The role of indoleamine 2, 3 dioxygenase in regulating host immunity to leishmania infection
Journal of Biomedical Science
The Role of Indoleamine 2, 3 Dioxygenase in Regulating Host Immunity to Leishmania Infection
Levi HC Makala 0
0 Georgia Health Sciences University, Medical College of Georgia, Department of Pediatrics, Hematology/oncology Section , Augusta, Georgia 30912 , USA
Pathogen persistence in immune-competent hosts represents an immunological paradox. Increasing evidence suggests that some pathogens, such as, Leishmania major (L. major) have evolved strategies and mechanisms that actively suppress host adaptive immunity. If this notion is correct conventional vaccination therapies may be ineffective in enhancing host immunity, unless natural processes that suppress host immunity are also targeted therapeutically. The key problem is that the basis of pathogen persistence in immune-competent individuals is unknown, despite decades of intense research. This fact, coupled with poor health care and a dearth of effective treatments means that these diseases will remain a scourge on humans unless a better understanding of why the immune system tolerates such infections emerges from research. Indoleamine 2,3-dioxygenase (IDO) has been shown to act as a molecular switch regulating host responses, and IDO inhibitor drugs shown to possess potential in enhancing host immunity to established leishmania infections. It is hoped that this review will help stimulate and help generate critical new knowledge pertaining to the IDO mechanism and how to exploit it to suppress T cell mediated immunity, thus offer an innovative approach to studying the basis of chronic leishmania infection in mice.
Leishimania major; Indoleamine 2; 3-dioxygenase; Mice; Leishmaniasis; Host Immunity; 1-methyl-d-tryptophan; plasmacytoid dendritic cell; regulatory T cell; draining lymph node
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Introduction
Chronic microbial infections, such as tuberculosis,
AIDS, malaria and leishmaniasis, are a global health
problem due to poor preventative health care in many
developing countries, and lack of effective vaccines and
drugs to prevent or clear chronic infections. Chronic
infections pose an immunological paradox because
pathogens persist in immune-competent hosts that, in
principle, ought to mount effective immune responses
leading to pathogen clearance. The fact that chronic
infections persist under such circumstances suggests
that pathogens exploit host immuno-regulatory
mechanisms to protect themselves (and infected cells) by
evading or actively suppressing host immunity. This
perspective provides the rationale for identifying natural
(host) immune-regulatory mechanisms exploited by
pathogens and using this new knowledge to improve
therapy.
This review summarizes new insights that are
emerging from recent studies, focusing on why Leishmania
persistence is achieved, and the other on DC subsets.
These may well be inter-connected. It is a well-known
fact that persistence is a hall mark of many parasitic
infections. In this review, we attempt to uncover a novel
mechanism by which Leishmania parasites circumvent
effector T cell responses through the induction of
indoleamine 2,3-dioxygenase (IDO) expression. Dendritic
cell subsets (DC) are central in regulating immunity,
often establishing immunologically privileged tissue
micro environments through the induction of of T
regulatory cells. One key concept is that only certain subsets
of DCs seem competent to express IDO, at least at the
level of functional immunoregulation. The factors that
influence the development and tissue distribution of
these IDO-competent DCs have yet to be determined.
Unanswered issues include whether the different
IDOcompetent subsets arise from one or multiple lineages;
and which signals during differentiation determine their
ability to express IDO. One key mechanism that
mediates many DC regulator functions is the production
of the immunomodulatory enzyme IDO. For pathogens
that cause chronic infection, for example leishmania,
exploitation of DC and/or regulation of IDO presents a
simple solution to persisting within a host. These two
focuses are described later on in the text.
Leishmania major is an obligate intracellular and
unicellular kinetoplastid protozoan flagellate that establishes
itself within the phagolysosome of host immune
competent cells, especially macrophages and dendritic cells
(DCs). In 1903, W.B. Leishman and C. Donovan
reported this new parasite at the turn of the century
[1,2]. Ronald Ross christened the new genus Leishmania
and the new species donovani in year 1903 [3]. L. major
infection (Leishmaniasis) in mice is a widely used model
of human infection that has yielded critical insights into
the immunobiology of leishmaniasis [4-6]. Leishmaniasis
as a parasitic disease manifests itself mainly in 3 clinical
forms; visceral leishmaniasis (VL), cutaneous
leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL), of
which VL is the most severe form of the disease. VL is
lethal if untreated and spontaneous cure is extremely
rare. Cutan (...truncated)