Biodiverse <italic toggle="yes">Histoplasma</italic> Species Elicit Distinct Patterns of Pulmonary Inflammation following Sublethal Infection

ABSTRACT Histoplasma is an endemic dimorphic fungus that can cause disease in healthy and immunocompromised individuals after the transition of inhaled spores into the facultative intracellular yeast form. There is substantial diversity among Histoplasma species, but it is not clear how this heterog...

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Autores principales:	Grant S. Jones, Victoria E. Sepúlveda, William E. Goldman
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Histoplasma alveolar macrophages histoplasmosis inflammation lung infection respiratory pathogens Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/38710f0b88af414fbaab3290bae78f32
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spelling	oai:doaj.org-article:38710f0b88af414fbaab3290bae78f322021-11-15T15:30:50ZBiodiverse <italic toggle="yes">Histoplasma</italic> Species Elicit Distinct Patterns of Pulmonary Inflammation following Sublethal Infection10.1128/mSphere.00742-202379-5042https://doaj.org/article/38710f0b88af414fbaab3290bae78f322020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00742-20https://doaj.org/toc/2379-5042ABSTRACT Histoplasma is an endemic dimorphic fungus that can cause disease in healthy and immunocompromised individuals after the transition of inhaled spores into the facultative intracellular yeast form. There is substantial diversity among Histoplasma species, but it is not clear how this heterogeneity impacts the progression of pathology and cellular immune responses during acute respiratory infection, which represents the vast majority of histoplasmosis disease burden. After inoculating mice intranasally with a sublethal inoculum, we characterized the immune response to Histoplasma capsulatum (strain G186A) and Histoplasma ohiense (strain G217B) using comprehensive flow cytometric and single-cell analyses. Within 8 days after inoculation, H. ohiense induced a significantly higher infiltration of neutrophils and inflammatory monocytes into the lung compared to H. capsulatum. Microscopic analysis of infected lung tissue revealed that although the total number of fungi was similar within inflamed lung lesions, we observed different species-dependent intracellular yeast distribution patterns. Inoculation with gfp-expressing strains indicated that H. ohiense, but not H. capsulatum, was associated primarily with alveolar macrophages early after infection. Interestingly, we observed a significant reduction in the total number of alveolar macrophages 12 to 16 days after H. ohiense, but not H. capsulatum infection, despite similar intracellular growth dynamics within AMJ2-C11 alveolar macrophages in vitro. Together, our data suggest that H. ohiense, but not H. capsulatum, preferentially interacts with alveolar macrophages early after infection, which may lead to a different course of inflammation and resolution despite similar rates of fungal clearance. IMPORTANCE Acute pulmonary histoplasmosis in healthy individuals comprises most of the disease burden caused by the fungal pathogen Histoplasma. Fungal pneumonia is frequently delayed in diagnosis and treatment due to a prolonged period of quiescence early during infection. In this study, we used a murine respiratory model of histoplasmosis to investigate how different Histoplasma species modulate lung inflammation throughout the complete course of infection. We propose that a relatively low, sublethal inoculum is ideal to model acute pulmonary histoplasmosis in humans, primarily due to the quiescent stage of fungal growth that occurs in the lungs of mice prior to the initiation of inflammation. Our results reveal the unique course of lung immunity associated with divergent species of Histoplasma and imply that the progression of clinical disease is considerably more heterogeneous than previously recognized.Grant S. JonesVictoria E. SepúlvedaWilliam E. GoldmanAmerican Society for MicrobiologyarticleHistoplasmaalveolar macrophageshistoplasmosisinflammationlung infectionrespiratory pathogensMicrobiologyQR1-502ENmSphere, Vol 5, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Histoplasma alveolar macrophages histoplasmosis inflammation lung infection respiratory pathogens Microbiology QR1-502
spellingShingle	Histoplasma alveolar macrophages histoplasmosis inflammation lung infection respiratory pathogens Microbiology QR1-502 Grant S. Jones Victoria E. Sepúlveda William E. Goldman Biodiverse <italic toggle="yes">Histoplasma</italic> Species Elicit Distinct Patterns of Pulmonary Inflammation following Sublethal Infection
description	ABSTRACT Histoplasma is an endemic dimorphic fungus that can cause disease in healthy and immunocompromised individuals after the transition of inhaled spores into the facultative intracellular yeast form. There is substantial diversity among Histoplasma species, but it is not clear how this heterogeneity impacts the progression of pathology and cellular immune responses during acute respiratory infection, which represents the vast majority of histoplasmosis disease burden. After inoculating mice intranasally with a sublethal inoculum, we characterized the immune response to Histoplasma capsulatum (strain G186A) and Histoplasma ohiense (strain G217B) using comprehensive flow cytometric and single-cell analyses. Within 8 days after inoculation, H. ohiense induced a significantly higher infiltration of neutrophils and inflammatory monocytes into the lung compared to H. capsulatum. Microscopic analysis of infected lung tissue revealed that although the total number of fungi was similar within inflamed lung lesions, we observed different species-dependent intracellular yeast distribution patterns. Inoculation with gfp-expressing strains indicated that H. ohiense, but not H. capsulatum, was associated primarily with alveolar macrophages early after infection. Interestingly, we observed a significant reduction in the total number of alveolar macrophages 12 to 16 days after H. ohiense, but not H. capsulatum infection, despite similar intracellular growth dynamics within AMJ2-C11 alveolar macrophages in vitro. Together, our data suggest that H. ohiense, but not H. capsulatum, preferentially interacts with alveolar macrophages early after infection, which may lead to a different course of inflammation and resolution despite similar rates of fungal clearance. IMPORTANCE Acute pulmonary histoplasmosis in healthy individuals comprises most of the disease burden caused by the fungal pathogen Histoplasma. Fungal pneumonia is frequently delayed in diagnosis and treatment due to a prolonged period of quiescence early during infection. In this study, we used a murine respiratory model of histoplasmosis to investigate how different Histoplasma species modulate lung inflammation throughout the complete course of infection. We propose that a relatively low, sublethal inoculum is ideal to model acute pulmonary histoplasmosis in humans, primarily due to the quiescent stage of fungal growth that occurs in the lungs of mice prior to the initiation of inflammation. Our results reveal the unique course of lung immunity associated with divergent species of Histoplasma and imply that the progression of clinical disease is considerably more heterogeneous than previously recognized.
format	article
author	Grant S. Jones Victoria E. Sepúlveda William E. Goldman
author_facet	Grant S. Jones Victoria E. Sepúlveda William E. Goldman
author_sort	Grant S. Jones
title	Biodiverse <italic toggle="yes">Histoplasma</italic> Species Elicit Distinct Patterns of Pulmonary Inflammation following Sublethal Infection
title_short	Biodiverse <italic toggle="yes">Histoplasma</italic> Species Elicit Distinct Patterns of Pulmonary Inflammation following Sublethal Infection
title_full	Biodiverse <italic toggle="yes">Histoplasma</italic> Species Elicit Distinct Patterns of Pulmonary Inflammation following Sublethal Infection
title_fullStr	Biodiverse <italic toggle="yes">Histoplasma</italic> Species Elicit Distinct Patterns of Pulmonary Inflammation following Sublethal Infection
title_full_unstemmed	Biodiverse <italic toggle="yes">Histoplasma</italic> Species Elicit Distinct Patterns of Pulmonary Inflammation following Sublethal Infection
title_sort	biodiverse <italic toggle="yes">histoplasma</italic> species elicit distinct patterns of pulmonary inflammation following sublethal infection
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/38710f0b88af414fbaab3290bae78f32
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Biodiverse <italic toggle="yes">Histoplasma</italic> Species Elicit Distinct Patterns of Pulmonary Inflammation following Sublethal Infection

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