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
Affiliations
Asma Ahmed
Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India; Infectious Disease Unit, St. John’s Research Institute, Bangalore, India
Himanshu Tripathi
Infectious Disease Unit, St. John’s Research Institute, Bangalore, India
Krista E. van Meijgaarden
Department of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands
Nirutha Chetan Kumar
Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India; Infectious Disease Unit, St. John’s Research Institute, Bangalore, India
Vasista Adiga
Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India; Infectious Disease Unit, St. John’s Research Institute, Bangalore, India; Department of Biotechnology, PES University, Bangalore, India
Srabanti Rakshit
Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India; Infectious Disease Unit, St. John’s Research Institute, Bangalore, India
Chaitra Parthiban
Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India; Infectious Disease Unit, St. John’s Research Institute, Bangalore, India
Sharon Eveline J
Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
George D’Souza
Department of Pulmonary Medicine, St. John’s Medical College, Bangalore, India
Mary Dias
Infectious Disease Unit, St. John’s Research Institute, Bangalore, India
Tom H.M. Ottenhoff
Department of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands
Mihai G. Netea
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Immunology and Metabolism, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany
Simone A. Joosten
Department of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands
Annapurna Vyakarnam
Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India; Infectious Disease Unit, St. John’s Research Institute, Bangalore, India; Department of Immunobiology, School of Immunology & Microbial Sciences, Faculty of Life Science & Medicine, King’s College, London, UK; Corresponding author
Summary: 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−CD14hi 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−CD14hi 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.
