Boosting efferocytosis in alveolar space using BCG vaccine to protect host against influenza pneumonia

PLoS One. 2017 Jul 7;12(7):e0180143. doi: 10.1371/journal.pone.0180143. eCollection 2017.

Abstract

Efferocytosis by alveolar phagocytes (APs) is pivotal in maintenance of lung homeostasis. Increased efferocytosis by APs results in protection against lethal acute lung injury due to pulmonary infections whereas defective efferocytosis by APs results in chronic lung inflammation. In this report, we show that pulmonary delivery of Bacillus Calmette-Guerin (BCG) significantly enhances efferocytosis by APs. Increased efferocytosis by APs maintains lung homeostasis and protects mice against lethal influenza pneumonia. Intranasally treated wild type C57Bl/6 (WT) mice with BCG showed significant increase in APs efferocytosis in vivo compared to their PBS-treated counterparts. All BCG-treated WT mice survived lethal influenza A virus (IAV) infection whereas all PBS-treated mice succumbed. BCG-induced resistance was abrogated by depleting AP prior to IAV infection. BCG treatment increased uptake, and digestion/removal of apoptotic cells by APs. BCG significantly increased the expression of TIM4 on APs and increased expression of Rab5 and Rab7. We demonstrated that increased efferocytosis by APs through pulmonary delivery of BCG initiated rapid clearance of apoptotic cells from the alveolar space, maintained lung homeostasis, reduced inflammation and protected host against lethal IAV pneumonia.

MeSH terms

  • Animals
  • BCG Vaccine / administration & dosage*
  • Disease Models, Animal
  • Humans
  • Inflammation / complications
  • Inflammation / drug therapy*
  • Inflammation / prevention & control
  • Inflammation / virology
  • Influenza A virus / drug effects
  • Influenza A virus / pathogenicity
  • Influenza, Human / complications
  • Influenza, Human / drug therapy*
  • Influenza, Human / prevention & control
  • Influenza, Human / virology
  • Lung / drug effects
  • Lung / pathology
  • Macrophages, Alveolar / drug effects
  • Macrophages, Alveolar / pathology
  • Mice
  • Phagocytes / drug effects
  • Phagocytes / pathology
  • Phagocytosis / drug effects
  • Pneumonia / complications
  • Pneumonia / drug therapy*
  • Pneumonia / prevention & control
  • Pneumonia / virology

Substances

  • BCG Vaccine

Grants and funding

This work was in part supported by grants to H. Shams from The University of Texas Health Science Center seed grant and the Flight Attendant Medical Research Institute (092015-Clinical Innovator Award and 123020-Clinical Innovator Award). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study.