Inhibition of Neutrophil Primary Granule Release during <named-content content-type="genus-species">Yersinia pestis</named-content> Pulmonary Infection

ABSTRACT Inhalation of Yersinia pestis causes primary pneumonic plague, the most severe manifestation of plague that is characterized by a dramatic neutrophil influx to the lungs. Neutrophils are ineffective during primary pneumonic plague, failing to control Y. pestis growth in the airways. However...

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Autores principales:	Kara R. Eichelberger, Grant S. Jones, William E. Goldman
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Yersinia pestis YopE YopH neutrophil degranulation plague primary granules Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/bd42b8c98d664f109f64ccc514bdd6d8
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spelling	oai:doaj.org-article:bd42b8c98d664f109f64ccc514bdd6d82021-11-15T15:54:47ZInhibition of Neutrophil Primary Granule Release during <named-content content-type="genus-species">Yersinia pestis</named-content> Pulmonary Infection10.1128/mBio.02759-192150-7511https://doaj.org/article/bd42b8c98d664f109f64ccc514bdd6d82019-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02759-19https://doaj.org/toc/2150-7511ABSTRACT Inhalation of Yersinia pestis causes primary pneumonic plague, the most severe manifestation of plague that is characterized by a dramatic neutrophil influx to the lungs. Neutrophils are ineffective during primary pneumonic plague, failing to control Y. pestis growth in the airways. However, the mechanisms by which Y. pestis resists neutrophil killing are incompletely understood. Here, we show that Y. pestis inhibits neutrophil degranulation, an important line of host innate immune defense. We observed that neutrophils from the lungs of mice infected intranasally with Y. pestis fail to release primary granules throughout the course of disease. Using a type III secretion system (T3SS) injection reporter strain, we determined that Y. pestis directly inhibits neutrophil granule release by a T3SS-dependent mechanism. Combinatorial mutant analysis revealed that a Y. pestis strain lacking both effectors YopE and YopH did not inhibit primary granule release and is killed by neutrophils both in vivo and in vitro. Similarly, Y. pestis strains injecting only YopE or YopH are able to inhibit the majority of primary granule release from human neutrophils. We determined that YopE and YopH block Rac2 activation and calcium flux, respectively, to inhibit neutrophil primary granule release in isolated human neutrophils. These results demonstrate that Y. pestis coordinates the inhibition of neutrophil primary granule release through the activities of two distinct effectors, and this inhibition promotes Y. pestis survival during primary pneumonic plague. IMPORTANCE Yersinia pestis is the causative agent of plague and is one of the deadliest human pathogens. The pneumonic form of Y. pestis infection has played a critical role in the severity of both historical and modern plague outbreaks, yet the host-pathogen interactions that govern the lethality of Yersinia pestis pulmonary infections are incompletely understood. Here, we report that Yersinia pestis inhibits neutrophil degranulation during infection, rendering neutrophils ineffective and allowing unrestricted growth of Y. pestis in the lungs. This coordinated inhibition of granule release not only demonstrates the pathogenic benefit of “silencing” lung neutrophils but also reveals specific host processes and pathways that could be manipulated to reduce the severity of primary pneumonic plague.Kara R. EichelbergerGrant S. JonesWilliam E. GoldmanAmerican Society for MicrobiologyarticleYersinia pestisYopEYopHneutrophil degranulationplagueprimary granulesMicrobiologyQR1-502ENmBio, Vol 10, Iss 6 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Yersinia pestis YopE YopH neutrophil degranulation plague primary granules Microbiology QR1-502
spellingShingle	Yersinia pestis YopE YopH neutrophil degranulation plague primary granules Microbiology QR1-502 Kara R. Eichelberger Grant S. Jones William E. Goldman Inhibition of Neutrophil Primary Granule Release during <named-content content-type="genus-species">Yersinia pestis</named-content> Pulmonary Infection
description	ABSTRACT Inhalation of Yersinia pestis causes primary pneumonic plague, the most severe manifestation of plague that is characterized by a dramatic neutrophil influx to the lungs. Neutrophils are ineffective during primary pneumonic plague, failing to control Y. pestis growth in the airways. However, the mechanisms by which Y. pestis resists neutrophil killing are incompletely understood. Here, we show that Y. pestis inhibits neutrophil degranulation, an important line of host innate immune defense. We observed that neutrophils from the lungs of mice infected intranasally with Y. pestis fail to release primary granules throughout the course of disease. Using a type III secretion system (T3SS) injection reporter strain, we determined that Y. pestis directly inhibits neutrophil granule release by a T3SS-dependent mechanism. Combinatorial mutant analysis revealed that a Y. pestis strain lacking both effectors YopE and YopH did not inhibit primary granule release and is killed by neutrophils both in vivo and in vitro. Similarly, Y. pestis strains injecting only YopE or YopH are able to inhibit the majority of primary granule release from human neutrophils. We determined that YopE and YopH block Rac2 activation and calcium flux, respectively, to inhibit neutrophil primary granule release in isolated human neutrophils. These results demonstrate that Y. pestis coordinates the inhibition of neutrophil primary granule release through the activities of two distinct effectors, and this inhibition promotes Y. pestis survival during primary pneumonic plague. IMPORTANCE Yersinia pestis is the causative agent of plague and is one of the deadliest human pathogens. The pneumonic form of Y. pestis infection has played a critical role in the severity of both historical and modern plague outbreaks, yet the host-pathogen interactions that govern the lethality of Yersinia pestis pulmonary infections are incompletely understood. Here, we report that Yersinia pestis inhibits neutrophil degranulation during infection, rendering neutrophils ineffective and allowing unrestricted growth of Y. pestis in the lungs. This coordinated inhibition of granule release not only demonstrates the pathogenic benefit of “silencing” lung neutrophils but also reveals specific host processes and pathways that could be manipulated to reduce the severity of primary pneumonic plague.
format	article
author	Kara R. Eichelberger Grant S. Jones William E. Goldman
author_facet	Kara R. Eichelberger Grant S. Jones William E. Goldman
author_sort	Kara R. Eichelberger
title	Inhibition of Neutrophil Primary Granule Release during <named-content content-type="genus-species">Yersinia pestis</named-content> Pulmonary Infection
title_short	Inhibition of Neutrophil Primary Granule Release during <named-content content-type="genus-species">Yersinia pestis</named-content> Pulmonary Infection
title_full	Inhibition of Neutrophil Primary Granule Release during <named-content content-type="genus-species">Yersinia pestis</named-content> Pulmonary Infection
title_fullStr	Inhibition of Neutrophil Primary Granule Release during <named-content content-type="genus-species">Yersinia pestis</named-content> Pulmonary Infection
title_full_unstemmed	Inhibition of Neutrophil Primary Granule Release during <named-content content-type="genus-species">Yersinia pestis</named-content> Pulmonary Infection
title_sort	inhibition of neutrophil primary granule release during <named-content content-type="genus-species">yersinia pestis</named-content> pulmonary infection
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/bd42b8c98d664f109f64ccc514bdd6d8
work_keys_str_mv	AT karareichelberger inhibitionofneutrophilprimarygranulereleaseduringnamedcontentcontenttypegenusspeciesyersiniapestisnamedcontentpulmonaryinfection AT grantsjones inhibitionofneutrophilprimarygranulereleaseduringnamedcontentcontenttypegenusspeciesyersiniapestisnamedcontentpulmonaryinfection AT williamegoldman inhibitionofneutrophilprimarygranulereleaseduringnamedcontentcontenttypegenusspeciesyersiniapestisnamedcontentpulmonaryinfection
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Inhibition of Neutrophil Primary Granule Release during <named-content content-type="genus-species">Yersinia pestis</named-content> Pulmonary Infection

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