Journal Article

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

Hinkle, Whitney S., Brissac, Terry, Gilley, Ryan P., Kumar, Nikhil, Shenoy, Anukul T., Wang, Yong, Tettelin, Hervé, Ott, Sandra, Daugherty, Sean C., Shetty, Amol C., Tallon, Luke J., Gonzalez-Juarbe, Norberto, Deshane, Jessy, Orihuela, Carlos J.

2017

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Antibiotics / Biofilms / Biology and Life Sciences / Blotting, Western / Cell cycle / Clonal deletion / Critical care / Disease Models, Animal / Extracellular matrix / Female / Flow Cytometry / Fluorescent Antibody Technique / Gene expression / Gene Expression Profiling / Genetic aspects / Genomes / Genomic islands / Genomics / Heart / Heart diseases / Immunology / Infiltration / Macrophages / Macrophages - immunology / Medicine / Medicine and Health Sciences / Mice / Mice, Inbred BALB C / Microbial drug resistance / Microscopy, Electron, Transmission / Myocarditis - immunology / Myocarditis - microbiology / Myocardium / Physiological aspects / Pneumococcal Infections - genetics / Pneumococcal Infections - immunology / Pneumolysin / Principal Component Analysis / Ribonucleic acid / RNA / Software / Streptococcus / Streptococcus infections / Streptococcus pneumoniae / Streptococcus pneumoniae - genetics / Streptococcus pneumoniae - immunology / Supervision / Tissues / Toxins / Transcriptome / Virulence / Virulence - genetics / Virulence - immunology