Translocated microbiome composition determines immunological outcome in treated HIV infection

Krystelle Nganou-Makamdop; Aarthi Talla; Ashish Arunkumar Sharma; Sam Darko; Amy Ransier; Farida Laboune; Jeffrey G. Chipman; Gregory J. Beilman; Torfi Hoskuldsson; Slim Fourati; Thomas E. Schmidt; Sahaana Arumugam; Noemia S. Lima; Damee Moon; Samuel Callisto; Jordan Schoephoerster; Jeffery Tomalka; Peter Mugyenyi; Francis Ssali; Proscovia Muloma; Patrick Ssengendo; Ana R. Leda; Ryan K. Cheu; Jacob K. Flynn; Antigoni Morou; Elsa Brunet-Ratnasingham; Benigno Rodriguez; Michael M. Lederman; Daniel E. Kaufmann; Nichole R. Klatt; Cissy Kityo; Jason M. Brenchley; Timothy W. Schacker; Rafick P. Sekaly; Daniel C. Douek

doi:10.1016/j.cell.2021.05.023

Translocated microbiome composition determines immunological outcome in treated HIV infection

Krystelle Nganou-Makamdop, Aarthi Talla, Ashish Arunkumar Sharma, Sam Darko, Amy Ransier, Farida Laboune, Jeffrey G. Chipman, Gregory J. Beilman, Torfi Hoskuldsson, Slim Fourati, Thomas E. Schmidt, Sahaana Arumugam, Noemia S. Lima, Damee Moon, Samuel Callisto, Jordan Schoephoerster, Jeffery Tomalka, Peter Mugyenyi, Francis Ssali, Proscovia MulomaPatrick Ssengendo, Ana R. Leda, Ryan K. Cheu, Jacob K. Flynn, Antigoni Morou, Elsa Brunet-Ratnasingham, Benigno Rodriguez, Michael M. Lederman, Daniel E. Kaufmann, Nichole R. Klatt, Cissy Kityo, Jason M. Brenchley, Timothy W. Schacker^*, Rafick P. Sekaly^*, Daniel C. Douek^*

^*Corresponding author for this work

Medicine, Allergy Division

Research output: Contribution to journal › Article › peer-review

53 Scopus citations

Abstract

The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity. Subsequently, decreased Serratia abundance and downregulation of innate cytokines allowed re-establishment of systemic T cell homeostasis promoting restoration of Th1 and Th2 gene expression signatures. Analyses of three other geographically distinct cohorts of treated HIV infection established a more generalized principle that changes in diversity and composition of translocated microbial species influence systemic inflammation and consequently CD4 T cell recovery.

Original language	English (US)
Pages (from-to)	3899-3914.e16
Journal	Cell
Volume	184
Issue number	15
DOIs	https://doi.org/10.1016/j.cell.2021.05.023
State	Published - Jul 22 2021

Funding

This work was funded in part by the intramural program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH); NIH grant R01-AI124965 to T.W.S.; Center for AIDS Research and Fasenmyer Foundation ( AI 36219 CWRU to M.M.L.), Canadian Institute for Health Research (CIHR) ( CIHR-168901 and NIH grant R01-HL092565 to D.E.K.); and NIH grants R01-DA043263 , R01-DA042712 , and R37-AI141258 to R.P.S. Bacterial cultures were supported by NIH grant R01-DK112254 to N.R.K. We thank R. Dutt with help processing samples. This work made use of the High Performance Computing Resources in the Core Facility for Advanced Research Computing at Case Western Reserve University.

Keywords

HIV
antiretroviral therapy
inflammation
microbiome
systems biology

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

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

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10.1016/j.cell.2021.05.023

Cite this

Nganou-Makamdop, K., Talla, A., Sharma, A. A., Darko, S., Ransier, A., Laboune, F., Chipman, J. G., Beilman, G. J., Hoskuldsson, T., Fourati, S., Schmidt, T. E., Arumugam, S., Lima, N. S., Moon, D., Callisto, S., Schoephoerster, J., Tomalka, J., Mugyenyi, P., Ssali, F., ... Douek, D. C. (2021). Translocated microbiome composition determines immunological outcome in treated HIV infection. Cell, 184(15), 3899-3914.e16. https://doi.org/10.1016/j.cell.2021.05.023

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title = "Translocated microbiome composition determines immunological outcome in treated HIV infection",

abstract = "The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity. Subsequently, decreased Serratia abundance and downregulation of innate cytokines allowed re-establishment of systemic T cell homeostasis promoting restoration of Th1 and Th2 gene expression signatures. Analyses of three other geographically distinct cohorts of treated HIV infection established a more generalized principle that changes in diversity and composition of translocated microbial species influence systemic inflammation and consequently CD4 T cell recovery.",

keywords = "HIV, antiretroviral therapy, inflammation, microbiome, systems biology",

author = "Krystelle Nganou-Makamdop and Aarthi Talla and Sharma, {Ashish Arunkumar} and Sam Darko and Amy Ransier and Farida Laboune and Chipman, {Jeffrey G.} and Beilman, {Gregory J.} and Torfi Hoskuldsson and Slim Fourati and Schmidt, {Thomas E.} and Sahaana Arumugam and Lima, {Noemia S.} and Damee Moon and Samuel Callisto and Jordan Schoephoerster and Jeffery Tomalka and Peter Mugyenyi and Francis Ssali and Proscovia Muloma and Patrick Ssengendo and Leda, {Ana R.} and Cheu, {Ryan K.} and Flynn, {Jacob K.} and Antigoni Morou and Elsa Brunet-Ratnasingham and Benigno Rodriguez and Lederman, {Michael M.} and Kaufmann, {Daniel E.} and Klatt, {Nichole R.} and Cissy Kityo and Brenchley, {Jason M.} and Schacker, {Timothy W.} and Sekaly, {Rafick P.} and Douek, {Daniel C.}",

note = "Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = jul,

day = "22",

doi = "10.1016/j.cell.2021.05.023",

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Nganou-Makamdop, K, Talla, A, Sharma, AA, Darko, S, Ransier, A, Laboune, F, Chipman, JG, Beilman, GJ, Hoskuldsson, T, Fourati, S, Schmidt, TE, Arumugam, S, Lima, NS, Moon, D, Callisto, S, Schoephoerster, J, Tomalka, J, Mugyenyi, P, Ssali, F, Muloma, P, Ssengendo, P, Leda, AR, Cheu, RK, Flynn, JK, Morou, A, Brunet-Ratnasingham, E, Rodriguez, B, Lederman, MM, Kaufmann, DE, Klatt, NR, Kityo, C, Brenchley, JM, Schacker, TW, Sekaly, RP & Douek, DC 2021, 'Translocated microbiome composition determines immunological outcome in treated HIV infection', Cell, vol. 184, no. 15, pp. 3899-3914.e16. https://doi.org/10.1016/j.cell.2021.05.023

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T1 - Translocated microbiome composition determines immunological outcome in treated HIV infection

AU - Nganou-Makamdop, Krystelle

AU - Talla, Aarthi

AU - Sharma, Ashish Arunkumar

AU - Darko, Sam

AU - Ransier, Amy

AU - Laboune, Farida

AU - Chipman, Jeffrey G.

AU - Beilman, Gregory J.

AU - Hoskuldsson, Torfi

AU - Fourati, Slim

AU - Schmidt, Thomas E.

AU - Arumugam, Sahaana

AU - Lima, Noemia S.

AU - Moon, Damee

AU - Callisto, Samuel

AU - Schoephoerster, Jordan

AU - Tomalka, Jeffery

AU - Mugyenyi, Peter

AU - Ssali, Francis

AU - Muloma, Proscovia

AU - Ssengendo, Patrick

AU - Leda, Ana R.

AU - Cheu, Ryan K.

AU - Flynn, Jacob K.

AU - Morou, Antigoni

AU - Brunet-Ratnasingham, Elsa

AU - Rodriguez, Benigno

AU - Lederman, Michael M.

AU - Kaufmann, Daniel E.

AU - Klatt, Nichole R.

AU - Kityo, Cissy

AU - Brenchley, Jason M.

AU - Schacker, Timothy W.

AU - Sekaly, Rafick P.

AU - Douek, Daniel C.

PY - 2021/7/22

Y1 - 2021/7/22

N2 - The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity. Subsequently, decreased Serratia abundance and downregulation of innate cytokines allowed re-establishment of systemic T cell homeostasis promoting restoration of Th1 and Th2 gene expression signatures. Analyses of three other geographically distinct cohorts of treated HIV infection established a more generalized principle that changes in diversity and composition of translocated microbial species influence systemic inflammation and consequently CD4 T cell recovery.

AB - The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity. Subsequently, decreased Serratia abundance and downregulation of innate cytokines allowed re-establishment of systemic T cell homeostasis promoting restoration of Th1 and Th2 gene expression signatures. Analyses of three other geographically distinct cohorts of treated HIV infection established a more generalized principle that changes in diversity and composition of translocated microbial species influence systemic inflammation and consequently CD4 T cell recovery.

KW - HIV

KW - antiretroviral therapy

KW - inflammation

KW - microbiome

KW - systems biology

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UR - http://www.scopus.com/inward/citedby.url?scp=85110739352&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.05.023

DO - 10.1016/j.cell.2021.05.023

M3 - Article

C2 - 34237254

AN - SCOPUS:85110739352

SN - 0092-8674

VL - 184

SP - 3899-3914.e16

JO - Cell

JF - Cell

IS - 15

ER -

Translocated microbiome composition determines immunological outcome in treated HIV infection

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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