Transcriptomic biomarker pathways associated with death in HIV-infected patients with cryptococcal meningitis

Irina Vlasova-St Louis; Abdu K. Musubire; David B. Meya; Henry W. Nabeta; Hesham Mohei; David R. Boulware; Paul R. Bohjanen

doi:10.1186/s12920-021-00914-1

Transcriptomic biomarker pathways associated with death in HIV-infected patients with cryptococcal meningitis

Irina Vlasova-St Louis, Abdu K. Musubire, David B. Meya, Henry W. Nabeta, Hesham Mohei, David R. Boulware, Paul R. Bohjanen

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4 Scopus citations

Abstract

Background: Cryptococcal meningitis (CM) is a major cause of death in HIV-infected patients in sub-Saharan Africa. Many CM patients experience cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS), which is often fatal. We sought to identify transcriptomic biomarker pathways in peripheral blood that are associated with or predict the development of death or fatal C-IRIS among patients with CM who were enrolled in the Cryptococcal Optimal ART Timing Trial. Methods: We assessed peripheral blood gene expression using next-generation RNA sequencing in 4 groups of patients with CM: (1) no C-IRIS or Death; (2) C-IRIS survivors; (3) fatal C-IRIS; (4) Death without C-IRIS. Gene expression was assessed at the time of ART initiation, at 1, 4, and 8 weeks on ART, and at the time of C-IRIS events. Results: We identified 12 inflammatory and stress response pathways, including interferon type 1 signaling, that were upregulated at the time of ART initiation in patients with future fatal C-IRIS, as compared with survivors. The upregulation of transcripts involved in innate immunity (inflammasome, Toll-like receptor signaling), was observed at the time of fatal or nonfatal C-IRIS events. At the time of fatal C-IRIS events, numerous transcripts within fMLP, Rho family GTPases, HMGB1, and other acute phase response signaling pathways were upregulated, which reflects the severity of inflammation and systemic oxidative stress. Patients who died without recognized C-IRIS also had increased expression of pathways associated with oxidative stress and tissue damage. Conclusions: Our results showed that overactivated innate immunity, involving Toll-like receptor/inflammasome pathways, and inflammation-induced oxidative stress, are associated with fatal outcomes. The results of this study provide insight into the molecular drivers of death and fatal C-IRIS to inform future diagnostic test development or guide targeted treatments.

Original language	English (US)
Article number	108
Journal	BMC Medical Genomics
Volume	14
Issue number	1
DOIs	https://doi.org/10.1186/s12920-021-00914-1
State	Published - Dec 2021

Bibliographical note

Funding Information:
This work was supported by AI096925, AI072068 National Institute of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) (to P.R.B), and Department of Medicine start-up fund to I.V-S. The parent trial was supported by AI089244 from National Institute of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) to D.B.M. and D.R.B. []. The funding bodies did not have any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2021, The Author(s).

Keywords

AIDS/HIV
Cryptococcal meningitis IRIS
Fatal immune reconstitution inflammatory syndrome
Transcriptomic biomarkers

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s12920-021-00914-1

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@article{a41072fa9f8347deb27ca5f7b19c89a3,

title = "Transcriptomic biomarker pathways associated with death in HIV-infected patients with cryptococcal meningitis",

abstract = "Background: Cryptococcal meningitis (CM) is a major cause of death in HIV-infected patients in sub-Saharan Africa. Many CM patients experience cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS), which is often fatal. We sought to identify transcriptomic biomarker pathways in peripheral blood that are associated with or predict the development of death or fatal C-IRIS among patients with CM who were enrolled in the Cryptococcal Optimal ART Timing Trial. Methods: We assessed peripheral blood gene expression using next-generation RNA sequencing in 4 groups of patients with CM: (1) no C-IRIS or Death; (2) C-IRIS survivors; (3) fatal C-IRIS; (4) Death without C-IRIS. Gene expression was assessed at the time of ART initiation, at 1, 4, and 8 weeks on ART, and at the time of C-IRIS events. Results: We identified 12 inflammatory and stress response pathways, including interferon type 1 signaling, that were upregulated at the time of ART initiation in patients with future fatal C-IRIS, as compared with survivors. The upregulation of transcripts involved in innate immunity (inflammasome, Toll-like receptor signaling), was observed at the time of fatal or nonfatal C-IRIS events. At the time of fatal C-IRIS events, numerous transcripts within fMLP, Rho family GTPases, HMGB1, and other acute phase response signaling pathways were upregulated, which reflects the severity of inflammation and systemic oxidative stress. Patients who died without recognized C-IRIS also had increased expression of pathways associated with oxidative stress and tissue damage. Conclusions: Our results showed that overactivated innate immunity, involving Toll-like receptor/inflammasome pathways, and inflammation-induced oxidative stress, are associated with fatal outcomes. The results of this study provide insight into the molecular drivers of death and fatal C-IRIS to inform future diagnostic test development or guide targeted treatments.",

keywords = "AIDS/HIV, Cryptococcal meningitis IRIS, Fatal immune reconstitution inflammatory syndrome, Transcriptomic biomarkers",

author = "{Vlasova-St Louis}, Irina and Musubire, {Abdu K.} and Meya, {David B.} and Nabeta, {Henry W.} and Hesham Mohei and Boulware, {David R.} and Bohjanen, {Paul R.}",

note = "Funding Information: This work was supported by AI096925, AI072068 National Institute of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) (to P.R.B), and Department of Medicine start-up fund to I.V-S. The parent trial was supported by AI089244 from National Institute of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) to D.B.M. and D.R.B. []. The funding bodies did not have any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1186/s12920-021-00914-1",

language = "English (US)",

volume = "14",

journal = "BMC Medical Genomics",

issn = "1755-8794",

publisher = "BioMed Central Ltd.",

number = "1",

}

TY - JOUR

T1 - Transcriptomic biomarker pathways associated with death in HIV-infected patients with cryptococcal meningitis

AU - Vlasova-St Louis, Irina

AU - Musubire, Abdu K.

AU - Meya, David B.

AU - Nabeta, Henry W.

AU - Mohei, Hesham

AU - Boulware, David R.

AU - Bohjanen, Paul R.

N1 - Funding Information: This work was supported by AI096925, AI072068 National Institute of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) (to P.R.B), and Department of Medicine start-up fund to I.V-S. The parent trial was supported by AI089244 from National Institute of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) to D.B.M. and D.R.B. []. The funding bodies did not have any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - Background: Cryptococcal meningitis (CM) is a major cause of death in HIV-infected patients in sub-Saharan Africa. Many CM patients experience cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS), which is often fatal. We sought to identify transcriptomic biomarker pathways in peripheral blood that are associated with or predict the development of death or fatal C-IRIS among patients with CM who were enrolled in the Cryptococcal Optimal ART Timing Trial. Methods: We assessed peripheral blood gene expression using next-generation RNA sequencing in 4 groups of patients with CM: (1) no C-IRIS or Death; (2) C-IRIS survivors; (3) fatal C-IRIS; (4) Death without C-IRIS. Gene expression was assessed at the time of ART initiation, at 1, 4, and 8 weeks on ART, and at the time of C-IRIS events. Results: We identified 12 inflammatory and stress response pathways, including interferon type 1 signaling, that were upregulated at the time of ART initiation in patients with future fatal C-IRIS, as compared with survivors. The upregulation of transcripts involved in innate immunity (inflammasome, Toll-like receptor signaling), was observed at the time of fatal or nonfatal C-IRIS events. At the time of fatal C-IRIS events, numerous transcripts within fMLP, Rho family GTPases, HMGB1, and other acute phase response signaling pathways were upregulated, which reflects the severity of inflammation and systemic oxidative stress. Patients who died without recognized C-IRIS also had increased expression of pathways associated with oxidative stress and tissue damage. Conclusions: Our results showed that overactivated innate immunity, involving Toll-like receptor/inflammasome pathways, and inflammation-induced oxidative stress, are associated with fatal outcomes. The results of this study provide insight into the molecular drivers of death and fatal C-IRIS to inform future diagnostic test development or guide targeted treatments.

AB - Background: Cryptococcal meningitis (CM) is a major cause of death in HIV-infected patients in sub-Saharan Africa. Many CM patients experience cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS), which is often fatal. We sought to identify transcriptomic biomarker pathways in peripheral blood that are associated with or predict the development of death or fatal C-IRIS among patients with CM who were enrolled in the Cryptococcal Optimal ART Timing Trial. Methods: We assessed peripheral blood gene expression using next-generation RNA sequencing in 4 groups of patients with CM: (1) no C-IRIS or Death; (2) C-IRIS survivors; (3) fatal C-IRIS; (4) Death without C-IRIS. Gene expression was assessed at the time of ART initiation, at 1, 4, and 8 weeks on ART, and at the time of C-IRIS events. Results: We identified 12 inflammatory and stress response pathways, including interferon type 1 signaling, that were upregulated at the time of ART initiation in patients with future fatal C-IRIS, as compared with survivors. The upregulation of transcripts involved in innate immunity (inflammasome, Toll-like receptor signaling), was observed at the time of fatal or nonfatal C-IRIS events. At the time of fatal C-IRIS events, numerous transcripts within fMLP, Rho family GTPases, HMGB1, and other acute phase response signaling pathways were upregulated, which reflects the severity of inflammation and systemic oxidative stress. Patients who died without recognized C-IRIS also had increased expression of pathways associated with oxidative stress and tissue damage. Conclusions: Our results showed that overactivated innate immunity, involving Toll-like receptor/inflammasome pathways, and inflammation-induced oxidative stress, are associated with fatal outcomes. The results of this study provide insight into the molecular drivers of death and fatal C-IRIS to inform future diagnostic test development or guide targeted treatments.

KW - AIDS/HIV

KW - Cryptococcal meningitis IRIS

KW - Fatal immune reconstitution inflammatory syndrome

KW - Transcriptomic biomarkers

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U2 - 10.1186/s12920-021-00914-1

DO - 10.1186/s12920-021-00914-1

M3 - Article

C2 - 33863324

AN - SCOPUS:85104490387

SN - 1755-8794

VL - 14

JO - BMC Medical Genomics

JF - BMC Medical Genomics

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ER -

Transcriptomic biomarker pathways associated with death in HIV-infected patients with cryptococcal meningitis

Abstract

Bibliographical note

Keywords

UN SDGs

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