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Glucuronoxylomannan intranasal challenge prior to Cryptococcus neoformans pulmonary infection enhances cerebral cryptococcosis in rodents

The encapsulated fungus Cryptococcus neoformans is the most common cause of fungal meningitis, with the highest rate of disease in patients with AIDS or immunosuppression. This microbe enters the human body via inhalation of infectious particles. C. neoformans capsular polysaccharide, in which the m...

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Autores principales: Lee, Hiu Ham, Carmichael, Dylan J., Ríbeiro, Victoria, Parisi, Dana N., Munzen, Melissa E., Charles-Niño, Claudia L., Hamed, Mohamed F., Kaur, Ettiman, Mishra, Ayush, Patel, Jiya, Rooklin, Rikki B., Sher, Amina, Carrillo-Sepulveda, Maria A., Eugenin, Eliseo A., Dores, Michael R., Martinez, Luis R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10171644/
https://www.ncbi.nlm.nih.gov/pubmed/37115795
http://dx.doi.org/10.1371/journal.ppat.1010941
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author Lee, Hiu Ham
Carmichael, Dylan J.
Ríbeiro, Victoria
Parisi, Dana N.
Munzen, Melissa E.
Charles-Niño, Claudia L.
Hamed, Mohamed F.
Kaur, Ettiman
Mishra, Ayush
Patel, Jiya
Rooklin, Rikki B.
Sher, Amina
Carrillo-Sepulveda, Maria A.
Eugenin, Eliseo A.
Dores, Michael R.
Martinez, Luis R.
author_facet Lee, Hiu Ham
Carmichael, Dylan J.
Ríbeiro, Victoria
Parisi, Dana N.
Munzen, Melissa E.
Charles-Niño, Claudia L.
Hamed, Mohamed F.
Kaur, Ettiman
Mishra, Ayush
Patel, Jiya
Rooklin, Rikki B.
Sher, Amina
Carrillo-Sepulveda, Maria A.
Eugenin, Eliseo A.
Dores, Michael R.
Martinez, Luis R.
author_sort Lee, Hiu Ham
collection PubMed
description The encapsulated fungus Cryptococcus neoformans is the most common cause of fungal meningitis, with the highest rate of disease in patients with AIDS or immunosuppression. This microbe enters the human body via inhalation of infectious particles. C. neoformans capsular polysaccharide, in which the major component is glucuronoxylomannan (GXM), extensively accumulates in tissues and compromises host immune responses. C. neoformans travels from the lungs to the bloodstream and crosses to the brain via transcytosis, paracytosis, or inside of phagocytes using a “Trojan horse” mechanism. The fungus causes life-threatening meningoencephalitis with high mortality rates. Hence, we investigated the impact of intranasal exogenous GXM administration on C. neoformans infection in C57BL/6 mice. GXM enhances cryptococcal pulmonary infection and facilitates fungal systemic dissemination and brain invasion. Pre-challenge of GXM results in detection of the polysaccharide in lungs, serum, and surprisingly brain, the latter likely reached through the nasal cavity. GXM significantly alters endothelial cell tight junction protein expression in vivo, suggesting significant implications for the C. neoformans mechanisms of brain invasion. Using a microtiter transwell system, we showed that GXM disrupts the trans-endothelial electrical resistance, weakening human brain endothelial cell monolayers co-cultured with pericytes, supportive cells of blood vessels/capillaries found in the blood-brain barrier (BBB) to promote C. neoformans BBB penetration. Our findings should be considered in the development of therapeutics to combat the devastating complications of cryptococcosis that results in an estimated ~200,000 deaths worldwide each year.
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spelling pubmed-101716442023-05-11 Glucuronoxylomannan intranasal challenge prior to Cryptococcus neoformans pulmonary infection enhances cerebral cryptococcosis in rodents Lee, Hiu Ham Carmichael, Dylan J. Ríbeiro, Victoria Parisi, Dana N. Munzen, Melissa E. Charles-Niño, Claudia L. Hamed, Mohamed F. Kaur, Ettiman Mishra, Ayush Patel, Jiya Rooklin, Rikki B. Sher, Amina Carrillo-Sepulveda, Maria A. Eugenin, Eliseo A. Dores, Michael R. Martinez, Luis R. PLoS Pathog Research Article The encapsulated fungus Cryptococcus neoformans is the most common cause of fungal meningitis, with the highest rate of disease in patients with AIDS or immunosuppression. This microbe enters the human body via inhalation of infectious particles. C. neoformans capsular polysaccharide, in which the major component is glucuronoxylomannan (GXM), extensively accumulates in tissues and compromises host immune responses. C. neoformans travels from the lungs to the bloodstream and crosses to the brain via transcytosis, paracytosis, or inside of phagocytes using a “Trojan horse” mechanism. The fungus causes life-threatening meningoencephalitis with high mortality rates. Hence, we investigated the impact of intranasal exogenous GXM administration on C. neoformans infection in C57BL/6 mice. GXM enhances cryptococcal pulmonary infection and facilitates fungal systemic dissemination and brain invasion. Pre-challenge of GXM results in detection of the polysaccharide in lungs, serum, and surprisingly brain, the latter likely reached through the nasal cavity. GXM significantly alters endothelial cell tight junction protein expression in vivo, suggesting significant implications for the C. neoformans mechanisms of brain invasion. Using a microtiter transwell system, we showed that GXM disrupts the trans-endothelial electrical resistance, weakening human brain endothelial cell monolayers co-cultured with pericytes, supportive cells of blood vessels/capillaries found in the blood-brain barrier (BBB) to promote C. neoformans BBB penetration. Our findings should be considered in the development of therapeutics to combat the devastating complications of cryptococcosis that results in an estimated ~200,000 deaths worldwide each year. Public Library of Science 2023-04-28 /pmc/articles/PMC10171644/ /pubmed/37115795 http://dx.doi.org/10.1371/journal.ppat.1010941 Text en © 2023 Lee et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Lee, Hiu Ham
Carmichael, Dylan J.
Ríbeiro, Victoria
Parisi, Dana N.
Munzen, Melissa E.
Charles-Niño, Claudia L.
Hamed, Mohamed F.
Kaur, Ettiman
Mishra, Ayush
Patel, Jiya
Rooklin, Rikki B.
Sher, Amina
Carrillo-Sepulveda, Maria A.
Eugenin, Eliseo A.
Dores, Michael R.
Martinez, Luis R.
Glucuronoxylomannan intranasal challenge prior to Cryptococcus neoformans pulmonary infection enhances cerebral cryptococcosis in rodents
title Glucuronoxylomannan intranasal challenge prior to Cryptococcus neoformans pulmonary infection enhances cerebral cryptococcosis in rodents
title_full Glucuronoxylomannan intranasal challenge prior to Cryptococcus neoformans pulmonary infection enhances cerebral cryptococcosis in rodents
title_fullStr Glucuronoxylomannan intranasal challenge prior to Cryptococcus neoformans pulmonary infection enhances cerebral cryptococcosis in rodents
title_full_unstemmed Glucuronoxylomannan intranasal challenge prior to Cryptococcus neoformans pulmonary infection enhances cerebral cryptococcosis in rodents
title_short Glucuronoxylomannan intranasal challenge prior to Cryptococcus neoformans pulmonary infection enhances cerebral cryptococcosis in rodents
title_sort glucuronoxylomannan intranasal challenge prior to cryptococcus neoformans pulmonary infection enhances cerebral cryptococcosis in rodents
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10171644/
https://www.ncbi.nlm.nih.gov/pubmed/37115795
http://dx.doi.org/10.1371/journal.ppat.1010941
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