Frank L. van de Veerdonk on Immune Responses to M. Tuberculosis
Fast Breaking Papers Commentary, December 2011
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Article: Mycobacterium tuberculosis induces IL-17A responses through TLR4 and dectin-1 and is critically dependent on endogenous IL-1
Authors: van de Veerdonk, FLV, et al. |
Frank L. van de Veerdonk talks with ScienceWatch.com and answers a few questions about this month's Fast Breaking Paper paper in the field of Immunology.
Why do you think your paper is highly
cited?
The manuscript is one of the first studies that have identified the pattern recognition receptors and pathways that are important for the induction of the Th17 response against Mycobacterium tuberculosis in humans.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
The study provides new insights into the host response against M. tuberculosis. During the experimental process of elucidating the pathways that are essential for the induction of the Th17 response, it became apparent that the IL-1 pathway played a dominant role in the mycobacterial-induced Th17 response in humans. The study linked the pathways and mechanisms that regulate IL-1 to the regulation of Th17 responses in mycobacterial disease, connecting different fields of research to one of the most important public health problems in the world: tuberculosis (TB).
Would you summarize the significance of your paper
in layman's terms?
TB is a major public health problem with an estimated two million deaths per year. The development of new vaccines or drug therapy is essential to overcome this problem. To identify new key elements that are important for this development, this study has elucidated the parts of the immune system that are important for the development of potent proinflammatory responses induced by cells of the immune system such as T helper cells.
T helper (Th) cells can be divided into Th1, Th2, and Th17. This paper has particularly focused on Th17 cells, which are called "17" since they produce the cytokine called IL-17, which recruits immune cells such as neutrophils to the site of inflammation and regulates these proinflammatory cells at the site of infection. Therefore, the Th17 response is a very potent response and could cause collateral damage if it is not tightly controlled. The identification of pathways that are important for this response could help to design a safe and effective vaccine or could be used to develop safe and novel treatment strategies against TB.
"I believe that understanding the interplay between the new IL-1 family members and adaptive immunity could have an important impact both on our understanding of immunity in terms of signaling networks, and has the potential to have a direct impact on the development of immunomodulatory treatment for patients with bacterial and fungal infections."
How did you become involved in this research, and
how would you describe the particular challenges, setbacks, and
successes that you have encountered along the way?
I was working on the fungal pathogen Candida albicans and wanted to identify the components of its cell wall, and the receptors of the human host response that were important for the development of Candida-specific Th17 responses in humans. I used a system of peripheral blood mononuclear cells (PBMCs) to study this response; however, I was never able to measure the cytokine IL-17.
After performing an ELISA on IL-17 in the supernatants from a forgotten experiment that stood way too long in the incubator, namely a week, I was able to measure IL-17. By using human fresh serum at a concentration of 10%, I was able to optimize the C. albicans-induced IL-17. This experimental setup opened an opportunity to study the Th17 response in humans.
As an internist specialized in infectious diseases I was not only interested in fungal infections, but also in other infectious diseases such as tuberculosis. M. tuberculosis is recognized by some of the same receptors as C. albicans and by using the same approach as with the C. albicans-induced Th17, I was able to identify the major pathways involved in the induction of the MTB-specific Th17 response.
When I was working on this project I had the privilege to work with Prof. Charles Dinarello, who has cloned and described IL-1, and who was on sabbatical in our lab. The dominant role for IL-1 and its regulating factors in this project opened many discussions with him and has resulted in new and exciting scientific projects.
Where do you see your research leading in the
future?
"TB is a major public health problem with an estimated two million deaths per year."
I recently got back from Denver where I worked in Charles Dinarello's laboratory on the functional roles of the new IL-1 family members. One of the major projects that I am focusing on at the moment is the role of the new IL-1 family members IL-36, IL-37, and IL-38 in polarizing T-helper responses in infectious diseases, for which I received a VENI grant from The Netherlands Organization for Scientific Research (NWO).
Furthermore, I want to elucidate the pathophysiological mechanisms that underlying allergic bronchopulmonary aspergillosis (ABPA). This is a very exciting project for me, since it integrates the fungal immunological knowledge that I have gathered over recent years with clinical practice with the aim of optimizing patient care. The Nijmegen Centre for Molecular Life Sciences (NCMLS) from the Radboud University Nijmegen Medical Centre in the Netherlands has funded this project.
These two projects will be the main focus of my future research and could only be made possible because of my past research activities.
Do you foresee any social or political
implications for your research?
These studies are expected to set the stage for the development of new treatment options against bacterial and fungal infections. Experts are warning for the rise of the incidence in "superbugs;" microorganisms that are practically resistant to all available antibiotics. Moreover, the rate of mortality and morbidity that is associated with invasive fungal infections is still unacceptably high despite our current treatment arsenal.
I believe that understanding the interplay between the new IL-1 family
members and adaptive immunity could have an important impact both on our
understanding of immunity in terms of signaling networks, and has the
potential to have a direct impact on the development of immunomodulatory
treatment for patients with bacterial and fungal infections. Furthermore,
it could provide a basis for designing new vaccines for the prevention of
infectious diseases or even lead to new treatment options in patients with
autoimmune diseases.
Frank L. van de Veerdonk, M.D., Ph.D.
Radboud University Nijmegen Medical Centre
Internal Medicine, Infectious diseases
Nijmegen, the Netherlands
KEYWORDS: HOST DEFENSE, MTB, IL-1 RECEPTOR PATHWAY, TH17 CELLS, TOLL-LIKE RECEPTORS, T-HELPER CELLS, MANNOSE RECEPTOR, CANDIDA ALBICANS, DENDRITIC CELLS, IMMUNE RESPONSE, RECOGNITION, INDUCTION, INFECTION, INNATE.