Paul S. Hoffman, PhD
Graduate School: Virginia Tech
Primary Appointment: Professor, Medicine, Infectious Diseases and International Health
Molecular Mechanisms of Microbial Pathogenesis
Email Address: email@example.com
My research program is focused on molecular mechanisms of microbial pathogenesis and we use as model systems the infection of HeLa cells by Legionella pneumophila (the agent of Legionnaires' disease) and the infection of mice with Helicobacter pylori (the ulcer causing bacterium). Legionella pneumophila is an intracellular parasite of fresh water amoeba that when transmitted by aerosol to humans often causes severe pneumonia. Legionnaires' disease is not a communicable disease and we have recently discovered that the transmissible form of this disease - a spore-like cyst - is not appreciably produced in alveolar macrophages. We are characterizing this newly discovered developmental cycle by proteome and genome profiling (Proteomics and QRT-PCR), by identifying key stage specific regulators and regulated genes, and by mechanistic analysis of early events of invasion that abrogate signal transduction networks required for phagolysosome fusion and redirect the bacteria to a replication proficient endosome enveloped by the endoplasmic reticulum.
We wish to know how super-virulent and metabolically dormant
(asleep) cyst-like-forms are pre-programmed so as to activate upon
contact with a host cell and through interactions with host cell
proteins, promote invasion and then we wish to know what the "wake up
call" is that activates the germination program to permit germination
of cysts into vegetative replicating bacteria. Legionella is a model
system for the study of obligate intracellular pathogens such as
Chlamydia and Coxiella.
We are interested in the host-parasite interaction of H. pylori with the gastric mucosa.
The highly motile bacteria reside about 10 to 30 meters above the gastric epithelial cells and we wish to know how that stay within this zone. We have recently discovered these bacteria use pH taxis to orient in a pH gradient that is most acidic near the lumen and most alkaline near the epithelial cells. We also know that tactic signals also involve oxygen, hydrogen and urea. By understanding how these tactic signals are translated into staying in this optimal zone, we can build new therapeutics that essentially blind the bacteria and cause them to not survive. Antibiotic resistance is increasing at an alarming rate and within 15 years the "superbugs" (resistant to all antibiotics) will account for 15% of all human infections and contribute to high mortality.
My laboratory has been involved in the study of drug resistance and in the development of new genomic/bioinformatic based strategies for identifying new microbial targets to aid the discovery of new therapeutics. We have identified the mode of action of a novel antiparasitic drug Nitazoxanide that is used world wide to treat parasitic infections caused by Entamoeba, Giardia, and Cryptosporidium. Mechanistic studies of this drug and others will lead to next generation therapeutics so critically needed to control infectious diseases. Also, checkout Canadian lab - microbiology.medicine.dal.ca/people/hoffman/ and genomics.medicine.dal.ca (DalGEN).
Day SR, Sifri CD, Hoffman PS. Infection of nonphagocytic host cells by legionella.Methods Mol Biol. 2013;954:463-78. doi: 10.1007/978-1-62703-161-5_28.
Warren CA, Opstal EJ, Riggins MS, Li Y, Moore JH, Kolling GL, Guerrant RL, Hoffman PS. Vancomycin Treatment's Association with Delayed Intestinal Tissue Injury, Clostridial Overgrowth and Recurrence of Clostridium difficile Infection in Mice. Antimicrob Agents Chemother. 2012 Nov 12.
Martínez-Júlvez M, Rojas AL, Olekhnovich I, Angarica VE, Hoffman PS, Sancho J. Structure of RdxA - an oxygen-insensitive nitroreductase essential for metronidazole activation in Helicobacter pylori. FEBS J. 2012 Dec;279(23):4306-17. doi: 10.1111/febs.12020. Epub 2012 Nov 7.
Dey R, Hoffman PS, Glomski IJ. Germination and amplification of anthrax spores by soil-dwelling amoebas. Appl Environ Microbiol. 2012 Nov;78(22):8075-81. doi: 10.1128/AEM.02034-12. Epub 2012 Sep 14.
Warren CA, van Opstal E, Ballard TE, Kennedy A, Wang X, Riggins M, Olekhnovich I, Warthan M, Kolling GL, Guerrant RL, Macdonald TL, Hoffman PS. Amixicile, a novel inhibitor of pyruvate: ferredoxin oxidoreductase, shows efficacy against Clostridium difficile in a mouse infection model. Antimicrob Agents Chemother. 2012 Aug;56(8):4103-11. doi: 10.1128/AAC.00360-12. Epub 2012 May 14.
Hoffman PS, Edelstein PH. Cell mediated immunity in Legionnaires' disease. Vaccine. 2011 Sep 2;29(38):6437-8; author reply 6439-40. doi: 10.1016/j.vaccine.2011.06.118. Epub 2011 Jul 14. No abstract available.
Costa LB, JohnBull EA, Reeves JT, Sevilleja JE, Freire RS, Hoffman PS, Lima AA, Oriá RB, Roche JK, Guerrant RL, Warren CA. Cryptosporidium-malnutrition interactions: mucosal disruption, cytokines, and TLR signaling in a weaned murine model. J Parasitol. 2011 Dec;97(6):1113-20. doi: 10.1645/GE-2848.1. Epub 2011 Jun 28.
Jameson-Lee M, Garduño RA, Hoffman PS. DsbA2 (27 kDa Com1-like protein) of Legionella pneumophila catalyses extracytoplasmic disulphide-bond formation in proteins including the Dot/Icm type IV secretion system. Mol Microbiol. 2011 May;80(3):835-52. doi: 10.1111/j.1365-2958.2011.07615.x. Epub 2011 Mar 22.
Ballard TE, Wang X, Olekhnovich I, Koerner T, Seymour C, Salamoun J, Warthan M, Hoffman PS, Macdonald TL. Synthesis and antimicrobial evaluation of nitazoxanide-based analogues: identification of selective and broad spectrum activity. ChemMedChem. 2011 Feb 7;6(2):362-77. doi: 10.1002/cmdc.201000475. Epub 2010 Dec 29.
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