sequences, deidentified metadata corresponding to in-house clinical isolates, and results obtained from mice experimentally challenged with clinical isolates, we will perform multiple bacterial genome wide association studies (bGWAS) to identify the genetic elements whose presence correlate with GPSC10 hyper-virulence. Genes identified as associated with cardiac damage will be deleted in diverse Spn, including GPSC10, and their contribution to disease verified in vivo. AIM 2: Determine how ZmpB contributes to cardiac damage and assess the protective efficacy of antibody. We will confirm the role of ZmpB not only in acute cardiac injury, but also with regard to the adverse cardiac remodeling and dysfunction that takes place post-infection. We will determine the molecular basis for its secretion, a novel feature of ZmpB versus other zinc metalloproteases found in Spn and determine the impact of blocking this process on virulence and disease. We will test if immunization with ZmpB confers cardiac protection and whether passive administration of antibody has therapeutic efficacy.