Impact of intermediate hyperglycemia and diabetes on immune dysfunction in tuberculosis

Clare Eckold; Vinod Kumar; January Weiner; Bachti Alisjahbana; Anca Lelia Riza; Katharina Ronacher; Jorge Coronel; Sarah Kerry-Barnard; Stephanus T. Malherbe; Leanie Kleynhans; Kim Stanley; Rovina Ruslami; Mihai Ioana; Cesar Ugarte-Gil; Gerhard Walzl; Reinout Van Crevel; Cisca Wijmenga; Julia A. Critchley; Hazel M. Dockrell; Jacqueline M. Cliff; J. Cliff; C. Eckold; D. Moore; U. Griffiths; Y. Laurence; R. Aarnouste; M. Netea; R. Van Crevel; C. Ruesen; E. Lachmandas; S. Kaufmann; M. Beigier; R. Golinski; S. Joosten; T. Ottenhoff; F. Vrieling; M. Haks; K. Ronacher; S. Malherbe; L. Kleynhans; B. Smith; K. Stanley; G. Van Der Spuy; A. Loxton; N. Chegou; M. Bosman; L. Thiart; C. Wagman; H. Tshivhula; M. Selamolela; N. Prins; W. Du Plessis; I. Van Rensburg; L. Du Toit; J. Critchley; S. Kerry-Barnard; F. Pearson; D. Grint; S. McAllister; P. Hill; A. Verrall; M. Ioana; A. Riza; R. Cioboata; M. Dudau; F. Nitu; I. Bazavan; M. Olteanu; C. Editoiu; A. Florescu; M. Mota; S. G. Popa; A. Firanescu; A. Popa; I. Gheonea; S. Bicuti; A. Lepadat; I. Vladu; D. Clenciu; M. Bicu; C. Streba; A. Demetrian; M. Ciurea; A. Cimpoeru; A. Ciocoiu; S. Dorobantu; R. Plesea; E. L. Popescu; M. Cucu; I. Streata; F. Burada; S. Serban-Sosoi; N. Panduru; E. Nicoli; M. Ciontea; I. Capitanescu; M. Olaru; T. Tataru; M. Papurica; I. Valutanu; V. Dubreu; L. Stamatoiu; V. Kumar; C. Wijmenga; J. Coronel; S. Lopez; R. Limascca; K. Villaizan; B. Castro; J. Flores; W. Solano; B. Alisjahbana; N. Soetedjo; P. Santoso; L. Chaidir; R. Koesoemadinata; N. Susilawati; J. Annisa; R. Livia; V. Yunivita; A. Soeroto; H. Permana; S. Imaculata; Y. Gunawan; N. Dewi; L. Apriani

doi:10.1093/cid/ciaa751

Impact of intermediate hyperglycemia and diabetes on immune dysfunction in tuberculosis

Clare Eckold, Vinod Kumar, January Weiner, Bachti Alisjahbana, Anca Lelia Riza, Katharina Ronacher, Jorge Coronel, Sarah Kerry-Barnard, Stephanus T. Malherbe, Leanie Kleynhans, Kim Stanley, Rovina Ruslami, Mihai Ioana, Cesar Ugarte-Gil, Gerhard Walzl, Reinout Van Crevel, Cisca Wijmenga, Julia A. Critchley, Hazel M. Dockrell, Jacqueline M. CliffJ. Cliff, C. Eckold, D. Moore, U. Griffiths, Y. Laurence, R. Aarnouste, M. Netea, R. Van Crevel, C. Ruesen, E. Lachmandas, S. Kaufmann, M. Beigier, R. Golinski, S. Joosten, T. Ottenhoff, F. Vrieling, M. Haks, K. Ronacher, S. Malherbe, L. Kleynhans, B. Smith, K. Stanley, G. Van Der Spuy, A. Loxton, N. Chegou, M. Bosman, L. Thiart, C. Wagman, H. Tshivhula, M. Selamolela, N. Prins, W. Du Plessis, I. Van Rensburg, L. Du Toit, J. Critchley, S. Kerry-Barnard, F. Pearson, D. Grint, S. McAllister, P. Hill, A. Verrall, M. Ioana, A. Riza, R. Cioboata, M. Dudau, F. Nitu, I. Bazavan, M. Olteanu, C. Editoiu, A. Florescu, M. Mota, S. G. Popa, A. Firanescu, A. Popa, I. Gheonea, S. Bicuti, A. Lepadat, I. Vladu, D. Clenciu, M. Bicu, C. Streba, A. Demetrian, M. Ciurea, A. Cimpoeru, A. Ciocoiu, S. Dorobantu, R. Plesea, E. L. Popescu, M. Cucu, I. Streata, F. Burada, S. Serban-Sosoi, N. Panduru, E. Nicoli, M. Ciontea, I. Capitanescu, M. Olaru, T. Tataru, M. Papurica, I. Valutanu, V. Dubreu, L. Stamatoiu, V. Kumar, C. Wijmenga, J. Coronel, S. Lopez, R. Limascca, K. Villaizan, B. Castro, J. Flores, W. Solano, B. Alisjahbana, N. Soetedjo, P. Santoso, L. Chaidir, R. Koesoemadinata, N. Susilawati, J. Annisa, R. Livia, V. Yunivita, A. Soeroto, H. Permana, S. Imaculata, Y. Gunawan, N. Dewi, L. Apriani

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

Abstract

Background: People with diabetes have an increased risk of developing active tuberculosis (TB) and are more likely to have poor TB-treatment outcomes, which may impact on control of TB as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in patients with active TB relative to healthy individuals. The effects of diabetes and intermediate hyperglycemia (IH) on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-TB comorbidity. Methods: Whole blood samples were collected from active TB patients with diabetes (glycated hemoglobin [HbA1c] ≥6.5%) or IH (HbA1c = 5.7% to <6.5%), TB-only patients, and healthy controls in 4 countries: South Africa, Romania, Indonesia, and Peru. Differential blood gene expression was determined by RNA-seq (n = 249). Results: Diabetes increased the magnitude of gene expression change in the host transcriptome in TB, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with IH and TB exhibited blood transcriptomes much more similar to patients with diabetes-TB than to patients with only TB. Both diabetes-TB and IH-TB patients had a decreased type I interferon response relative to TB-only patients. Conclusions: Comorbidity in individuals with both TB and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type I interferon responses in comorbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in individuals with IH, showing that altered immunity to TB may also be present in this group. The TB disease outcomes in individuals with IH diagnosed with TB should be investigated further.

Original language	English (US)
Pages (from-to)	69-78
Number of pages	10
Journal	Clinical Infectious Diseases
Volume	72
Issue number	1
DOIs	https://doi.org/10.1093/cid/ciaa751
State	Published - Jan 1 2021
Externally published	Yes

Keywords

diabetes
hyperglycemia
inflammation
tuberculosis

ASJC Scopus subject areas

Microbiology (medical)
Infectious Diseases

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10.1093/cid/ciaa751

Cite this

Eckold, C., Kumar, V., Weiner, J., Alisjahbana, B., Riza, A. L., Ronacher, K., Coronel, J., Kerry-Barnard, S., Malherbe, S. T., Kleynhans, L., Stanley, K., Ruslami, R., Ioana, M., Ugarte-Gil, C., Walzl, G., Van Crevel, R., Wijmenga, C., Critchley, J. A., Dockrell, H. M., ... Apriani, L. (2021). Impact of intermediate hyperglycemia and diabetes on immune dysfunction in tuberculosis. Clinical Infectious Diseases, 72(1), 69-78. https://doi.org/10.1093/cid/ciaa751

Eckold, C, Kumar, V, Weiner, J, Alisjahbana, B, Riza, AL, Ronacher, K, Coronel, J, Kerry-Barnard, S, Malherbe, ST, Kleynhans, L, Stanley, K, Ruslami, R, Ioana, M, Ugarte-Gil, C, Walzl, G, Van Crevel, R, Wijmenga, C, Critchley, JA, Dockrell, HM, Cliff, JM, Cliff, J, Eckold, C, Moore, D, Griffiths, U, Laurence, Y, Aarnouste, R, Netea, M, Van Crevel, R, Ruesen, C, Lachmandas, E, Kaufmann, S, Beigier, M, Golinski, R, Joosten, S, Ottenhoff, T, Vrieling, F, Haks, M, Ronacher, K, Malherbe, S, Kleynhans, L, Smith, B, Stanley, K, Van Der Spuy, G, Loxton, A, Chegou, N, Bosman, M, Thiart, L, Wagman, C, Tshivhula, H, Selamolela, M, Prins, N, Du Plessis, W, Van Rensburg, I, Du Toit, L, Critchley, J, Kerry-Barnard, S, Pearson, F, Grint, D, McAllister, S, Hill, P, Verrall, A, Ioana, M, Riza, A, Cioboata, R, Dudau, M, Nitu, F, Bazavan, I, Olteanu, M, Editoiu, C, Florescu, A, Mota, M, Popa, SG, Firanescu, A, Popa, A, Gheonea, I, Bicuti, S, Lepadat, A, Vladu, I, Clenciu, D, Bicu, M, Streba, C, Demetrian, A, Ciurea, M, Cimpoeru, A, Ciocoiu, A, Dorobantu, S, Plesea, R, Popescu, EL, Cucu, M, Streata, I, Burada, F, Serban-Sosoi, S, Panduru, N, Nicoli, E, Ciontea, M, Capitanescu, I, Olaru, M, Tataru, T, Papurica, M, Valutanu, I, Dubreu, V, Stamatoiu, L, Kumar, V, Wijmenga, C, Coronel, J, Lopez, S, Limascca, R, Villaizan, K, Castro, B, Flores, J, Solano, W, Alisjahbana, B, Soetedjo, N, Santoso, P, Chaidir, L, Koesoemadinata, R, Susilawati, N, Annisa, J, Livia, R, Yunivita, V, Soeroto, A, Permana, H, Imaculata, S, Gunawan, Y, Dewi, N & Apriani, L 2021, 'Impact of intermediate hyperglycemia and diabetes on immune dysfunction in tuberculosis', Clinical Infectious Diseases, vol. 72, no. 1, pp. 69-78. https://doi.org/10.1093/cid/ciaa751

@article{f0596359cdf3487e91a4f6e18ba3c02f,

title = "Impact of intermediate hyperglycemia and diabetes on immune dysfunction in tuberculosis",

abstract = "Background: People with diabetes have an increased risk of developing active tuberculosis (TB) and are more likely to have poor TB-treatment outcomes, which may impact on control of TB as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in patients with active TB relative to healthy individuals. The effects of diabetes and intermediate hyperglycemia (IH) on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-TB comorbidity. Methods: Whole blood samples were collected from active TB patients with diabetes (glycated hemoglobin [HbA1c] ≥6.5%) or IH (HbA1c = 5.7% to <6.5%), TB-only patients, and healthy controls in 4 countries: South Africa, Romania, Indonesia, and Peru. Differential blood gene expression was determined by RNA-seq (n = 249). Results: Diabetes increased the magnitude of gene expression change in the host transcriptome in TB, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with IH and TB exhibited blood transcriptomes much more similar to patients with diabetes-TB than to patients with only TB. Both diabetes-TB and IH-TB patients had a decreased type I interferon response relative to TB-only patients. Conclusions: Comorbidity in individuals with both TB and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type I interferon responses in comorbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in individuals with IH, showing that altered immunity to TB may also be present in this group. The TB disease outcomes in individuals with IH diagnosed with TB should be investigated further.",

keywords = "diabetes, hyperglycemia, inflammation, tuberculosis",

author = "Clare Eckold and Vinod Kumar and January Weiner and Bachti Alisjahbana and Riza, {Anca Lelia} and Katharina Ronacher and Jorge Coronel and Sarah Kerry-Barnard and Malherbe, {Stephanus T.} and Leanie Kleynhans and Kim Stanley and Rovina Ruslami and Mihai Ioana and Cesar Ugarte-Gil and Gerhard Walzl and {Van Crevel}, Reinout and Cisca Wijmenga and Critchley, {Julia A.} and Dockrell, {Hazel M.} and Cliff, {Jacqueline M.} and J. Cliff and C. Eckold and D. Moore and U. Griffiths and Y. Laurence and R. Aarnouste and M. Netea and {Van Crevel}, R. and C. Ruesen and E. Lachmandas and S. Kaufmann and M. Beigier and R. Golinski and S. Joosten and T. Ottenhoff and F. Vrieling and M. Haks and K. Ronacher and S. Malherbe and L. Kleynhans and B. Smith and K. Stanley and {Van Der Spuy}, G. and A. Loxton and N. Chegou and M. Bosman and L. Thiart and C. Wagman and H. Tshivhula and M. Selamolela and N. Prins and {Du Plessis}, W. and {Van Rensburg}, I. and {Du Toit}, L. and J. Critchley and S. Kerry-Barnard and F. Pearson and D. Grint and S. McAllister and P. Hill and A. Verrall and M. Ioana and A. Riza and R. Cioboata and M. Dudau and F. Nitu and I. Bazavan and M. Olteanu and C. Editoiu and A. Florescu and M. Mota and Popa, {S. G.} and A. Firanescu and A. Popa and I. Gheonea and S. Bicuti and A. Lepadat and I. Vladu and D. Clenciu and M. Bicu and C. Streba and A. Demetrian and M. Ciurea and A. Cimpoeru and A. Ciocoiu and S. Dorobantu and R. Plesea and Popescu, {E. L.} and M. Cucu and I. Streata and F. Burada and S. Serban-Sosoi and N. Panduru and E. Nicoli and M. Ciontea and I. Capitanescu and M. Olaru and T. Tataru and M. Papurica and I. Valutanu and V. Dubreu and L. Stamatoiu and V. Kumar and C. Wijmenga and J. Coronel and S. Lopez and R. Limascca and K. Villaizan and B. Castro and J. Flores and W. Solano and B. Alisjahbana and N. Soetedjo and P. Santoso and L. Chaidir and R. Koesoemadinata and N. Susilawati and J. Annisa and R. Livia and V. Yunivita and A. Soeroto and H. Permana and S. Imaculata and Y. Gunawan and N. Dewi and L. Apriani",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.",

year = "2021",

month = jan,

day = "1",

doi = "10.1093/cid/ciaa751",

language = "English (US)",

volume = "72",

pages = "69--78",

journal = "Clinical Infectious Diseases",

issn = "1058-4838",

publisher = "Oxford University Press",

number = "1",

}

TY - JOUR

T1 - Impact of intermediate hyperglycemia and diabetes on immune dysfunction in tuberculosis

AU - Eckold, Clare

AU - Kumar, Vinod

AU - Weiner, January

AU - Alisjahbana, Bachti

AU - Riza, Anca Lelia

AU - Ronacher, Katharina

AU - Coronel, Jorge

AU - Kerry-Barnard, Sarah

AU - Malherbe, Stephanus T.

AU - Kleynhans, Leanie

AU - Stanley, Kim

AU - Ruslami, Rovina

AU - Ioana, Mihai

AU - Ugarte-Gil, Cesar

AU - Walzl, Gerhard

AU - Van Crevel, Reinout

AU - Wijmenga, Cisca

AU - Critchley, Julia A.

AU - Dockrell, Hazel M.

AU - Cliff, Jacqueline M.

AU - Cliff, J.

AU - Eckold, C.

AU - Moore, D.

AU - Griffiths, U.

AU - Laurence, Y.

AU - Aarnouste, R.

AU - Netea, M.

AU - Van Crevel, R.

AU - Ruesen, C.

AU - Lachmandas, E.

AU - Kaufmann, S.

AU - Beigier, M.

AU - Golinski, R.

AU - Joosten, S.

AU - Ottenhoff, T.

AU - Vrieling, F.

AU - Haks, M.

AU - Ronacher, K.

AU - Malherbe, S.

AU - Kleynhans, L.

AU - Smith, B.

AU - Stanley, K.

AU - Van Der Spuy, G.

AU - Loxton, A.

AU - Chegou, N.

AU - Bosman, M.

AU - Thiart, L.

AU - Wagman, C.

AU - Tshivhula, H.

AU - Selamolela, M.

AU - Prins, N.

AU - Du Plessis, W.

AU - Van Rensburg, I.

AU - Du Toit, L.

AU - Critchley, J.

AU - Kerry-Barnard, S.

AU - Pearson, F.

AU - Grint, D.

AU - McAllister, S.

AU - Hill, P.

AU - Verrall, A.

AU - Ioana, M.

AU - Riza, A.

AU - Cioboata, R.

AU - Dudau, M.

AU - Nitu, F.

AU - Bazavan, I.

AU - Olteanu, M.

AU - Editoiu, C.

AU - Florescu, A.

AU - Mota, M.

AU - Popa, S. G.

AU - Firanescu, A.

AU - Popa, A.

AU - Gheonea, I.

AU - Bicuti, S.

AU - Lepadat, A.

AU - Vladu, I.

AU - Clenciu, D.

AU - Bicu, M.

AU - Streba, C.

AU - Demetrian, A.

AU - Ciurea, M.

AU - Cimpoeru, A.

AU - Ciocoiu, A.

AU - Dorobantu, S.

AU - Plesea, R.

AU - Popescu, E. L.

AU - Cucu, M.

AU - Streata, I.

AU - Burada, F.

AU - Serban-Sosoi, S.

AU - Panduru, N.

AU - Nicoli, E.

AU - Ciontea, M.

AU - Capitanescu, I.

AU - Olaru, M.

AU - Tataru, T.

AU - Papurica, M.

AU - Valutanu, I.

AU - Dubreu, V.

AU - Stamatoiu, L.

AU - Kumar, V.

AU - Wijmenga, C.

AU - Coronel, J.

AU - Lopez, S.

AU - Limascca, R.

AU - Villaizan, K.

AU - Castro, B.

AU - Flores, J.

AU - Solano, W.

AU - Alisjahbana, B.

AU - Soetedjo, N.

AU - Santoso, P.

AU - Chaidir, L.

AU - Koesoemadinata, R.

AU - Susilawati, N.

AU - Annisa, J.

AU - Livia, R.

AU - Yunivita, V.

AU - Soeroto, A.

AU - Permana, H.

AU - Imaculata, S.

AU - Gunawan, Y.

AU - Dewi, N.

AU - Apriani, L.

PY - 2021/1/1

Y1 - 2021/1/1

N2 - Background: People with diabetes have an increased risk of developing active tuberculosis (TB) and are more likely to have poor TB-treatment outcomes, which may impact on control of TB as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in patients with active TB relative to healthy individuals. The effects of diabetes and intermediate hyperglycemia (IH) on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-TB comorbidity. Methods: Whole blood samples were collected from active TB patients with diabetes (glycated hemoglobin [HbA1c] ≥6.5%) or IH (HbA1c = 5.7% to <6.5%), TB-only patients, and healthy controls in 4 countries: South Africa, Romania, Indonesia, and Peru. Differential blood gene expression was determined by RNA-seq (n = 249). Results: Diabetes increased the magnitude of gene expression change in the host transcriptome in TB, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with IH and TB exhibited blood transcriptomes much more similar to patients with diabetes-TB than to patients with only TB. Both diabetes-TB and IH-TB patients had a decreased type I interferon response relative to TB-only patients. Conclusions: Comorbidity in individuals with both TB and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type I interferon responses in comorbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in individuals with IH, showing that altered immunity to TB may also be present in this group. The TB disease outcomes in individuals with IH diagnosed with TB should be investigated further.

AB - Background: People with diabetes have an increased risk of developing active tuberculosis (TB) and are more likely to have poor TB-treatment outcomes, which may impact on control of TB as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in patients with active TB relative to healthy individuals. The effects of diabetes and intermediate hyperglycemia (IH) on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-TB comorbidity. Methods: Whole blood samples were collected from active TB patients with diabetes (glycated hemoglobin [HbA1c] ≥6.5%) or IH (HbA1c = 5.7% to <6.5%), TB-only patients, and healthy controls in 4 countries: South Africa, Romania, Indonesia, and Peru. Differential blood gene expression was determined by RNA-seq (n = 249). Results: Diabetes increased the magnitude of gene expression change in the host transcriptome in TB, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with IH and TB exhibited blood transcriptomes much more similar to patients with diabetes-TB than to patients with only TB. Both diabetes-TB and IH-TB patients had a decreased type I interferon response relative to TB-only patients. Conclusions: Comorbidity in individuals with both TB and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type I interferon responses in comorbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in individuals with IH, showing that altered immunity to TB may also be present in this group. The TB disease outcomes in individuals with IH diagnosed with TB should be investigated further.

KW - diabetes

KW - hyperglycemia

KW - inflammation

KW - tuberculosis

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UR - http://www.scopus.com/inward/citedby.url?scp=85092218343&partnerID=8YFLogxK

U2 - 10.1093/cid/ciaa751

DO - 10.1093/cid/ciaa751

M3 - Article

C2 - 32533832

AN - SCOPUS:85092218343

SN - 1058-4838

VL - 72

SP - 69

EP - 78

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

IS - 1

ER -

Impact of intermediate hyperglycemia and diabetes on immune dysfunction in tuberculosis

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