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Understanding the mechanism by which the mammalian innate immune system mounts a specific and highly regulated immune response against invading pathogens is crucial for the development of effective anti-microbial drugs. For the past 20 years, the pathogen-associated molecular pattern (PAMP) hypothesis has been used to explain how our innate immune system responds to various pathogens. By this model, inflammation is initiated when germline-encoded receptors recognize common microbial ligands, such as peptidoglycans, LPS or flagella. There is a critical problem with this model: it does not explain how the innate immune system can differentiate between pathogens and harmless microbes, since these PAMPs are not pathogen-specific.
The key question that Seblewongel Asrat, a PhD student in Molecular Microbiology, and her adviser Ralph Isberg are trying to address is how our immune system can discriminate between virulent pathogens that impose danger to the host from harmless microorganisms. Their data thus far are consistent with the model in which enzymatic activities produced by a pathogen are recognized by the host innate immune system in concert with PAMPs, resulting in a response that leads to pathogen-specific cytokine production that cannot be induced by PAMPs alone.
Seble has shown that after contact with macrophages, the intracellular Gram-negative bacterium Legionella pneumophila stimulates a unique pathogen-specific response that is the consequence of simultaneous recognition of PAMPs and pathogen-specific protein activities. This host response is likely to be seen with a large number of pathogens, as both the PAMPs and the microbial activities are encoded by many other pathogens. The disease caused by L. pneumophila, Legionnaires' disease, is a severe pneumonia that results from growth of the bacterium within alveolar macrophages. After encounter with macrophages, the pathogen translocates over two hundred bacterial proteins into the host cell through its Type IV protein secretion system. These translocated proteins, many of which have enzymatic activities, serve various purposes, including inhibition of host cell protein translation.
Interestingly, infection of macrophages with L. pneumophila leads to the production of various pro-inflammatory cytokines, which are produced in spite of the fact that host cell protein synthesis is blocked by the bacterium. Our goal is to determine the molecular basis for how protein translation inhibition leads to selective synthesis of few genes associated with inflammation. By understanding this response, we hope to generate a universal model for how pathogens uniquely regulate pro-inflammatory cytokine production in a fashion not observed with harmless bacteria.