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Published online before print September 27, 2006
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Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
1 Correspondence: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892, USA. E-mail: hrosenberg{at}niaid.nih.gov
In this Pivotal Advance manuscript, Lee-Ann Allen and Ramona McCaffrey define a novel mechanism of host-pathogen immune evasion and enhanced virulence. Specifically, they demonstrate that serum-opsonized Francisella tularensis are phagocytosed appropriately by neutrophils, but live bacteria actively inhibit the assembly of the bactericidal NADPH oxidase on the intracellular phagosome. These live bacteria ultimately escape from the phagosome and persist in the neutrophil cytosol.
Dr. Allen, before we proceed to your specific findings in this manuscript, can you provide the general reader of JLB with some background on the disease spectrum of tularemia? What specifically is the concern regarding its potential use as a bioweapon?
LA: Francisella tularensis is a gram-negative coccobacillus that can promote a broad spectrum of disease in humans [1 , 2 ]. There are four subspecies: tularensis, holartica, mediasiatica, and novicida, although only tularensis and holarctica cause disease in humans. Disease can be transmitted via insect bite, skin contact, ingestion of contaminated meat, or direct inhalation of bacteria.
Infections with F. tularensis subsp. tularensis are limited to the North American continent. The disease spectrum includes the more common cutaneous, ulceroglandular disease; however, when transmitted via the aerosol route, as few as ten bacteria can cause a rapid onset, fatal overwhelming pneumonia. The basis for this extraordinary virulence is not clear, but one can easily envision how this agent might be used as a bioweapons agent. The US actually amassed stores of F. tularensis at Fort Detrick during the 1960s for potential bioweapons use [3 ].
In your Pivotal Advance publication, you show that serum opsonized live bacteria are phagocytosed by neutrophils, but the membrane and cytosolic components of the NADPH oxidase do not assemble appropriately. What sorts of approaches are you taking to determine what interactions are taking place?
LA: We are examining this issue using both biochemical and genetic approaches to discern which aspects of NADPH oxidase assembly and activation are affected by Francisella. Our preliminary work suggests that multiple virulence factors may be involved. In the future it will be important to look at these interactions in vivo, but this is not a simple task given the many differences between human and murine neutrophils and the fact that most in vivo studies are performed using F. tularensis subsp. novicida, which is not a human pathogen.
Is just oxidase assembly eliminated, or has all intracellular trafficking ceased?
LA: We have some electron micrographs taken within 5 min to 6 h after phagocytosis which suggest that granule mobilization is also disrupted, as we see no evidence of granules fusing with the phagosome. Thus, our data suggest that, once the F. tularensis pathogen is phagocytosed, a number of subsequent neutrophil responses are impaired.
On a more personal note—what was your inspiration for a career in science? What do you enjoy most about what you do every day?
LA: I have not always wanted to be a research scientist. I began college in the accelerated M.D. program at University of California at Riverside. However, I found that I preferred pure science to the idea of taking care of patients. Senior year, I changed my major to Biochemistry and then spent two years in a cardiac electrophysiology lab before ultimately deciding to go to graduate school. Since then, I have been very focused on a laboratory-based academic career.
One of things I really like most about science is the surprise. Things are always changing, there is always a new puzzle to be solved, and there is always something new and different to do.
You remarked on your role in the Inflammation Program at the University of Iowa. Can you tell us more about this initiative?
LA: This is a relatively new program at the University of Iowa, and I was recruited to join by Bill Nauseef. The concept is to bring together researchers with a broad common interest in the physiology and pathophysiology of the inflammatory response. Right now, the program includes 11 faculty members and 60 individuals overall with diverse yet shared interests. The program shares joint lab space and we co-mentor students. This is a wonderful intellectual environment with a very strong base in phagocyte biology and host–pathogen interactions [4 ].
Your students have rated you as an outstanding teacher and mentor. Do you have any specific advice for young scientists?
LA: In addition to mentoring the students in my laboratory group, I teach immunology to second-year dental students, and I share in teaching a graduate cell biology course, a bacterial pathogenesis survey course, and a larger undergraduate course in basic immunology.
As far as advice—science can be rewarding and exciting. You have to do what you love to do and above all else, be passionate and completely committed since this is what gets you through the hard times.
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