Streptococcus pneumoniae in the heart subvert the host response through biofilm-mediated resident macrophage killing

PLoS Pathogens

Luke J. Tallon¹  Jessy Deshane¹  Carlos J. Orihuela¹  Amol C. Shetty¹  Yong Wang¹  Sandra Ott¹  Nikhil Kumar²  Terry Brissac²  Anukul T. Shenoy³  Whitney S. Hinkle³  Sean C. Daugherty³  Ryan P. Gilley³  Norberto Gonzalez-Juarbe⁴  Hervé Tettelin⁴ 

[1] Department of Microbiology and Immunology, Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United States of America;Department of Microbiology, Immunology, and Molecular Genetics, The University of Texas Health San Antonio, San Antonio, TX, United States of America;Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL, United States of America;Division of Pulmonary, Allergy & Critical Care Medicine, The University of Alabama at Birmingham, Birmingham, AL, United States of America

关键词: Heart;    Biofilms;    Gene expression;    Macrophages;    Bacterial biofilms;    Blood;    Pneumococcus;    Neutrophils;   

DOI  :  10.1371/journal.ppat.1006582

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

For over 130 years, invasive pneumococcal disease has been associated with the presence of extracellular planktonic pneumococci, i.e. diplococci or short chains in affected tissues. Herein, we show that Streptococcus pneumoniae that invade the myocardium instead replicate within cellular vesicles and transition into non-purulent biofilms. Pneumococci within mature cardiac microlesions exhibited salient biofilm features including intrinsic resistance to antibiotic killing and the presence of an extracellular matrix. Dual RNA-seq and subsequent principal component analyses of heart- and blood-isolated pneumococci confirmed the biofilm phenotype in vivo and revealed stark anatomical site-specific differences in virulence gene expression; the latter having major implications on future vaccine antigen selection. Our RNA-seq approach also identified three genomic islands as exclusively expressed in vivo. Deletion of one such island, Region of Diversity 12, resulted in a biofilm-deficient and highly inflammogenic phenotype within the heart; indicating a possible link between the biofilm phenotype and a dampened host-response. We subsequently determined that biofilm pneumococci released greater amounts of the toxin pneumolysin than did planktonic or RD12 deficient pneumococci. This allowed heart-invaded wildtype pneumococci to kill resident cardiac macrophages and subsequently subvert cytokine/chemokine production and neutrophil infiltration into the myocardium. This is the first report for pneumococcal biofilm formation in an invasive disease setting. We show that biofilm pneumococci actively suppress the host response through pneumolysin-mediated immune cell killing. As such, our findings contradict the emerging notion that biofilm pneumococci are passively immunoquiescent.

【 授权许可】

CC BY