Study Paves Way to Better Identify and Treat Important Pathogen
The bacterium Klebsiella pneumonia (photo by NIAID, CC BY 2.0)
Not all of the cells in our body truly belong to us; up to six percent of our body mass is made up of bacteria. Some of these bacteria are “opportunistic” pathogens – they lie low waiting for an advantageous moment at which to begin infection. Researchers in the Department of Molecular and Cellular Biology have investigated one such opportunistic pathogenic bacterium, Klebsiella pneumoniae, and discovered genes responsible for the molecular variation in the bacteria’s outer surface – information that could lead to improved diagnosis and new treatments for this pathogen.
K. pneumoniae is found globally and primarily infects people with compromised health. It causes blood infections, urinary tract infections, and abscesses in the liver - conditions that can be life-threatening for those who are already ill or hospitalized. K. pneumoniae is increasingly resistant to many of the drugs commonly used to treat bacterial infections, and the need for alternative treatments is rising rapidly. To help address this challenge, Prof. Chris Whitfield and his laboratory are studying carbohydrate chains found on the surface of the bacteria called “O antigens”. Like other surface molecules on pathogenic bacteria, O antigens can be useful for developing vaccines or other immune system-based treatments to treat infections – but only if their structure is similar across different strains of the bacteria.
“O antigens are good targets for immunotherapeutic treatments because they have a limited diversity. Currently, four different carbohydrate structures, or ‘serotypes’, cover up to 80% of the Klebsiella isolates in clinical circulation,” says Whitfield.
To better understand the origin of variation in O antigens – and gain a more accurate picture of their natural diversity – Whitfield’s lab determined which genes produce different O antigens in K. pneumoniae. They examined a gene called wbbY, which normally plays a role in producing the O1 antigen, and discovered that a mutation in this gene causes O2ac to be produced instead. The finding may introduce another way to distinguish strains of K. pneumoniae and improve diagnostic accuracy.
The researchers also described the activities of two genetic regions, gmlABC and gmlABD, which produce enzymes that differentially modify O2a, the precursor to generate distinct O antigen variants, shedding further light on the mechanisms that lead to variation in O antigens.
The results complete an understanding of the genetic basis of variation in a family of structurally-related O antigens in K. pneumoniae, knowledge that will facilitate future research on diagnostic, preventative, and therapeutic agents that target the pathogen.
The study also complements ongoing work in the Whitfield lab on fundamental aspects of the function of glycosyltransferases, the enzymes that produce and modify O antigens and other carbohydrate structures, and their potential role in glycoengineering. Glycoengineering is an exciting and highly promising area of research where bacteria are manipulated to assemble natural or designed carbohydrate groups on proteins for therapeutic applications. For example, glycosyltransferases can be used to modify the proteins targeted by antibodies and enhance their ability to trigger an immune response to a pathogen.
“Primarily we are interested in glycoengineering for immunotherapeutics. To optimize the cellular production systems, we want to know ‘How do proteins come together and work as an efficient assembly machine?’” says Whitfield.
He and his research team have interactions with researchers in biotech-pharma who exploit glycoengineering to develop improved disease treatments.
This study was funded by the National Science and Engineering Research Council of Canada.
Read the full story in the Journal of Biological Chemistry.
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