Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1785039465560932352 |
---|---|
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. |
format | Online Article Text |
id | pubmed-10171644 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT leehiuham glucuronoxylomannanintranasalchallengepriortocryptococcusneoformanspulmonaryinfectionenhancescerebralcryptococcosisinrodents AT carmichaeldylanj glucuronoxylomannanintranasalchallengepriortocryptococcusneoformanspulmonaryinfectionenhancescerebralcryptococcosisinrodents AT ribeirovictoria glucuronoxylomannanintranasalchallengepriortocryptococcusneoformanspulmonaryinfectionenhancescerebralcryptococcosisinrodents AT parisidanan glucuronoxylomannanintranasalchallengepriortocryptococcusneoformanspulmonaryinfectionenhancescerebralcryptococcosisinrodents AT munzenmelissae glucuronoxylomannanintranasalchallengepriortocryptococcusneoformanspulmonaryinfectionenhancescerebralcryptococcosisinrodents AT charlesninoclaudial glucuronoxylomannanintranasalchallengepriortocryptococcusneoformanspulmonaryinfectionenhancescerebralcryptococcosisinrodents AT hamedmohamedf glucuronoxylomannanintranasalchallengepriortocryptococcusneoformanspulmonaryinfectionenhancescerebralcryptococcosisinrodents AT kaurettiman glucuronoxylomannanintranasalchallengepriortocryptococcusneoformanspulmonaryinfectionenhancescerebralcryptococcosisinrodents AT mishraayush glucuronoxylomannanintranasalchallengepriortocryptococcusneoformanspulmonaryinfectionenhancescerebralcryptococcosisinrodents AT pateljiya glucuronoxylomannanintranasalchallengepriortocryptococcusneoformanspulmonaryinfectionenhancescerebralcryptococcosisinrodents AT rooklinrikkib glucuronoxylomannanintranasalchallengepriortocryptococcusneoformanspulmonaryinfectionenhancescerebralcryptococcosisinrodents AT sheramina glucuronoxylomannanintranasalchallengepriortocryptococcusneoformanspulmonaryinfectionenhancescerebralcryptococcosisinrodents AT carrillosepulvedamariaa glucuronoxylomannanintranasalchallengepriortocryptococcusneoformanspulmonaryinfectionenhancescerebralcryptococcosisinrodents AT eugenineliseoa glucuronoxylomannanintranasalchallengepriortocryptococcusneoformanspulmonaryinfectionenhancescerebralcryptococcosisinrodents AT doresmichaelr glucuronoxylomannanintranasalchallengepriortocryptococcusneoformanspulmonaryinfectionenhancescerebralcryptococcosisinrodents AT martinezluisr glucuronoxylomannanintranasalchallengepriortocryptococcusneoformanspulmonaryinfectionenhancescerebralcryptococcosisinrodents |