Leukocyte Inflammatory Responses Provoked by Pneumococcal Sialidase

ABSTRACT Cell surface expression of sialic acid has been reported to decrease during immune cell activation, but the significance and regulation of this phenomenon are still being investigated. The major human bacterial pathogen Streptococcus pneumoniae causes pneumonia, sepsis and meningitis, often...

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Autores principales:	Yung-Chi Chang, Satoshi Uchiyama, Ajit Varki, Victor Nizet
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2012
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9f7ec4c8f9a74c54b33cdd0d7976a754
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spelling	oai:doaj.org-article:9f7ec4c8f9a74c54b33cdd0d7976a7542021-11-15T15:39:02ZLeukocyte Inflammatory Responses Provoked by Pneumococcal Sialidase10.1128/mBio.00220-112150-7511https://doaj.org/article/9f7ec4c8f9a74c54b33cdd0d7976a7542012-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00220-11https://doaj.org/toc/2150-7511ABSTRACT Cell surface expression of sialic acid has been reported to decrease during immune cell activation, but the significance and regulation of this phenomenon are still being investigated. The major human bacterial pathogen Streptococcus pneumoniae causes pneumonia, sepsis and meningitis, often accompanied by strong inflammatory responses. S. pneumoniae expresses a sialidase (NanA) that contributes to mucosal colonization, platelet clearance, and blood-brain barrier penetration. Using wild-type and isogenic NanA-deficient mutant strains, we showed that S. pneumoniae NanA can desialylate the surface of human THP-1 monocytes, leading to increased ERK phosphorylation, NF-κB activation, and proinflammatory cytokine release. S. pneumoniae NanA expression also stimulates interleukin-8 release and extracellular trap formation from human neutrophils. A mechanistic contribution of unmasking of inhibitory Siglec-5 from cis sialic acid interactions to the proinflammatory effect of NanA is suggested by decreased SHP-2 recruitment to the Siglec-5 intracellular domain and RNA interference studies. Finally, NanA increased production of proinflammatory cytokines in a murine intranasal challenge model of S. pneumoniae pneumonia. IMPORTANCE Sialic acids decorate the surface of all mammalian cells and play important roles in physiology, development, and evolution. Siglecs are sialic acid-binding receptors on the surface of immune cells, many of which engage in cis interactions with host sialoglycan ligands and dampen inflammatory responses through transduction of inhibitory signals. Recently, certain bacterial pathogens have been shown to suppress leukocyte innate immune responses by molecular mimicry of host sialic acid structures and engagement of inhibitory Siglecs. Our present work shows that the converse can be true, i.e., that a microbial sialic acid-cleaving enzyme can induce proinflammatory responses, which are in part mediated by unmasking of an inhibitory Siglec. We conclude that host leukocytes are poised to detect and respond to microbial sialidase activity with exaggerated inflammatory responses, which could be beneficial or detrimental to the host depending on the site, stage and magnitude of infection.Yung-Chi ChangSatoshi UchiyamaAjit VarkiVictor NizetAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 3, Iss 1 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Yung-Chi Chang Satoshi Uchiyama Ajit Varki Victor Nizet Leukocyte Inflammatory Responses Provoked by Pneumococcal Sialidase
description	ABSTRACT Cell surface expression of sialic acid has been reported to decrease during immune cell activation, but the significance and regulation of this phenomenon are still being investigated. The major human bacterial pathogen Streptococcus pneumoniae causes pneumonia, sepsis and meningitis, often accompanied by strong inflammatory responses. S. pneumoniae expresses a sialidase (NanA) that contributes to mucosal colonization, platelet clearance, and blood-brain barrier penetration. Using wild-type and isogenic NanA-deficient mutant strains, we showed that S. pneumoniae NanA can desialylate the surface of human THP-1 monocytes, leading to increased ERK phosphorylation, NF-κB activation, and proinflammatory cytokine release. S. pneumoniae NanA expression also stimulates interleukin-8 release and extracellular trap formation from human neutrophils. A mechanistic contribution of unmasking of inhibitory Siglec-5 from cis sialic acid interactions to the proinflammatory effect of NanA is suggested by decreased SHP-2 recruitment to the Siglec-5 intracellular domain and RNA interference studies. Finally, NanA increased production of proinflammatory cytokines in a murine intranasal challenge model of S. pneumoniae pneumonia. IMPORTANCE Sialic acids decorate the surface of all mammalian cells and play important roles in physiology, development, and evolution. Siglecs are sialic acid-binding receptors on the surface of immune cells, many of which engage in cis interactions with host sialoglycan ligands and dampen inflammatory responses through transduction of inhibitory signals. Recently, certain bacterial pathogens have been shown to suppress leukocyte innate immune responses by molecular mimicry of host sialic acid structures and engagement of inhibitory Siglecs. Our present work shows that the converse can be true, i.e., that a microbial sialic acid-cleaving enzyme can induce proinflammatory responses, which are in part mediated by unmasking of an inhibitory Siglec. We conclude that host leukocytes are poised to detect and respond to microbial sialidase activity with exaggerated inflammatory responses, which could be beneficial or detrimental to the host depending on the site, stage and magnitude of infection.
format	article
author	Yung-Chi Chang Satoshi Uchiyama Ajit Varki Victor Nizet
author_facet	Yung-Chi Chang Satoshi Uchiyama Ajit Varki Victor Nizet
author_sort	Yung-Chi Chang
title	Leukocyte Inflammatory Responses Provoked by Pneumococcal Sialidase
title_short	Leukocyte Inflammatory Responses Provoked by Pneumococcal Sialidase
title_full	Leukocyte Inflammatory Responses Provoked by Pneumococcal Sialidase
title_fullStr	Leukocyte Inflammatory Responses Provoked by Pneumococcal Sialidase
title_full_unstemmed	Leukocyte Inflammatory Responses Provoked by Pneumococcal Sialidase
title_sort	leukocyte inflammatory responses provoked by pneumococcal sialidase
publisher	American Society for Microbiology
publishDate	2012
url	https://doaj.org/article/9f7ec4c8f9a74c54b33cdd0d7976a754
work_keys_str_mv	AT yungchichang leukocyteinflammatoryresponsesprovokedbypneumococcalsialidase AT satoshiuchiyama leukocyteinflammatoryresponsesprovokedbypneumococcalsialidase AT ajitvarki leukocyteinflammatoryresponsesprovokedbypneumococcalsialidase AT victornizet leukocyteinflammatoryresponsesprovokedbypneumococcalsialidase
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Leukocyte Inflammatory Responses Provoked by Pneumococcal Sialidase

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