Cryptococcal Genotype Influences Immunologic Response and Human Clinical Outcome after Meningitis

ABSTRACT In sub-Saharan Africa, cryptococcal meningitis (CM) continues to be a predominant cause of AIDS-related mortality. Understanding virulence and improving clinical treatments remain important. To characterize the role of the fungal strain genotype in clinical disease, we analyzed 140 Cryptoco...

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Autores principales:	Darin L. Wiesner, Oleksandr Moskalenko, Jennifer M. Corcoran, Tami McDonald, Melissa A. Rolfes, David B. Meya, Henry Kajumbula, Andrew Kambugu, Paul R. Bohjanen, Joseph F. Knight, David R. Boulware, Kirsten Nielsen
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2012
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/43e33bdd951044ad86aeb9081474604e
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spelling	oai:doaj.org-article:43e33bdd951044ad86aeb9081474604e2021-11-15T15:39:12ZCryptococcal Genotype Influences Immunologic Response and Human Clinical Outcome after Meningitis10.1128/mBio.00196-122150-7511https://doaj.org/article/43e33bdd951044ad86aeb9081474604e2012-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00196-12https://doaj.org/toc/2150-7511ABSTRACT In sub-Saharan Africa, cryptococcal meningitis (CM) continues to be a predominant cause of AIDS-related mortality. Understanding virulence and improving clinical treatments remain important. To characterize the role of the fungal strain genotype in clinical disease, we analyzed 140 Cryptococcus isolates from 111 Ugandans with AIDS and CM. Isolates consisted of 107 nonredundant Cryptococcus neoformans var. grubii strains and 8 C. neoformans var. grubii/neoformans hybrid strains. Multilocus sequence typing (MLST) was used to characterize genotypes, yielding 15 sequence types and 4 clonal clusters. The largest clonal cluster consisted of 74 isolates. The results of Burst and phylogenetic analysis suggested that the C. neoformans var. grubii strains could be separated into three nonredundant evolutionary groups (Burst group 1 to group 3). Patient mortality was differentially associated with the different evolutionary groups (P = 0.04), with the highest mortality observed among Burst group 1, Burst group 2, and hybrid strains. Compared to Burst group 3 strains, Burst group 1 strains were associated with higher mortality (P = 0.02), exhibited increased capsule shedding (P = 0.02), and elicited a more pronounced Th2 response during ex vivo cytokine release assays with strain-specific capsule stimulation (P = 0.02). The results of these analyses suggest that cryptococcal strain variation can be an important determinant of human immune responses and mortality. IMPORTANCE Cryptococcus neoformans is a common life-threatening human fungal pathogen that is responsible for an estimated 1 million cases of meningitis in HIV-infected patients annually. Virulence factors that are important in human disease have been identified, yet the impacts of the fungal strain genotype on virulence and outcomes of human infection remain poorly understood. Using an analysis of strain variation based on in vitro assays and clinical data from Ugandans living with AIDS and cryptococcal infection, we report that strain genotype predicts the type of immune response and mortality risk. These studies suggest that knowledge of the strain genotype during human infections could be used to predict disease outcomes and lead to improved treatment approaches aimed at targeting the specific combination of pathogen virulence and host response.Darin L. WiesnerOleksandr MoskalenkoJennifer M. CorcoranTami McDonaldMelissa A. RolfesDavid B. MeyaHenry KajumbulaAndrew KambuguPaul R. BohjanenJoseph F. KnightDavid R. BoulwareKirsten NielsenAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 3, Iss 5 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Darin L. Wiesner Oleksandr Moskalenko Jennifer M. Corcoran Tami McDonald Melissa A. Rolfes David B. Meya Henry Kajumbula Andrew Kambugu Paul R. Bohjanen Joseph F. Knight David R. Boulware Kirsten Nielsen Cryptococcal Genotype Influences Immunologic Response and Human Clinical Outcome after Meningitis
description	ABSTRACT In sub-Saharan Africa, cryptococcal meningitis (CM) continues to be a predominant cause of AIDS-related mortality. Understanding virulence and improving clinical treatments remain important. To characterize the role of the fungal strain genotype in clinical disease, we analyzed 140 Cryptococcus isolates from 111 Ugandans with AIDS and CM. Isolates consisted of 107 nonredundant Cryptococcus neoformans var. grubii strains and 8 C. neoformans var. grubii/neoformans hybrid strains. Multilocus sequence typing (MLST) was used to characterize genotypes, yielding 15 sequence types and 4 clonal clusters. The largest clonal cluster consisted of 74 isolates. The results of Burst and phylogenetic analysis suggested that the C. neoformans var. grubii strains could be separated into three nonredundant evolutionary groups (Burst group 1 to group 3). Patient mortality was differentially associated with the different evolutionary groups (P = 0.04), with the highest mortality observed among Burst group 1, Burst group 2, and hybrid strains. Compared to Burst group 3 strains, Burst group 1 strains were associated with higher mortality (P = 0.02), exhibited increased capsule shedding (P = 0.02), and elicited a more pronounced Th2 response during ex vivo cytokine release assays with strain-specific capsule stimulation (P = 0.02). The results of these analyses suggest that cryptococcal strain variation can be an important determinant of human immune responses and mortality. IMPORTANCE Cryptococcus neoformans is a common life-threatening human fungal pathogen that is responsible for an estimated 1 million cases of meningitis in HIV-infected patients annually. Virulence factors that are important in human disease have been identified, yet the impacts of the fungal strain genotype on virulence and outcomes of human infection remain poorly understood. Using an analysis of strain variation based on in vitro assays and clinical data from Ugandans living with AIDS and cryptococcal infection, we report that strain genotype predicts the type of immune response and mortality risk. These studies suggest that knowledge of the strain genotype during human infections could be used to predict disease outcomes and lead to improved treatment approaches aimed at targeting the specific combination of pathogen virulence and host response.
format	article
author	Darin L. Wiesner Oleksandr Moskalenko Jennifer M. Corcoran Tami McDonald Melissa A. Rolfes David B. Meya Henry Kajumbula Andrew Kambugu Paul R. Bohjanen Joseph F. Knight David R. Boulware Kirsten Nielsen
author_facet	Darin L. Wiesner Oleksandr Moskalenko Jennifer M. Corcoran Tami McDonald Melissa A. Rolfes David B. Meya Henry Kajumbula Andrew Kambugu Paul R. Bohjanen Joseph F. Knight David R. Boulware Kirsten Nielsen
author_sort	Darin L. Wiesner
title	Cryptococcal Genotype Influences Immunologic Response and Human Clinical Outcome after Meningitis
title_short	Cryptococcal Genotype Influences Immunologic Response and Human Clinical Outcome after Meningitis
title_full	Cryptococcal Genotype Influences Immunologic Response and Human Clinical Outcome after Meningitis
title_fullStr	Cryptococcal Genotype Influences Immunologic Response and Human Clinical Outcome after Meningitis
title_full_unstemmed	Cryptococcal Genotype Influences Immunologic Response and Human Clinical Outcome after Meningitis
title_sort	cryptococcal genotype influences immunologic response and human clinical outcome after meningitis
publisher	American Society for Microbiology
publishDate	2012
url	https://doaj.org/article/43e33bdd951044ad86aeb9081474604e
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Cryptococcal Genotype Influences Immunologic Response and Human Clinical Outcome after Meningitis

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