| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Published online before print December 1, 2006
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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, National Institutes of Health, Bethesda, Maryland 20892, USA. E-mail: hrosenberg{at}niaid.nih.gov
In this Pivotal Advance manuscript, the authors address the "paradox of Salmonella immunity and immunosuppression," a term coined to describe the observation that mitogen-unresponsive spleen cells were recovered from mice that had generated immunity to Salmonella [1
]. In this work, Ms. Srinivasan and Dr. McSorley use adoptive transfer technology to demonstrate that immunosuppression is also an in vivo phenomenon and is not limited to CD4+ T cells with specificity for Salmonella antigens. Specifically, the authors show that CD4+ T cells (either flagellin-specific or OVA-specific) introduced into Salmonella-infected mice and subsequently activated in vivo by co-injection of respective peptide and endotoxin have only a limited ability to respond by producing IL-2 or TNF-
.
This is quite an interesting observation. Do you think CD4+ T cell suppression is uniquely related to the pathogenesis of Salmonella infection? What are your theories about the mechanism as they relate to CD4+ T cells?
SMc: To the best of my knowledge, there are no other bacterial infections that have been shown to promote CD4+ T cell suppression in exactly this way. We think that this observed suppression may be most important in the setting of super-infection or co-infection with Salmonella and another pathogen, such as occurs in developing countries where typhoid and many other infectious diseases are endemic. Interestingly, the effects of LPS on bacterial growth are similar to the lethal synergism between LPS and infection with the non-cytopathic RNA virus lymphocytic choriomeningitis virus (LCMV) [2 ]. We actually came upon this observation while investigating the way in which Salmonella evades T cell responses, and discovered that suppression was caused by the LPS used in our re-stimulation assay.
AS: As far as mechanism, I would guess that this occurs in vivo via interactions with intermediary cells, most likely macrophages.
SMc: I would agree. The observed suppression may not be a purely intrinsic feature of activated CD4+ T cells in Salmonella infected mice. As to hypotheses, LPS may induce excessive production of nitric oxide or other effectors from macrophages, which, although protective at low concentrations, may result in T cell suppression at higher concentrations. Signaling through TLRs may be an essential feature. It would be intriguing to explore the LPS-mediated CD4+ T cell suppression in Salmonella-infected MyD88- and specific TLR-gene-deleted mice.
In the text, you note that the mouse model of Salmonella infection differs from the human disease, but it is "the best that we have." What are some of the specific differences between human infection and the mouse model? Is there any evidence for T cell suppression in human disease?
AS: We have not yet collected any evidence for CD4+ T cell suppression in human disease, although this would be meaningful goal for the future. There are definitely well-characterized similarities and differences between the mouse model and the human disease. Among the similarities, both mice and humans develop systemic disease which affects primarily the liver and spleen.
SMc: Likewise, the route of Salmonella entry is via the intestinal Peyer’s patches, which is the same in both humans who acquire the disease naturally and in mouse models, and the cell tropism for macrophages is likewise the same in both. The most notable difference is that in human subjects, salmonella-induced enteritis involves bloody diarrhea, while mice are not susceptible to this complication [3 ].
A question for you specifically, Dr. McSorley. Why Salmonella? What intrigues you specifically about this work?
SMc: I actually came upon this field initially quite by chance, as part of my Ph.D. work in the laboratory of Dr. Foo Y. Liew [4 ]. It wound up being quite appealing, and I came back to it after a hiatus of working in the diabetes field [5 ]. It’s quite an interesting area, and there are not too many laboratories working on Salmonella immunology, particularly considering the significance of the problem in developing nations around the world. Not only does this make for a less competitive atmosphere for funding, it gives a younger researcher the chance to make a significant imprint on an emerging field of study.
And for you, Ms. Srinivasan—what is particularly attractive to you about this avenue of research? What are your plans for the future?
AS: I have a medical background, and I joined Dr. McSorley’s lab after graduation from Jawaharlal Institute of Post Graduate Medical Education and Research, Pondicherry University, India. I really enjoy working with in vivo models [6 , 7 ]. I enjoy developing new models, particularly ones with relevance to human infectious disease. I hope to complete my graduate work in December 2006 and to continue with postdoctoral work in an academic laboratory.
And a question for each of you in turn. Where will this work take you, both in the short and long terms?
AS: I would be most interested in pursuing questions related to the mechanism of T cell suppression.
SMc: I actually want to approach this project from a somewhat different perspective. There is certainly a large literature on immune suppression, particularly if you want to look at this subject within the overall field of bacterial super-infection and bacterial co-infection. What I would like to do is develop a model of co-infection that takes into account the fact that pathogens often coexist in a single host at the same time—sort of the "anti-reductionist approach." Given that many individuals in the developing world are in fact suffering from multiple diseases at once, we need to contemplate the larger reality of potential immunosuppressive effects.
Dr. McSorley, when I "Googled" you in preparation for this interview, I came across your letters to Nature in 2003 and 2005 on the subject of religion, bioethics, and society [8 , 9 ]. As someone employed in direct translational research, you have a particularly strong voice on this subject. Would you be willing to tell us a bit more about your thoughts on medical research and medical ethics?
SMc: I think scientists have an unfortunate but longstanding tradition of disregarding viewpoints from religious individuals, with the tacit assumption that religious people are generally uneducated. This is simply untrue. Religious voices need to be heard in all areas of society, but particularly so when discussing bioethics. Scientists may be good at understanding data, but they should be aware that they are not uniquely qualified to make ethical decisions that affect all members of society. Everyone in our society has a right to have his or her opinions heard and respected in determining societal ethics, whether they have advanced scientific training or not. Indeed, this is the very basis of a healthy representative democracy.
Is there anything else you would like readers to know about this work or yourselves?
SMc: It is gratifying to have our work recognized in this way by the journal and to receive some positive referee comments for a change!
|
Related Article
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
