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Front. Immunol. | doi: 10.3389/fimmu.2018.00869

BCG-induced Trained Immunity is not protective for Experimental Influenza A/Anhui/1/2013 (H7N9) Infection in Mice

  • 1Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Netherlands
  • 2Radboud Centre for Infectious Diseases, Radboud University Nijmegen Medical Centre, Netherlands
  • 3Bandim Health Project, State Serum Institute (SSI), Denmark
  • 4Odense University Hospital, University of Southern Denmark Odense, Denmark
  • 5Department of Immunology, Triskelion B.V., Netherlands
  • 6Laboratory of Pediatric Infectious Diseases, Radboud University Nijmegen Medical Centre, Netherlands
  • 7Life and Medical Sciences Institute (LIMES), Universität Bonn, Germany
  • 8Aduro Biotech (Netherlands), Netherlands

Avian influenza A of the subtype H7N9 has been responsible for almost 1600 confirmed human infections and more than 600 deaths since its first outbreak in 2013. Although sustained human-to-human transmission has not been reported yet, further adaptations to humans in the viral genome could potentially lead to an influenza pandemic, which may have severe consequences due to the absence of pre-existent immunity to this strain at population level. Currently there is no influenza A (H7N9) vaccine available. Therefore, in case of a pandemic outbreak, alternative preventive approaches are needed, ideally even independent of the type of influenza virus outbreak. Bacillus Calmette-Guérin (BCG) is known to induce strong heterologous immunological effects, and it has been shown that BCG protects against non-related infection challenges in several mouse models. BCG immunization of mice as well as human induces trained innate immune responses, resulting in increased cytokine responses upon subsequent ex-vivo PBMC restimulation. We investigated whether BCG (SSI-Denmark)-induced trained immunity may protect against a lethal avian influenza A/Anhui/1/2013 (H7N9) challenge. Here we show that isolated splenocytes as well as peritoneal macrophages of BCG-immunized BALB/c mice displayed a trained immunity phenotype resulting in increased innate cytokine responses upon ex-vivo restimulation. However, after H7N9 infection, no significant differences were found between the BCG immunized and the vehicle control group at the level of survival, weight loss, pulmonary influenza A nucleoprotein staining, or histopathology. In conclusion, BCG-induced trained immunity did not result in protection in an oseltamivir-sensitive influenza A/Anhui/1/2013 (H7N9) challenge mouse model.

Keywords: avian influenza A/Anhui/1/2013 (H7N9), BCG, trained immunity, innate innate memory, oseltamivir.

Received: 22 Jan 2018; Accepted: 09 Apr 2018.

Edited by:

Liwu Li, Virginia Tech, United States

Reviewed by:

Suraj Sable, Division of Tuberculosis Elimination, Centers for Disease Control and Prevention
Christopher B. Lawrence, Virginia Tech, United States  

Copyright: © 2018 de Bree, Marijnissen, Kel, Rosendahl, Aaby, Stabell Benn, Wijnands, Diavatopoulos, van Crevel, Joosten, Netea and Dulos. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Renoud J. Marijnissen, Triskelion B.V., Department of Immunology, Zeist, Netherlands,