Zinc homeostasis at the host-pathogen interface

This project aims to investigate how bacterial pathogens that cause severe respiratory infections in people with Cystic Fibrosis are able to compete with the human host for the essential nutrient zinc. If we can understand how bacteria obtain this key nutrient from the human body during an infection, we may be able to design new drugs that kill these bacteria by blocking zinc uptake.

CF primary

Researchers

Research background

The Burkholderia cepacia complex (Bcc) is a group of at least 21 species of bacteria widely distributed in the environment. They are best known for causing severe respiratory infections in people with Cystic Fibrosis (CF). Whilst all Bcc species have been isolated from CF patients, B. cenocepacia and B. multivorans are responsible for 85-97% of cases.

Infections often result in an accelerated decline in pulmonary function and can lead to the development of ‘cepacia syndrome’ that is characterised by a fatal necrotising pneumonia and bacteraemia. Bcc bacteria are naturally resistant to many antibiotics in clinical use, making infections difficult to eradicate. There are currently no standard drug regimens for the treatment of these infections, and no vaccines available. The epidemiology of Bcc bacteria is not limited to CF, with infections also occurring in people with chronic granulomatous disease, and nosocomial infections reported in other patient groups.

In order to survive, pathogens must acquire the essential nutrients they need for growth in competition with the host. Zinc is an essential nutrient for bacteria, required for the function of numerous proteins. During infection, the host attempts to deprive bacteria of essential zinc in a process of nutritional immunity. A key aim of this project is to understand how the major CF pathogen B. cenocepacia is able to compete with the host for zinc and overcome nutritional immunity.

Research aims

Zinc scavenging is a critical aspect of bacterial pathogenesis, but is poorly understood in Burkholderia species that are a significant health concern in Cystic Fibrosis (CF) patients. This project forms the basis of an ambitious, long-term program of research aimed at addressing two key questions:

1. How do Burkholderia species, which are ordinarily environmental bacteria, acquire zinc in competition with the host?

2. Can we reduce the virulence of Burkholderia species by restricting zinc uptake in vivo?

Projected outocmes

Members of the Burkholderia cepacia complex are a significant threat to the health of patients susceptible to opportunistic infections. Given that they have significant natural resistance to antibiotics, the identification of novel drug targets, offers enormous potential benefits.  Since zinc is likely to be essential for the ability of these bacteria to cause infections, a detailed understanding of zinc acquisition mechanisms could lead to the development of novel therapies targeting these systems.