CD4+ T-cell-independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection

Taylor W. Foreman, Smriti Mehra, Denae N. LoBato, Adel Malek, Xavier Alvarez, Nadia A. Golden, Allison N. Bucşan, Peter J. Didier, Lara A. Doyle-Meyers, Kasi E. Russell-Lodrigue, Chad J. Roy, James Blanchard, Marcelo J. Kuroda, Andrew A. Lackner, John Chan, Shabaana A. Khader, William R. Jacobs, Deepak Kaushal

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The synergy between Mycobacterium tuberculosis (Mtb) and HIV in coinfected patients has profoundly impacted global mortality because of tuberculosis (TB) and AIDS. HIV significantly increases rates of reactivation of latent TB infection (LTBI) to active disease, with the decline in CD4+ T cells believed to be the major causality. In this study, nonhuman primates were coinfected with Mtb and simian immunodeficiency virus (SIV), recapitulating human coinfection. A majority of animals exhibited rapid reactivation of Mtb replication, progressing to disseminated TB and increased SIV-associated pathology. Although a severe loss of pulmonary CD4+ T cells was observed in all coinfected macaques, a subpopulation of the animals was still able to prevent reactivation and maintain LTBI. Investigation of pulmonary immune responses and pathology in this cohort demonstrated that increased CD8+ memory T-cell proliferation, higher granzyme B production, and expanded B-cell follicles correlated with protection from reactivation. Our findings reveal mechanisms that control SIV- and TB-associated pathology. These CD4-independent protective immune responses warrant further studies in HIV coinfected humans able to control their TB infection. Moreover, these findings will provide insight into natural immunity to Mtb and will guide development of novel vaccine strategies and immunotherapies.

Original languageEnglish (US)
Pages (from-to)E5636-E5644
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number38
DOIs
StatePublished - Sep 20 2016

Fingerprint

Latent Tuberculosis
Macaca
Coinfection
Mycobacterium tuberculosis
Simian Immunodeficiency Virus
Tuberculosis
HIV
T-Lymphocytes
Pathology
Granzymes
Lung
Infection
Innate Immunity
Causality
Immunotherapy
Primates
Acquired Immunodeficiency Syndrome
B-Lymphocytes
Vaccines
Cell Proliferation

Keywords

  • B cells
  • CD4 T cells
  • CD8 T cells
  • Nonhuman primate
  • Tuberculosis

ASJC Scopus subject areas

  • General

Cite this

CD4+ T-cell-independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection. / Foreman, Taylor W.; Mehra, Smriti; LoBato, Denae N.; Malek, Adel; Alvarez, Xavier; Golden, Nadia A.; Bucşan, Allison N.; Didier, Peter J.; Doyle-Meyers, Lara A.; Russell-Lodrigue, Kasi E.; Roy, Chad J.; Blanchard, James; Kuroda, Marcelo J.; Lackner, Andrew A.; Chan, John; Khader, Shabaana A.; Jacobs, William R.; Kaushal, Deepak.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 38, 20.09.2016, p. E5636-E5644.

Research output: Contribution to journalArticle

Foreman, TW, Mehra, S, LoBato, DN, Malek, A, Alvarez, X, Golden, NA, Bucşan, AN, Didier, PJ, Doyle-Meyers, LA, Russell-Lodrigue, KE, Roy, CJ, Blanchard, J, Kuroda, MJ, Lackner, AA, Chan, J, Khader, SA, Jacobs, WR & Kaushal, D 2016, 'CD4+ T-cell-independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 38, pp. E5636-E5644. https://doi.org/10.1073/pnas.1611987113
Foreman, Taylor W. ; Mehra, Smriti ; LoBato, Denae N. ; Malek, Adel ; Alvarez, Xavier ; Golden, Nadia A. ; Bucşan, Allison N. ; Didier, Peter J. ; Doyle-Meyers, Lara A. ; Russell-Lodrigue, Kasi E. ; Roy, Chad J. ; Blanchard, James ; Kuroda, Marcelo J. ; Lackner, Andrew A. ; Chan, John ; Khader, Shabaana A. ; Jacobs, William R. ; Kaushal, Deepak. / CD4+ T-cell-independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 38. pp. E5636-E5644.
@article{0bc66cdb9ef54f9094d46af6db611391,
title = "CD4+ T-cell-independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection",
abstract = "The synergy between Mycobacterium tuberculosis (Mtb) and HIV in coinfected patients has profoundly impacted global mortality because of tuberculosis (TB) and AIDS. HIV significantly increases rates of reactivation of latent TB infection (LTBI) to active disease, with the decline in CD4+ T cells believed to be the major causality. In this study, nonhuman primates were coinfected with Mtb and simian immunodeficiency virus (SIV), recapitulating human coinfection. A majority of animals exhibited rapid reactivation of Mtb replication, progressing to disseminated TB and increased SIV-associated pathology. Although a severe loss of pulmonary CD4+ T cells was observed in all coinfected macaques, a subpopulation of the animals was still able to prevent reactivation and maintain LTBI. Investigation of pulmonary immune responses and pathology in this cohort demonstrated that increased CD8+ memory T-cell proliferation, higher granzyme B production, and expanded B-cell follicles correlated with protection from reactivation. Our findings reveal mechanisms that control SIV- and TB-associated pathology. These CD4-independent protective immune responses warrant further studies in HIV coinfected humans able to control their TB infection. Moreover, these findings will provide insight into natural immunity to Mtb and will guide development of novel vaccine strategies and immunotherapies.",
keywords = "B cells, CD4 T cells, CD8 T cells, Nonhuman primate, Tuberculosis",
author = "Foreman, {Taylor W.} and Smriti Mehra and LoBato, {Denae N.} and Adel Malek and Xavier Alvarez and Golden, {Nadia A.} and Bucşan, {Allison N.} and Didier, {Peter J.} and Doyle-Meyers, {Lara A.} and Russell-Lodrigue, {Kasi E.} and Roy, {Chad J.} and James Blanchard and Kuroda, {Marcelo J.} and Lackner, {Andrew A.} and John Chan and Khader, {Shabaana A.} and Jacobs, {William R.} and Deepak Kaushal",
year = "2016",
month = "9",
day = "20",
doi = "10.1073/pnas.1611987113",
language = "English (US)",
volume = "113",
pages = "E5636--E5644",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "38",

}

TY - JOUR

T1 - CD4+ T-cell-independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection

AU - Foreman, Taylor W.

AU - Mehra, Smriti

AU - LoBato, Denae N.

AU - Malek, Adel

AU - Alvarez, Xavier

AU - Golden, Nadia A.

AU - Bucşan, Allison N.

AU - Didier, Peter J.

AU - Doyle-Meyers, Lara A.

AU - Russell-Lodrigue, Kasi E.

AU - Roy, Chad J.

AU - Blanchard, James

AU - Kuroda, Marcelo J.

AU - Lackner, Andrew A.

AU - Chan, John

AU - Khader, Shabaana A.

AU - Jacobs, William R.

AU - Kaushal, Deepak

PY - 2016/9/20

Y1 - 2016/9/20

N2 - The synergy between Mycobacterium tuberculosis (Mtb) and HIV in coinfected patients has profoundly impacted global mortality because of tuberculosis (TB) and AIDS. HIV significantly increases rates of reactivation of latent TB infection (LTBI) to active disease, with the decline in CD4+ T cells believed to be the major causality. In this study, nonhuman primates were coinfected with Mtb and simian immunodeficiency virus (SIV), recapitulating human coinfection. A majority of animals exhibited rapid reactivation of Mtb replication, progressing to disseminated TB and increased SIV-associated pathology. Although a severe loss of pulmonary CD4+ T cells was observed in all coinfected macaques, a subpopulation of the animals was still able to prevent reactivation and maintain LTBI. Investigation of pulmonary immune responses and pathology in this cohort demonstrated that increased CD8+ memory T-cell proliferation, higher granzyme B production, and expanded B-cell follicles correlated with protection from reactivation. Our findings reveal mechanisms that control SIV- and TB-associated pathology. These CD4-independent protective immune responses warrant further studies in HIV coinfected humans able to control their TB infection. Moreover, these findings will provide insight into natural immunity to Mtb and will guide development of novel vaccine strategies and immunotherapies.

AB - The synergy between Mycobacterium tuberculosis (Mtb) and HIV in coinfected patients has profoundly impacted global mortality because of tuberculosis (TB) and AIDS. HIV significantly increases rates of reactivation of latent TB infection (LTBI) to active disease, with the decline in CD4+ T cells believed to be the major causality. In this study, nonhuman primates were coinfected with Mtb and simian immunodeficiency virus (SIV), recapitulating human coinfection. A majority of animals exhibited rapid reactivation of Mtb replication, progressing to disseminated TB and increased SIV-associated pathology. Although a severe loss of pulmonary CD4+ T cells was observed in all coinfected macaques, a subpopulation of the animals was still able to prevent reactivation and maintain LTBI. Investigation of pulmonary immune responses and pathology in this cohort demonstrated that increased CD8+ memory T-cell proliferation, higher granzyme B production, and expanded B-cell follicles correlated with protection from reactivation. Our findings reveal mechanisms that control SIV- and TB-associated pathology. These CD4-independent protective immune responses warrant further studies in HIV coinfected humans able to control their TB infection. Moreover, these findings will provide insight into natural immunity to Mtb and will guide development of novel vaccine strategies and immunotherapies.

KW - B cells

KW - CD4 T cells

KW - CD8 T cells

KW - Nonhuman primate

KW - Tuberculosis

UR - http://www.scopus.com/inward/record.url?scp=84988653880&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84988653880&partnerID=8YFLogxK

U2 - 10.1073/pnas.1611987113

DO - 10.1073/pnas.1611987113

M3 - Article

VL - 113

SP - E5636-E5644

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 38

ER -