Macrophages as drivers of an opportunistic infection

Abstract

Opportunistic pathogens are a worldwide cause of mortality and morbidity, and infections with intrinsically antibiotic-resistant pathogens have a large clinical, social and economic impact. Bacteria belonging to the Burkholderia cepacia complex (Bcc), ubiquitous in natural and industrial environments, are notorious pathogens for individuals with cystic fibrosis (CF). In addition, Burkholderia cenocepacia is emerging as the culprit of non-CF related, sometimes fatal infections. Knowledge of the underlying infection mechanism of these pathogens is important for efficient treatment, however, to date not much is known about the lifestyle of Bcc bacteria during infection. In our recent study published in PLoS Pathogens, we provide experimental evidence that macrophages are critically important for proliferation of B. cenocepacia, and are major drivers of fatal pro-inflammatory infections in zebrafish larvae. This is in agreement with recent clinical information showing that B. cenocepacia is mainly localised in phagocytes in infected CF lungs. A predominant intramacrophage stage and a host-detrimental role for macrophages have major implications for treatment strategies of both CF and non-CF infections. Intracellular survival of bacteria traditionally classified as extracellular, including Staphylococcus aureus and Pseudomonas aeruginosa, is an emerging theme. Our finding that macrophages are essential for proliferation of B. cenocepacia in the host suggests a new paradigm for Bcc infections and urges the development of novel anti-infectious therapies to efficiently disarm these intrinsically antibiotic resistant facultative intracellular pathogens.

Keywords: Burkholderia cenocepacia; biofilms; cystic fibrosis; intracellular bacteria; macrophages; nosocomial infections; opportunistic infections; zebrafish.

Figure 1. FIGURE 1: B. cenocepacia requires macrophages for efficient replication and the induction of acute pro-inflammatory disease.

Zebrafish larvae are highly sensitive to infection with B. cenocepacia K56-2. Injection of a small inoculum (5 - 50 colony forming units) causes rapid pro-inflammatory fatal disease that requires the presence of macrophages, but not neutrophils. Macrophages are important for the observed increase in il1b expression. In the absence of macrophages, either using a Pu.1 morpholino knockdown approach or chemical ablation based on the Metronidazole / Nitroreductase system, B. cenocepacia K56-2 is unable to proliferate as in wildtype. This phenomenon was observed when the bacteria were injected intravenously and subcutaneously.