TY - JOUR
T1 - Human immune response varies by the degree of relative cryptococcal antigen shedding
AU - Boulware, David R.
AU - von Hohenberg, Maximilian
AU - Rolfes, Melissa A.
AU - Bahr, Nathan C.
AU - Rhein, Joshua
AU - Akampurira, Andrew
AU - Williams, Darlisha A.
AU - Taseera, Kabanda
AU - Schutz, Charlotte
AU - McDonald, Tami
AU - Muzoora, Conrad
AU - Meintjes, Graeme
AU - Meya, David B.
AU - Nielsen, Kirsten
AU - Hullsiek, Katherine Huppler
AU - Musubire, Abdu K.
AU - Nabeta, Henry W.
AU - Thienemann, Friedrich
AU - Rajasingham, Radha
AU - Scriven, James E.
AU - Mwesigy, James
AU - Wagubi, Robert
AU - Kajumbula, Henry
AU - Ndyetukira, Jane Francis
AU - Ahimbisibwe, Cynthia
AU - Kugonza, Florence
AU - Ndyatunga, Liberica
AU - Noeme, Busingye
AU - Memela, Brian
AU - Sigila, Yolisa
AU - Sadiq, Alisat
AU - Magwayi, Monica
AU - Kwizera, Richard
AU - Ninsiima, Emily
AU - Najjuka, Grace
AU - Strain, Anna
AU - Wiesner, Darin
AU - Nanteza, Catherine
AU - Mushagara, Rhina
AU - Hassanally, Leya
AU - Namawejje, Mariam
AU - Ssennono, Mark
AU - Kiragga, Agnes
AU - Butler, Elissa K.
AU - For the Cryptococcal Optimal ART Timing (COAT) Trial Team
N1 - Publisher Copyright:
© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - Background. Cerebrospinal fluid (CSF) cryptococcal glucuronoxylomannan antigen (CrAg) titers generally correlate with quantitative fungal culture burden; however, correlation is not precise. Some patients have higher CrAg titers with lower fungal burdens and vice versa. We hypothesized that the relative discordancy between CrAg titer and quantitative culture burden reflects the relative degree of CrAg shedding by Cryptococcus neoformans and is associated with human immune responses. Methods. One hundred ninety human immunodeficiency virus-infected individuals with cryptococcal meningitis were enrolled in Uganda and South Africa. We compared initial CSF CrAg titers relative to their CSF quantitative cultures to determine low (n = 58), intermediate (n = 68), or high (n = 64) CrAg shedders. We compared cytokines measured by Luminex multiplex assay on cryopreserved CSF and 10-week mortality across shedding groups using linear and logistic regression and distribution of genotypes by multilocus sequence typing. Results. The relative degree of CrAg shedding was positively associated with increasing CSF levels of the following: interleukin (IL)-6, IL-7, IL-8, and tumor necrosis factor-α (each P < 0.01), which are all secreted by antigen-presenting cells and negatively associated with vascular endothelial growth factor (P = .01). In addition, IL-5, IL-13, granulocyte colony-stimulating factor, and macrophage chemotactic protein were decreased in low-CrAg shedders compared with intermediate shedders (each P ≤ .01). Type 1 T-helper cells (Th1) cytokine responses and 10-week mortality did not differ between the shedding groups. Cryptococcal genotypes were equally distributed across shedding groups. Conclusions. Discordancy between CrAg shedding and expected shedding based on quantitative fungal burden is associated with detectable immunologic differences in CSF, primarily among secreted cytokines and chemokines produced by antigen-presenting cells and Th2.
AB - Background. Cerebrospinal fluid (CSF) cryptococcal glucuronoxylomannan antigen (CrAg) titers generally correlate with quantitative fungal culture burden; however, correlation is not precise. Some patients have higher CrAg titers with lower fungal burdens and vice versa. We hypothesized that the relative discordancy between CrAg titer and quantitative culture burden reflects the relative degree of CrAg shedding by Cryptococcus neoformans and is associated with human immune responses. Methods. One hundred ninety human immunodeficiency virus-infected individuals with cryptococcal meningitis were enrolled in Uganda and South Africa. We compared initial CSF CrAg titers relative to their CSF quantitative cultures to determine low (n = 58), intermediate (n = 68), or high (n = 64) CrAg shedders. We compared cytokines measured by Luminex multiplex assay on cryopreserved CSF and 10-week mortality across shedding groups using linear and logistic regression and distribution of genotypes by multilocus sequence typing. Results. The relative degree of CrAg shedding was positively associated with increasing CSF levels of the following: interleukin (IL)-6, IL-7, IL-8, and tumor necrosis factor-α (each P < 0.01), which are all secreted by antigen-presenting cells and negatively associated with vascular endothelial growth factor (P = .01). In addition, IL-5, IL-13, granulocyte colony-stimulating factor, and macrophage chemotactic protein were decreased in low-CrAg shedders compared with intermediate shedders (each P ≤ .01). Type 1 T-helper cells (Th1) cytokine responses and 10-week mortality did not differ between the shedding groups. Cryptococcal genotypes were equally distributed across shedding groups. Conclusions. Discordancy between CrAg shedding and expected shedding based on quantitative fungal burden is associated with detectable immunologic differences in CSF, primarily among secreted cytokines and chemokines produced by antigen-presenting cells and Th2.
KW - Cerebrospinal fluid
KW - Cryptococcal meningitis
KW - Cryptococcus
KW - HIV/AIDS
KW - Immune response
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U2 - 10.1093/ofid/ofv194
DO - 10.1093/ofid/ofv194
M3 - Article
C2 - 26807426
AN - SCOPUS:85000386346
SN - 2328-8957
VL - 3
JO - Open Forum Infectious Diseases
JF - Open Forum Infectious Diseases
IS - 1
ER -
