Nancy Freitag

Professor

Ph.D., University of California at Los Angeles

Room 8053 COMRB, Tel: 312-355-4903

My lab's research is focused on understanding how pathogens make themselves at home within human cells, and to discover the mechanisms used by mammalian cells to fight off pathogenic intruders.

Listeria monocytogenes as a model intracellular bacterial pathogen

Intracellular pathogens are responsible for devastating amounts of morbidity and mortality worldwide. The list of intracellular infectious agents that have had a significant impact on global health and economy includes viral pathogens (responsible for AIDS, hepatitis, influenza), protozoan parasites (causative agents of Chagas disease, malaria, leishmaniasis), and bacterial pathogens (including the agents responsible for tuberculosis, chlamydia, leprosy). The understanding of the molecular and cellular basis of intracellular pathogenesis is limited, and this lack of knowledge in many instances has severely reduced the ability to develop effective means of combating or preventing infection.

My lab has chosen to study Listeria monocytogenes because it is an important agent of food-borne infections and also because it serves as a very useful model system for exploring the intracellular interactions that take place between pathogen and host. We are working to define the mechanisms used by L. monocytogenes to survive within human cells to determine if similar strategies are used by other deadly parasites. L. monocytogenes is a bacterium that is commonly found in the environment, and we are interested in determining how environmental organisms make the sometimes deadly transition from the outside environment to being inside a mammalian host.

We are working to understand how L. monocytogenes senses the different host environments it encounters during the course of infection, and how it regulates the expression of virulence factors within the host. We have isolated a number of bacterial mutants that appear to be 'locked' into a virulent state. We are currently using these mutants to identify new virulence gene products expressed within host cells and to determine the regulatory mechanisms that enable the bacteria to switch from life in the dirt to life within host cells. We are also taking advantage of a new host system that will allow us to explore early host defenses to Listeria infection. Surprisingly, the common fruit fly fights off bacterial infection using many of the same defenses as human cells. We can explore and identify defensive strategies in the fly and then look for their counterparts in humans. This approach may enable us to define new ways of combating bacterial infections.

Themes

  • Regulation of bacterial virulence gene expression within host cells
  • Host responses to bacterial infection
  • Pathogen survival within host cells

Accomplishments

  • Identified key regulatory switches used by the bacteria to makes themselves at home within human cells. These switches must be engaged at the proper time to promote bacterial infection.
  • Isolated bacterial mutants that ‘think’ they are inside of host cells. These mutants produce proteins in broth culture that are normally only made within infected cells. We are beginning to identify these proteins and discover their functional roles in disease.
  • Developed a new host system that will allow us to explore early host defenses to Listeria infection. Surprisingly, the common fruit fly fights off bacterial infection using many of the same defenses as human cells. We can explore and identify defensive strategies in the fly and then look for their counterparts in humans.

These accomplishments will be useful for:

  • Improved diagnostics. L. monocytogenes looks very different when it’s inside vs. outside of host cells. Improved food detection strategies must be designed to recognize intracellular and extracellular bacteria.
  • Improved therapies. Significant mortality occurs in patients with listeriosis even with antibiotic therapy. By defining the spectrum of host defenses used to fight bacterial infection, we may be able to develop ways of improving those defenses and strengthening the host attack.
  • Insights into host survival strategies for other pathogens.