Relative Contributions of Extracellular and Internalized Bacteria to Early Macrophage Proinflammatory Responses to <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>

ABSTRACT Both intracellular immune sensing and extracellular innate immune sensing have been implicated in initiating macrophage proinflammatory cytokine responses to Streptococcus pneumoniae. The S. pneumoniae capsule, a major virulence determinant, prevents phagocytosis, and we hypothesized that t...

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Autores principales:	Jimstan Periselneris, Giuseppe Ercoli, Tracey Pollard, Suneeta Chimalapati, Emilie Camberlein, Gabriella Szylar, Catherine Hyams, Gillian Tomlinson, Fernanda C. Petersen, R. Andres Floto, Mahdad Noursadeghi, Jeremy S. Brown
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Streptococcus pneumoniae capsule TLR2 inflammation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d089ef97c70043238d89741d49e77722
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spelling	oai:doaj.org-article:d089ef97c70043238d89741d49e777222021-11-15T15:59:41ZRelative Contributions of Extracellular and Internalized Bacteria to Early Macrophage Proinflammatory Responses to <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>10.1128/mBio.02144-192150-7511https://doaj.org/article/d089ef97c70043238d89741d49e777222019-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02144-19https://doaj.org/toc/2150-7511ABSTRACT Both intracellular immune sensing and extracellular innate immune sensing have been implicated in initiating macrophage proinflammatory cytokine responses to Streptococcus pneumoniae. The S. pneumoniae capsule, a major virulence determinant, prevents phagocytosis, and we hypothesized that this would reduce activation of host innate inflammatory responses by preventing activation of intracellular proinflammatory signaling pathways. We investigated this hypothesis in human monocyte-derived macrophages stimulated with encapsulated or isogenic unencapsulated mutant S. pneumoniae. Unexpectedly, despite strongly inhibiting bacterial internalization, the capsule resulted in enhanced inflammatory cytokine production by macrophages infected with S. pneumoniae. Experiments using purified capsule material and a Streptococcus mitis mutant expressing an S. pneumoniae serotype 4 capsule indicated these differences required whole bacteria and were not due to proinflammatory effects of the capsule itself. Transcriptional profiling demonstrated relatively few differences in macrophage gene expression profiles between infections with encapsulated S. pneumoniae and those with unencapsulated S. pneumoniae, largely limited to reduced expression of proinflammatory genes in response to unencapsulated bacteria, predicted to be due to reduced activation of the NF-κB family of transcription factors. Blocking S. pneumoniae internalization using cytochalasin D had minimal effects on the inflammatory response to S. pneumoniae. Experiments using murine macrophages indicated that the affected genes were dependent on Toll-like receptor 2 (TLR2) activation, although not through direct stimulation of TLR2 by capsule polysaccharide. Our data demonstrate that the early macrophage proinflammatory response to S. pneumoniae is mainly dependent on extracellular bacteria and reveal an unexpected proinflammatory effect of encapsulated S. pneumoniae that could contribute to disease pathogenesis. IMPORTANCE Multiple extra- and intracellular innate immune receptors have been identified that recognize Streptococcus pneumoniae, but the relative contributions of intra- versus extracellular bacteria to the inflammatory response were unknown. We have shown that intracellular S. pneumoniae contributes surprisingly little to the inflammatory responses, with production of important proinflammatory cytokines largely dependent on extracellular bacteria. Furthermore, although we expected the S. pneumoniae polysaccharide capsule to block activation of the host immune system by reducing bacterial internalization and therefore activation of intracellular innate immune receptors, there was an increased inflammatory response to encapsulated compared to unencapsulated bacteria, which is likely to contribute to disease pathogenesis.Jimstan PeriselnerisGiuseppe ErcoliTracey PollardSuneeta ChimalapatiEmilie CamberleinGabriella SzylarCatherine HyamsGillian TomlinsonFernanda C. PetersenR. Andres FlotoMahdad NoursadeghiJeremy S. BrownAmerican Society for MicrobiologyarticleStreptococcus pneumoniaecapsuleTLR2inflammationMicrobiologyQR1-502ENmBio, Vol 10, Iss 5 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Streptococcus pneumoniae capsule TLR2 inflammation Microbiology QR1-502
spellingShingle	Streptococcus pneumoniae capsule TLR2 inflammation Microbiology QR1-502 Jimstan Periselneris Giuseppe Ercoli Tracey Pollard Suneeta Chimalapati Emilie Camberlein Gabriella Szylar Catherine Hyams Gillian Tomlinson Fernanda C. Petersen R. Andres Floto Mahdad Noursadeghi Jeremy S. Brown Relative Contributions of Extracellular and Internalized Bacteria to Early Macrophage Proinflammatory Responses to <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>
description	ABSTRACT Both intracellular immune sensing and extracellular innate immune sensing have been implicated in initiating macrophage proinflammatory cytokine responses to Streptococcus pneumoniae. The S. pneumoniae capsule, a major virulence determinant, prevents phagocytosis, and we hypothesized that this would reduce activation of host innate inflammatory responses by preventing activation of intracellular proinflammatory signaling pathways. We investigated this hypothesis in human monocyte-derived macrophages stimulated with encapsulated or isogenic unencapsulated mutant S. pneumoniae. Unexpectedly, despite strongly inhibiting bacterial internalization, the capsule resulted in enhanced inflammatory cytokine production by macrophages infected with S. pneumoniae. Experiments using purified capsule material and a Streptococcus mitis mutant expressing an S. pneumoniae serotype 4 capsule indicated these differences required whole bacteria and were not due to proinflammatory effects of the capsule itself. Transcriptional profiling demonstrated relatively few differences in macrophage gene expression profiles between infections with encapsulated S. pneumoniae and those with unencapsulated S. pneumoniae, largely limited to reduced expression of proinflammatory genes in response to unencapsulated bacteria, predicted to be due to reduced activation of the NF-κB family of transcription factors. Blocking S. pneumoniae internalization using cytochalasin D had minimal effects on the inflammatory response to S. pneumoniae. Experiments using murine macrophages indicated that the affected genes were dependent on Toll-like receptor 2 (TLR2) activation, although not through direct stimulation of TLR2 by capsule polysaccharide. Our data demonstrate that the early macrophage proinflammatory response to S. pneumoniae is mainly dependent on extracellular bacteria and reveal an unexpected proinflammatory effect of encapsulated S. pneumoniae that could contribute to disease pathogenesis. IMPORTANCE Multiple extra- and intracellular innate immune receptors have been identified that recognize Streptococcus pneumoniae, but the relative contributions of intra- versus extracellular bacteria to the inflammatory response were unknown. We have shown that intracellular S. pneumoniae contributes surprisingly little to the inflammatory responses, with production of important proinflammatory cytokines largely dependent on extracellular bacteria. Furthermore, although we expected the S. pneumoniae polysaccharide capsule to block activation of the host immune system by reducing bacterial internalization and therefore activation of intracellular innate immune receptors, there was an increased inflammatory response to encapsulated compared to unencapsulated bacteria, which is likely to contribute to disease pathogenesis.
format	article
author	Jimstan Periselneris Giuseppe Ercoli Tracey Pollard Suneeta Chimalapati Emilie Camberlein Gabriella Szylar Catherine Hyams Gillian Tomlinson Fernanda C. Petersen R. Andres Floto Mahdad Noursadeghi Jeremy S. Brown
author_facet	Jimstan Periselneris Giuseppe Ercoli Tracey Pollard Suneeta Chimalapati Emilie Camberlein Gabriella Szylar Catherine Hyams Gillian Tomlinson Fernanda C. Petersen R. Andres Floto Mahdad Noursadeghi Jeremy S. Brown
author_sort	Jimstan Periselneris
title	Relative Contributions of Extracellular and Internalized Bacteria to Early Macrophage Proinflammatory Responses to <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>
title_short	Relative Contributions of Extracellular and Internalized Bacteria to Early Macrophage Proinflammatory Responses to <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>
title_full	Relative Contributions of Extracellular and Internalized Bacteria to Early Macrophage Proinflammatory Responses to <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>
title_fullStr	Relative Contributions of Extracellular and Internalized Bacteria to Early Macrophage Proinflammatory Responses to <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>
title_full_unstemmed	Relative Contributions of Extracellular and Internalized Bacteria to Early Macrophage Proinflammatory Responses to <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>
title_sort	relative contributions of extracellular and internalized bacteria to early macrophage proinflammatory responses to <named-content content-type="genus-species">streptococcus pneumoniae</named-content>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/d089ef97c70043238d89741d49e77722
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Relative Contributions of Extracellular and Internalized Bacteria to Early Macrophage Proinflammatory Responses to <named-content content-type="genus-species">Streptococcus pneumoniae</named-content>

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