Analysis of host responses to Mycobacterium tuberculosis antigens in a multi-site study of subjects with different TB and HIV infection states in sub-Saharan Africa

Jayne S Sutherland; Maeve K Lalor; Gillian F Black; Lyn R Ambrose; Andre G Loxton; Novel N Chegou; Desta Kassa; Adane Mihret; Rawleigh Howe; Harriet Mayanja-Kizza; Marie P Gomez; Simon Donkor; Kees Franken; Willem Hanekom; Michel R Klein; Shreemanta K Parida; W Henry Boom; Bonnie A Thiel; Amelia C Crampin; Martin Ota; Gerhard Walzl; Tom H M Ottenhoff; Hazel M Dockrell; Stefan H E Kaufmann

doi:10.1371/journal.pone.0074080

Analysis of host responses to Mycobacterium tuberculosis antigens in a multi-site study of subjects with different TB and HIV infection states in sub-Saharan Africa

Jayne S Sutherland, Maeve K Lalor, Gillian F Black, Lyn R Ambrose, Andre G Loxton, Novel N Chegou, Desta Kassa, Adane Mihret, Rawleigh Howe, Harriet Mayanja-Kizza, Marie P Gomez, Simon Donkor, Kees Franken, Willem Hanekom, Michel R Klein, Shreemanta K Parida, W Henry Boom, Bonnie A Thiel, Amelia C Crampin, Martin OtaGerhard Walzl, Tom H M Ottenhoff, Hazel M Dockrell, Stefan H E Kaufmann,

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

Abstract

BACKGROUND: Tuberculosis (TB) remains a global health threat with 9 million new cases and 1.4 million deaths per year. In order to develop a protective vaccine, we need to define the antigens expressed by Mycobacterium tuberculosis (Mtb), which are relevant to protective immunity in high-endemic areas.

METHODS: We analysed responses to 23 Mtb antigens in a total of 1247 subjects with different HIV and TB status across 5 geographically diverse sites in Africa (South Africa, The Gambia, Ethiopia, Malawi and Uganda). We used a 7-day whole blood assay followed by IFN-γ ELISA on the supernatants. Antigens included PPD, ESAT-6 and Ag85B (dominant antigens) together with novel resuscitation-promoting factors (rpf), reactivation proteins, latency (Mtb DosR regulon-encoded) antigens, starvation-induced antigens and secreted antigens.

RESULTS: There was variation between sites in responses to the antigens, presumably due to underlying genetic and environmental differences. When results from all sites were combined, HIV- subjects with active TB showed significantly lower responses compared to both TST(-) and TST(+) contacts to latency antigens (Rv0569, Rv1733, Rv1735, Rv1737) and the rpf Rv0867; whilst responses to ESAT-6/CFP-10 fusion protein (EC), PPD, Rv2029, TB10.3, and TB10.4 were significantly higher in TST(+) contacts (LTBI) compared to TB and TST(-) contacts fewer differences were seen in subjects with HIV co-infection, with responses to the mitogen PHA significantly lower in subjects with active TB compared to those with LTBI and no difference with any antigen.

CONCLUSIONS: Our multi-site study design for testing novel Mtb antigens revealed promising antigens for future vaccine development. The IFN-γ ELISA is a cheap and useful tool for screening potential antigenicity in subjects with different ethnic backgrounds and across a spectrum of TB and HIV infection states. Analysis of cytokines other than IFN-γ is currently on-going to determine correlates of protection, which may be useful for vaccine efficacy trials.

Original language	English
Article number	e74080
Number of pages	1
Journal	PLoS ONE [E]
Volume	8
Issue number	9
DOIs	https://doi.org/10.1371/journal.pone.0074080 https://doi.org/10.1371/journal.pone.0074080
Publication status	Published - 2013

Keywords

Adult
Africa South of the Sahara
Antigens, Bacterial
CD4 Lymphocyte Count
Cluster Analysis
Coinfection
Female
HIV Infections
Humans
Interferon-gamma
Male
Middle Aged
Mycobacterium tuberculosis
Tuberculosis
Young Adult
Journal Article
Research Support, Non-U.S. Gov't

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Sutherland, J. S., Lalor, M. K., Black, G. F., Ambrose, L. R., Loxton, A. G., Chegou, N. N., Kassa, D., Mihret, A., Howe, R., Mayanja-Kizza, H., Gomez, M. P., Donkor, S., Franken, K., Hanekom, W., Klein, M. R., Parida, S. K., Boom, W. H., Thiel, B. A., Crampin, A. C. (2013). Analysis of host responses to Mycobacterium tuberculosis antigens in a multi-site study of subjects with different TB and HIV infection states in sub-Saharan Africa. PLoS ONE [E], 8(9), Article e74080. https://doi.org/10.1371/journal.pone.0074080, https://doi.org/10.1371/journal.pone.0074080

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title = "Analysis of host responses to Mycobacterium tuberculosis antigens in a multi-site study of subjects with different TB and HIV infection states in sub-Saharan Africa",

abstract = "BACKGROUND: Tuberculosis (TB) remains a global health threat with 9 million new cases and 1.4 million deaths per year. In order to develop a protective vaccine, we need to define the antigens expressed by Mycobacterium tuberculosis (Mtb), which are relevant to protective immunity in high-endemic areas.METHODS: We analysed responses to 23 Mtb antigens in a total of 1247 subjects with different HIV and TB status across 5 geographically diverse sites in Africa (South Africa, The Gambia, Ethiopia, Malawi and Uganda). We used a 7-day whole blood assay followed by IFN-γ ELISA on the supernatants. Antigens included PPD, ESAT-6 and Ag85B (dominant antigens) together with novel resuscitation-promoting factors (rpf), reactivation proteins, latency (Mtb DosR regulon-encoded) antigens, starvation-induced antigens and secreted antigens.RESULTS: There was variation between sites in responses to the antigens, presumably due to underlying genetic and environmental differences. When results from all sites were combined, HIV- subjects with active TB showed significantly lower responses compared to both TST(-) and TST(+) contacts to latency antigens (Rv0569, Rv1733, Rv1735, Rv1737) and the rpf Rv0867; whilst responses to ESAT-6/CFP-10 fusion protein (EC), PPD, Rv2029, TB10.3, and TB10.4 were significantly higher in TST(+) contacts (LTBI) compared to TB and TST(-) contacts fewer differences were seen in subjects with HIV co-infection, with responses to the mitogen PHA significantly lower in subjects with active TB compared to those with LTBI and no difference with any antigen.CONCLUSIONS: Our multi-site study design for testing novel Mtb antigens revealed promising antigens for future vaccine development. The IFN-γ ELISA is a cheap and useful tool for screening potential antigenicity in subjects with different ethnic backgrounds and across a spectrum of TB and HIV infection states. Analysis of cytokines other than IFN-γ is currently on-going to determine correlates of protection, which may be useful for vaccine efficacy trials.",

keywords = "Adult, Africa South of the Sahara, Antigens, Bacterial, CD4 Lymphocyte Count, Cluster Analysis, Coinfection, Female, HIV Infections, Humans, Interferon-gamma, Male, Middle Aged, Mycobacterium tuberculosis, Tuberculosis, Young Adult, Journal Article, Research Support, Non-U.S. Gov't",

author = "Sutherland, {Jayne S} and Lalor, {Maeve K} and Black, {Gillian F} and Ambrose, {Lyn R} and Loxton, {Andre G} and Chegou, {Novel N} and Desta Kassa and Adane Mihret and Rawleigh Howe and Harriet Mayanja-Kizza and Gomez, {Marie P} and Simon Donkor and Kees Franken and Willem Hanekom and Klein, {Michel R} and Parida, {Shreemanta K} and Boom, {W Henry} and Thiel, {Bonnie A} and Crampin, {Amelia C} and Martin Ota and Gerhard Walzl and Ottenhoff, {Tom H M} and Dockrell, {Hazel M} and Kaufmann, {Stefan H E} and Frank Miedema and Leonie Ran and Ronald Jacobi and {van Baarle}, Debbie",

year = "2013",

doi = "10.1371/journal.pone.0074080",

language = "English",

volume = "8",

journal = "PLoS ONE [E]",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "9",

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Sutherland, JS, Lalor, MK, Black, GF, Ambrose, LR, Loxton, AG, Chegou, NN, Kassa, D, Mihret, A, Howe, R, Mayanja-Kizza, H, Gomez, MP, Donkor, S, Franken, K, Hanekom, W, Klein, MR, Parida, SK, Boom, WH, Thiel, BA, Crampin, AC, Ota, M, Walzl, G, Ottenhoff, THM, Dockrell, HM, Kaufmann, SHE 2013, 'Analysis of host responses to Mycobacterium tuberculosis antigens in a multi-site study of subjects with different TB and HIV infection states in sub-Saharan Africa', PLoS ONE [E], vol. 8, no. 9, e74080. https://doi.org/10.1371/journal.pone.0074080, https://doi.org/10.1371/journal.pone.0074080

TY - JOUR

T1 - Analysis of host responses to Mycobacterium tuberculosis antigens in a multi-site study of subjects with different TB and HIV infection states in sub-Saharan Africa

AU - Sutherland, Jayne S

AU - Lalor, Maeve K

AU - Black, Gillian F

AU - Ambrose, Lyn R

AU - Loxton, Andre G

AU - Chegou, Novel N

AU - Kassa, Desta

AU - Mihret, Adane

AU - Howe, Rawleigh

AU - Mayanja-Kizza, Harriet

AU - Gomez, Marie P

AU - Donkor, Simon

AU - Franken, Kees

AU - Hanekom, Willem

AU - Klein, Michel R

AU - Parida, Shreemanta K

AU - Boom, W Henry

AU - Thiel, Bonnie A

AU - Crampin, Amelia C

AU - Ota, Martin

AU - Walzl, Gerhard

AU - Ottenhoff, Tom H M

AU - Dockrell, Hazel M

AU - Kaufmann, Stefan H E

AU - Miedema, Frank

AU - Ran, Leonie

AU - Jacobi, Ronald

AU - van Baarle, Debbie

PY - 2013

Y1 - 2013

N2 - BACKGROUND: Tuberculosis (TB) remains a global health threat with 9 million new cases and 1.4 million deaths per year. In order to develop a protective vaccine, we need to define the antigens expressed by Mycobacterium tuberculosis (Mtb), which are relevant to protective immunity in high-endemic areas.METHODS: We analysed responses to 23 Mtb antigens in a total of 1247 subjects with different HIV and TB status across 5 geographically diverse sites in Africa (South Africa, The Gambia, Ethiopia, Malawi and Uganda). We used a 7-day whole blood assay followed by IFN-γ ELISA on the supernatants. Antigens included PPD, ESAT-6 and Ag85B (dominant antigens) together with novel resuscitation-promoting factors (rpf), reactivation proteins, latency (Mtb DosR regulon-encoded) antigens, starvation-induced antigens and secreted antigens.RESULTS: There was variation between sites in responses to the antigens, presumably due to underlying genetic and environmental differences. When results from all sites were combined, HIV- subjects with active TB showed significantly lower responses compared to both TST(-) and TST(+) contacts to latency antigens (Rv0569, Rv1733, Rv1735, Rv1737) and the rpf Rv0867; whilst responses to ESAT-6/CFP-10 fusion protein (EC), PPD, Rv2029, TB10.3, and TB10.4 were significantly higher in TST(+) contacts (LTBI) compared to TB and TST(-) contacts fewer differences were seen in subjects with HIV co-infection, with responses to the mitogen PHA significantly lower in subjects with active TB compared to those with LTBI and no difference with any antigen.CONCLUSIONS: Our multi-site study design for testing novel Mtb antigens revealed promising antigens for future vaccine development. The IFN-γ ELISA is a cheap and useful tool for screening potential antigenicity in subjects with different ethnic backgrounds and across a spectrum of TB and HIV infection states. Analysis of cytokines other than IFN-γ is currently on-going to determine correlates of protection, which may be useful for vaccine efficacy trials.

AB - BACKGROUND: Tuberculosis (TB) remains a global health threat with 9 million new cases and 1.4 million deaths per year. In order to develop a protective vaccine, we need to define the antigens expressed by Mycobacterium tuberculosis (Mtb), which are relevant to protective immunity in high-endemic areas.METHODS: We analysed responses to 23 Mtb antigens in a total of 1247 subjects with different HIV and TB status across 5 geographically diverse sites in Africa (South Africa, The Gambia, Ethiopia, Malawi and Uganda). We used a 7-day whole blood assay followed by IFN-γ ELISA on the supernatants. Antigens included PPD, ESAT-6 and Ag85B (dominant antigens) together with novel resuscitation-promoting factors (rpf), reactivation proteins, latency (Mtb DosR regulon-encoded) antigens, starvation-induced antigens and secreted antigens.RESULTS: There was variation between sites in responses to the antigens, presumably due to underlying genetic and environmental differences. When results from all sites were combined, HIV- subjects with active TB showed significantly lower responses compared to both TST(-) and TST(+) contacts to latency antigens (Rv0569, Rv1733, Rv1735, Rv1737) and the rpf Rv0867; whilst responses to ESAT-6/CFP-10 fusion protein (EC), PPD, Rv2029, TB10.3, and TB10.4 were significantly higher in TST(+) contacts (LTBI) compared to TB and TST(-) contacts fewer differences were seen in subjects with HIV co-infection, with responses to the mitogen PHA significantly lower in subjects with active TB compared to those with LTBI and no difference with any antigen.CONCLUSIONS: Our multi-site study design for testing novel Mtb antigens revealed promising antigens for future vaccine development. The IFN-γ ELISA is a cheap and useful tool for screening potential antigenicity in subjects with different ethnic backgrounds and across a spectrum of TB and HIV infection states. Analysis of cytokines other than IFN-γ is currently on-going to determine correlates of protection, which may be useful for vaccine efficacy trials.

KW - Adult

KW - Africa South of the Sahara

KW - Antigens, Bacterial

KW - CD4 Lymphocyte Count

KW - Cluster Analysis

KW - Coinfection

KW - Female

KW - HIV Infections

KW - Humans

KW - Interferon-gamma

KW - Male

KW - Middle Aged

KW - Mycobacterium tuberculosis

KW - Tuberculosis

KW - Young Adult

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1371/journal.pone.0074080

DO - 10.1371/journal.pone.0074080

M3 - Article

C2 - 24040170

SN - 1932-6203

VL - 8

JO - PLoS ONE [E]

JF - PLoS ONE [E]

IS - 9

M1 - e74080

ER -

Analysis of host responses to Mycobacterium tuberculosis antigens in a multi-site study of subjects with different TB and HIV infection states in sub-Saharan Africa

Abstract

Keywords

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