Jörn Coers, PhD
Director, Center for Host Microbial Interactions
419 JONES Building
Box 3580 DUMC
Durham, N.C. 27710
Phone: (919) 684-7109
Fax: (919) 684-2790
Vertebrates maintain a sophisticated network of specialized immune cells that includes innate lymphoid cells, professional antigen presenting cells, B cells and T cells. This network of professional immune cells is often equated with the immune system. However, more often than not professional immune cells exert their function indirectly through the secretion of pro-inflammatory cytokines that bind to their cognate receptors on the surface of non-immune cells and thereby instruct these non-immune cells to enter a state of heightened resistance towards intracellular pathogens. This cytokine-induced state of heightened resistance is due to the upregulation of various cell-autonomous defense modules. Our lab studies cytokine-induced cell-autonomous immunity and its role in infectious and autoimmune diseases. Specifically, we are in pursuit of finding answers to the following questions:
How does the innate immune system detect the location of bacterial and protozoan pathogens within an infected cell?
We are interested in Interferon (IFN)-stimulated host defense mechanisms against intracellular bacterial and protozoan pathogens that include Toxoplasma gondii, Chlamydia trachomatis, Legionella pneumophila and Shigella flexneri. To exert their antimicrobial activities, many IFN-induced host proteins must specifically localize to pathogen-containing vacuoles (PVs) or cytosolic pathogens. The mechanisms by which the host recognizes and discriminates between ‘non-self’ PVs or ‘non-self’ cytosolic bacteria and endogenous ‘self’ membranous structures, such as mitochondria or the Golgi apparatus, are not well understood. One of the main interests of our lab is to unveil molecular mechanisms that underlie the specific delivery of antimicrobial proteins to intracellular pathogens. Towards this goal we are taking the following complementary approaches:
- We conduct functional genomics screens to identify host genes required for the delivery of antimicrobial host proteins to intracellular sites of infection.
- We use bacterial genetics, cell biological and biochemical techniques to determine what PV- or bacteria-associated patterns are recognized by the innate immune response.
How do infected cells combat bacterial and protozoan pathogens?
We are interested in defining the network of cell-autonomous defense modules recruited to intracellular sites of infection and used by infected host cells to eliminate intracellular bacterial and protozoan pathogens. Towards this goal we are taking the following approaches:
We use proteomics to identify novel antimicrobial host proteins delivered to PVs and cytosolic bacterial pathogens
- We conduct functional genomics screens to identify host genes required for cell-autonomous host resistance
- We employ bacterial genetics to identify bacterial virulence factors required for the evasion of cell-autonomous defense pathways
What are the in vivo functions of cell-autonomous defense modules in host resistance, inflammation and autoimmunity?
To understand the in vivo relevance of cell-autonomous immune functions, we engineer and study genetic mouse models that include, for example, mice bearing Cas9/sgRNA-induced loss-of–function alleles in novel host defense genes. We use these mice to study the pathogenesis of infections diseases, sepsis and autoimmune diseases. A specific interest of the lab is to understand how the obligate intracellular bacterial pathogen C. trachomatis can cause chronic genital infections, infertility and other complications in women. We and others have found that humans and mice differ substantially in their respective IFN-induced cell-autonomous defense pathways and that these differences emerge as key determinants of host tropism. Therefore, we have developed mouse models that more accurately reflect the pathogenesis of human C. trachomatis infections. The study of these mouse models will support the development of more effective, alternative therapeutic strategies to treat Chlamydia and other microbial infections.