Project 2
Jordan P. Metcalf, M.D.
Role of B. anthracis Toxins in Human Inhalation Anthrax
The lung is the critical site of entry for the most deadly form of anthrax infection, inhalation anthrax. Inhalation anthrax is relatively unique in that germinated growing bacteria of the causative agent of this disease, B.anthracis, does not cause disease at the site of entry. Instead the spore form of the organism is taken up by resident lung cells and carried through lung lymphatic ducts to the thoracic lymph nodes, where the organism then disseminates to cause the lethal terminal phase of the disease.
There are many unanswered questions about this deadly disease. It is not known why disease does not occur at the site of entry, or what cells take the pathogen out of the lung to the lymph nodes. Most importantly, it is not known what role B.anthracis toxins (lethal toxin, LT; edema toxin, ET) play in this process. Our goal is to answer these questions. Mouse models and mouse cell lines used to study anthrax suggest that LT and ET do not play a significant role in the pathogenesis of inhalation anthrax. This may be the case for mice but may not apply to humans. Cell lines of mouse macrophages, a type of white blood cell of the immune system, are very sensitive to the immunosuppressive effects of LT and express anthrax toxin receptors. We have determined that human lung macrophages efficiently kill the growing, vegetative form of the bacteria, do not express toxin receptors and are resistant to immunosuppressive effects of LT.
We are testing the idea that toxins are very important in the early stages of inhalation anthrax and that the role of key lung cells is due to variable expression of the toxins. To do this we are using a novel human lung organ culture model as well as animal models. We are characterizing the human lung cells that internalize B.anthracis and the state of the pathogen in these cells. In addition, we are determining the role that the toxins play in inhalation anthrax, and whether downregulation of anthrax toxin receptors in the lung organ culture model decreases internalization, survival and escape of the pathogen in human lung.
Dozmorov M, Wu W, Chakrabarty K, Booth JL, Hurst RE, Coggeshall KM, Metcalf JP. Gene expression profiling of human alveolar macrophages infected by B. anthracis spores demonstrates TNF-alpha and NF-kappab are key components of the innate immune response to the pathogen. BMC Infect Dis 9:152, 2009. [Abstract]
Wu W, Mehta H, Chakrabarty K, Booth JL, Duggan ES, Patel KB, Ballard JD, Coggeshall KM, Metcalf JP. Resistance of human alveolar macrophages to Bacillus anthracis lethal toxin. J Immunol 183:5799-5806, 2009. [Abstract]
Chakrabarty K, Wu W, Booth JL, Duggan ES, Nagle NN, Coggeshall KM, Metcalf JP. Human lung innate immune response to Bacillus anthracis spore infection. Infect Immun 75:3729-3738, 2007. [Abstract]
Chakrabarty K, Wu W, Booth JL, Duggan ES, Coggeshall KM, Metcalf JP. Bacillus anthracis spores stimulate cytokine and chemokine innate immune responses in human alveolar macrophages through multiple mitogen-activated protein kinase pathways. Infect Immun 74:4430-4438, 2006. [Abstract]
