BCG revaccination in adults enhances pro-inflammatory markers of trained immunity along with anti-inflammatory pathways

Asma Ahmed; Himanshu Tripathi; Krista E van Meijgaarden; Nirutha Chetan Kumar; Vasista Adiga; Srabanti Rakshit; Chaitra Parthiban; Sharon Eveline J; George D'Souza; Mary Dias; Tom H M Ottenhoff; Mihai G Netea; Simone A Joosten; Annapurna Vyakarnam

doi:10.1016/j.isci.2023.107889

BCG revaccination in adults enhances pro-inflammatory markers of trained immunity along with anti-inflammatory pathways

iScience. 2023 Sep 9;26(10):107889. doi: 10.1016/j.isci.2023.107889. eCollection 2023 Oct 20.

Authors

Asma Ahmed^{1

2}, Himanshu Tripathi², Krista E van Meijgaarden³, Nirutha Chetan Kumar^{1

2}, Vasista Adiga^{1

2

4}, Srabanti Rakshit^{1

2}, Chaitra Parthiban^{1

2}, Sharon Eveline J¹, George D'Souza⁵, Mary Dias², Tom H M Ottenhoff³, Mihai G Netea^{6

7}, Simone A Joosten³, Annapurna Vyakarnam^{1

2

8}

Affiliations

¹ Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India.
² Infectious Disease Unit, St. John's Research Institute, Bangalore, India.
³ Department of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands.
⁴ Department of Biotechnology, PES University, Bangalore, India.
⁵ Department of Pulmonary Medicine, St. John's Medical College, Bangalore, India.
⁶ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
⁷ Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
⁸ Department of Immunobiology, School of Immunology & Microbial Sciences, Faculty of Life Science & Medicine, King's College, London, UK.

Abstract

This study characterized mechanisms of Bacille Calmette-Guérin (BCG) revaccination-induced trained immunity (TI) in India. Adults, BCG vaccinated at birth, were sampled longitudinally before and after a second BCG dose. BCG revaccination significantly elevated tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 in HLA-DR⁺CD16^-CD14^hi monocytes, demonstrating induction of TI. Mycobacteria-specific CD4⁺ T cell interferon (IFN) γ, IL-2, and TNF-α were significantly higher in re-vaccinees and correlated positively with HLA-DR⁺CD16^-CD14^hi TI responses. This, however, did not translate into increased mycobacterial growth control, measured by mycobacterial growth inhibition assay (MGIA). Post revaccination, elevated secreted TNF-α, IL-1β, and IL-6 to "heterologous" fungal, bacterial, and enhanced CXCL-10 and IFNα to viral stimuli were also observed concomitant with increased anti-inflammatory cytokine, IL-1RA. RNA sequencing after revaccination highlighted a BCG and LPS induced signature which included upregulated IL17 and TNF pathway genes and downregulated key inflammatory genes: CXCL11, CCL24, HLADRA, CTSS, CTSC. Our data highlight a balanced immune response comprising pro- and anti-inflammatory mediators to be a feature of BCG revaccination-induced immunity.

Keywords: Immune response; Immunity; Immunology; Molecular biology; Omics; Transcriptomics.