February 25, 2010 at 4:12 am #2815HarrisonKeymaster2 pts
Laboratory of Clinical Infectious Diseases
Steven M. Holland, M.D.
Chief, Laboratory of Clinical Infectious Diseases
Chief, Immunopathogenesis Section, LCID
Tenured Investigator, Immunopathogenesis Section
Dr. Holland received his M.D. from the Johns Hopkins University School of Medicine in 1983, where he stayed as a resident in internal medicine, assistant chief of service in medicine, and fellow in infectious diseases. He came to NIH in 1989 as a National Research Council fellow in the Laboratory of Molecular Microbiology, working on transcriptional regulation of HIV. In 1991, Dr. Holland joined the Laboratory of Host Defenses, shifting his research to the host side, with a focus on phagocyte defects and their associated infections. His work centered on the pathogenesis and management of chronic granulomatous disease, as well as other congenital immune defects affecting phagocytes, including those predisposing to mycobacterial diseases. In 2004, he became chief of the LCID.
Description of Research Program
The Immunopathogenesis Sections therapeutic and research programs take a fully integrated approach to infectious disease, incorporating the molecular genetics of the host and the pathogen as well as mechanisms of pathogenesis that allow the development and study of novel therapeutics. The integrated bench-to-bedside model is intrinsic to the Immunopathogenesis Sections approach and is reflected in the close involvement of trainees (both M.D. and Ph.D.) in laboratory work and in the clinical appreciation of disease, which together add new insights into mechanisms of action and avenues of therapy. New protocols in staphylococcal infections, idiopathic CD4 lymphocytopenia, and drug-resistant tuberculosis are in progress.
Major Areas of Research
[*]Immune defects of phagocytes: chronic granulomatous disease, hyper IgE (Jobs) syndrome, leukocyte adhesion deficiency
[*]Cytokines in the pathogenesis and therapy of infections
[*]Susceptibility to disseminated mycobacterial infections, such as autoantibodies to interferon gamma and defects in the interferon gamma/IL-12 pathway
[*]Mechanisms of mycobacterial pathogenesis
[*]Mechanisms of bacterial pathogenesis (e.g., Burkholderia)
[*]Mechanisms of airway dysfunction
March 26, 2010 at 4:31 pm #2816HarrisonKeymaster2 pts
Question: What kinds of progress has the NIH made in tackling nosocomial infections — in terms of diagnosis and treatment?
Answer: So nosocomial infections, as you know are an enormous problem for not only our nation, but for all other people who traffic through hospitals. And we have been working very hard on these issues and there are several critical areas. For most hospitalized patients, the big, players are going to be staphylococcal infections, which you hear referred to as MRSA and that comes in two varieties. Theres the hospital-acquired variety and the community-acquired variety, and we have large programs in our institute in understanding staphylococcal virulence, transmission and susceptibility.
So those are organisms that are highly transmissible between individuals and thats why you get them in the community. Theres another one called Staphylococcus epidermidis, or Staph epi, and these are organisms that inhabit our skin normally. Although they are typical flora, when people have a breach, such as with surgery or a catheter or something like that, they can cause infections. They occur in the hospital, so theyre referred to as nosocomial, but they can be very difficult and theyre particularly difficult when they get into prosthetic devices like catheters, joints or things like that. So again, theres a large program in our institute in understanding the biology of Staph epidermidis and understanding why that organism causes infection and understanding how to treat it. There are then, so those are what are called gram-positive bacteria, the small things that are blue the way that we look at them in the microlab. And then there are the things that are gram-negative; that is, theyre pink in the microlab. And those organisms are in a group referred to as Acinetobacter. You may have heard these in a variety of contexts, and these are very severe and difficult infections that are transmitted among sick patients in hospitals and really are a major focus of work now, both in our own laboratories and in the microbiology laboratory here at the NIH.
Question: What connection is, is there, if any between bacterial biofilms, which can be gram-negative, gram-positive and chronic and persistent disease?
Answer: So biofilms, as you point out, are a big feature, or are thought to be a big feature, in bacterial persistence. And basically, just to be sure were on the same page, bacteria, when they live together, they signal to each other, and they create a slime in which they like to hang out. And that slime then makes them, it changes their metabolic rate somewhat, and it also is difficult to penetrate with antibacterials, and presumably, its difficult for neutrophils and other host materials to penetrate as well.
Exactly how biofilms impair bacterial elimination is still a little unclear to me. That is, we all agree they exist, we all agree that they, they seem like they ought to make life more difficult, and yet, sometimes were able to treat them successfully and sometimes were not. Im not sure that I understand the difference between why sometimes we win and sometimes we lose. It seems like many organisms are able to form biofilms and understanding the biology behind that has really been quite exciting in terms of recognizing that, at some very real level, bacteria talk to each other just like we do, and they send out signals that say, you know, Lets, lets go one way, lets get a beer, lets go out for a pizza. I mean, they are willing to talk to each other in ways that I dont think we appreciated 20 years ago.
Question: Just to build on that, doctor, can you comment on the link between polymicrobial biofilms and antibiotic resistance?
Question: Moving on to systemic infections, there are some published studies that indicate Chlamydia pneumoniae, for example, can cause a number of different arthritic syndromes. Can you speak to the joint disease or arthritic issues?
Answer: I cant speak to those directly. But certainly Chlamydia have been a source of tremendous interest in the infectious disease community for a long time now. They cause a variety of syndromes. Some live in the lung, some outside the lung. Trying to sort out how extensive Chlamydia involvement is has been complicated by the fact that theyre very difficult to culture and theyre not all that easy to see, under various circumstances. That being said, the treatments for Chlamydia now are relatively good, and are relatively effective and well-tolerated. So Im no longer expert in all of the different manifestations of Chlamydia infection, but suffice it to say that they are organisms that are intracellular, that like to go inside of things and that gives them a certain stealthiness that makes them difficult to get at.
Some of the joint syndromes have been associated with Chlamydia, like other intracellular organisms like mycoplasma and others. It is difficult sometimes to differentiate between what we call reactive problems, that is, the immune system gets switched on, it gets confused, it then attacks joints, thinking its doing its right job against Chlamydia, but, in fact, it, it happens to be doing the right thing against your left knee, or something like that. And so these reactive arthritides can be very difficult to differentiate from direct infection, and they may all respond to the same therapy that is getting rid of the infection in the lung, and they also get rid of some of the manifestations elsewhere.
Question: Where are the pathogenic bacteria found in perhaps the public environment or the hospital environment that could be a potential risk factor?
Answer: Well, as most people appreciate, the single greatest reservoir for resistant bacteria is really us, and in the hospital environment and in the community environment it is overwhelmingly the inadvertent, unintended, unfortunate transmission of pathogenic bacteria carried on one person causing them probably no distress being transferred to another.
So, in the hospital setting, that can be infection carrier, it can be bacteria carried by healthcare workers, carried by staff, carried by visitors who inadvertently and unintentionally give those exposures to people who are momentarily susceptible because theyve had surgery, because theyre acutely ill, because theyre getting treated for cancer or something else, and this really accounts for an enormous amount of nosocomial infection. Of course, other sources include, water sources and inadequate sterilization of materials, and occasionally environmental sources, that is, the floor, the bed, the faucets.
All those are important to control, and theyre certainly topics of great focus by hospital epidemiologists around the world, but still, the most crucial step in preventing nosocomial transmission of anything is hand washing. And there, if we simply did that right, and it sounds simple, but like a lot of simple things — its not. If we just did that right, we would have many, many, many fewer problems.
Question: There are many other promising areas of research that we dont have the time to get into today. Did you want to mention any of these, doctor?
Answer: Well, there are many different areas that are essential to trying to keep a global perspective on infection and I would just mention that some of the areas where weve made the most progress — which sometimes takes time to evolve into treatment — in the area of exploring immune susceptibility. That is, when we look at what weve learned about, why people get infected with different things from the study of HIV. I mean, obviously, the study of HIV was directed at developing treatment on it, trying to improve lives. But one of the consequences of that was to learn more about what lymphocytes do and monocytes do and how they interact and what their crosstalk is, and so on, and this has fueled enormous amounts of understanding that is now being applied to bone marrow transplantation and the treatment of cancer and the mechanisms for treating tuberculosis and other diseases. And I would just point out that some of the most fertile ground for discovery continues to be in immune susceptibility. When we identify patients who have unexpected problems, to study those in detail and say, Wait, you know, why did this happen to this person? What was their reason for getting it? Sometimes they had a car accident, they had a joint replaced, they had a, a problem come up that we all understand, but occasionally its not that, and then its the careful dissection of why things happen that leads us to the mechanism.
And when we get to that mechanism that tells us, “Ah, these are the critical factors for prevention of staphylococcal infection or acinetobacter infection or herpes infection.” And its through that kind of careful, detailed, mechanistic work that I think we understand a mechanism that leads us forward toward understanding how were going to translate that information from one person or one family into approaches that might be important for populations.
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