Changes in Transcript, Metabolite, and Antibody Reactivity During the Early Protective Immune Response in Humans to Mycobacterium tuberculosis Infection

January Weiner; Teresa Domaszewska; Simon Donkor; Stefan H E Kaufmann; Philip C Hill; Jayne S Sutherland

doi:10.1093/cid/ciz785

Changes in Transcript, Metabolite, and Antibody Reactivity During the Early Protective Immune Response in Humans to Mycobacterium tuberculosis Infection

Clin Infect Dis. 2020 Jun 24;71(1):30-40. doi: 10.1093/cid/ciz785.

Authors

January Weiner¹, Teresa Domaszewska¹, Simon Donkor², Stefan H E Kaufmann^{1

3}, Philip C Hill^{2

4}, Jayne S Sutherland²

Affiliations

¹ Max Planck Institute for Infection Biology, Berlin, Germany.
² Vaccines and Immunity Theme, Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, Banjul, The Gambia.
³ Hagler Institute for Advanced Study, Texas A&M University, College Station, USA.
⁴ Otago University, Otago, New Zealand.

Abstract

Background: Strategies to prevent Mycobacterium tuberculosis (Mtb) infection are urgently required. In this study, we aimed to identify correlates of protection against Mtb infection.

Methods: Two groups of Mtb-exposed contacts of tuberculosis (TB) patients were recruited and classified according to their Mtb infection status using the tuberculin skin test (TST; cohort 1) or QuantiFERON (QFT; cohort 2). A negative reading at baseline with a positive reading at follow-up classified TST or QFT converters and a negative reading at both time points classified TST or QFT nonconverters. Ribonucleic acid sequencing, Mtb proteome arrays, and metabolic profiling were performed.

Results: Several genes were found to be differentially expressed at baseline between converters and nonconverters. Gene set enrichment analysis revealed a distinct B-cell gene signature in TST nonconverters compared to converters. When infection status was defined by QFT, enrichment of type I interferon was observed. A remarkable area under the curve (AUC) of 1.0 was observed for IgA reactivity to Rv0134 and an AUC of 0.98 for IgA reactivity to both Rv0629c and Rv2188c. IgG reactivity to Rv3223c resulted in an AUC of 0.96 and was markedly higher compared to TST nonconverters. We also identified several differences in metabolite profiles, including changes in biomarkers of inflammation, fatty acid metabolism, and bile acids. Pantothenate (vitamin B5) was significantly increased in TST nonconverters compared to converters at baseline (q = 0.0060).

Conclusions: These data provide new insights into the early protective response to Mtb infection and possible avenues to interfere with Mtb infection, including vitamin B5 supplementation.Analysis of blood from highly exposed household contacts from The Gambia who never develop latent Mycobacterium tuberculosis infection shows distinct transcriptomic, antibody, and metabolomic profiles compared to those who develop latent tuberculosis infection but prior to any signs of infection.

Keywords: RNA sequencing; immunology; mtb proteome arrays; mtb resisters; tuberculosis.

Publication types

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

MeSH terms

Gambia
Humans
Immunity
Latent Tuberculosis* / diagnosis
Mycobacterium tuberculosis* / genetics
Tuberculin Test
Tuberculosis* / diagnosis

Abstract

Publication types

MeSH terms

Grants and funding