Redefining Virulence of Bacterial Pathogens

Harry Mobley [Microbe (2015) 10(6):239]

Investigators identifying virulence genes at first did so by examining transposon mutants or individual gene mutations. Mutants of bacterial pathogens were then assessed in animals, whose symptoms mimicked human disease. Later, genome-wide screens were developed whereby genes and proteins that influence virulence could be identifıed, including via signature-tagged mutagenesis (STM), in vivo expression technology
(IVET), and in vivo-induced antigen technology (IVIAT).

Investigators then began to use RT-PCR to measure expression of individual genes, including within infected tissues. Microarray technology enables us to estimate global gene expression under defined culture conditions such as nitrogen limitation, oxygenation, and osmotic stress.

These efforts led to our conventional view of microbial virulence, with its focus on adhesins, iron acquisition, toxins, secretion, and motility, as well as on bacteria with genes such as those on horizontally transferred pathogenicity-associated islands that are not found in commensal strains.

Now, however, we also must consider what metabolic pathways are in play when microbial pathogens infect their hosts. What’s for dinner? How are these bacteria metabolizing available molecules to colonize a particular body site? Which import and export systems are active during infection?

Because mutations in these systems should reduce fitness, we should measure transcription under relevant conditions. For pathogens that infect humans, those conditions require analysis during infections whenever possible. This approach rests on the hypothesis that virulence is the sum of required metabolic pathways, traditional virulence determinants, upregulated transport systems, and other functions.

➤ With many virulence genes already identified, it is time to consider metabolic pathways and export-import systems that also contribute to the infectious process.
➤ In some cases, metabolic pathways may be missing or inactive without affecting virulence; similarly, expression of specific virulence genes may vary from one strain to another without affecting the overall course of an infection.
➤ Specific host settings can determine which bacterial virulence genes are expressed.

Measuring bacterial gene expression and metabolism during infections provides a more comprehensive view of virulence in action. Therefore, virulence can be redefined as the sum of classical virulence factors, requisite metabolic pathways, and key import and export pumps. Measuring gene expression in vivo is critical to defining virulence of bacterial pathogens.