Dissociation of interferon-gamma production and resistance to leishmaniasis in the absence of tumor necrosis factor

Fromm, Phillip Dieter (2010) Dissociation of interferon-gamma production and resistance to leishmaniasis in the absence of tumor necrosis factor. PhD thesis, James Cook University.

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The delineation of T helper 1(Th1) and T helper 2 (Th2) responses in promoting resistance and susceptibility to experimental cutaneous leishmaniasis has provided a substantial contribution to the understanding of the molecular basis of T cell differentiation in the context of infectious disease. Dysregulation of these processes renders the host susceptible to disease pathogenesis or immuno-pathology. Yet, the paradigm of resistance and susceptibility fails if the adaptive immune systems is not coupled adequately to the innate immune system. The pleiotropic cytokine Tumor necrosis factor (TNF) is involved in numerous aspects of homeostatic and inflammatory processes involved with immune cell function. Dysregulation of TNF production is associated with autoimmune diseases such as Rheumatoid Arthritis, or can render the host susceptible to infectious diseases. The mechanisms however, by which the overproduction of, or the lack of TNF promotes these extreme outcomes is still relatively unknown. Here, I analsysed the genetic contribution of the different major components of the TNF signalling family to elucidate how TNF confers protection to infection with the intracellular protozoan parasite Leishmania major.

Co-operative induction of inducible nitric oxide synthase (iNOS) in mononuclear phagocytes by Interferon gamma and TNF provides the basis for an effective immune response to L. major. In the absence of TNF the normally resistant C57BL/6 mouse strain develops a fatal visceralising form of leishmaniasis. Protection from this fatal outcome is dependent on the expression of the trans-membrane but not the soluble form of TNF through an interaction with TNFR1, however the mechanism by which this interaction confers protection remains unknown.

Here I demonstrate that this susceptibility to infection does not result from altered CD4+ effector T cell differentiation or inpaired induction of iNOS. T cell activation is greatly increased in the absence of TNF, however enhancement of activation as measured by increased CD44 expression does not reflect positively on the clinical outcome. CD44+ CD4+ T cells from L. major infected TNF-deficient mice showed similar transcriptional up-regulation of both Tbx-21 and Ifn-γ compared to WT controls but showed reduced expression of both Gata-3 and Il-10 indicating a more polarized T cell response. This was similarly accompanied by increased levels of IFN-γ that was observed locally and systemically in the absence of either TNF or TNFR1. The up-regulation of IFN-γ in both resistant B6.WT and susceptible B6.TNF-deficient mouse strains correlated with the induction of iNOS that was predominantly expressed by infiltrating CCR2+ inflammatory monocytes. Despite equivalent induction of iNOS in both the lesion and draining lymph node, expression of iNOS and location of L. major amastigotes showed distinct cellular compartmentalization. While iNOS expression was restricted to CCR2+ inflammatory monocytes, a novel CD11b+, iNOS-, Ly6G-, Ly6Clow, CCR2low population was observed that was highly parasitised and accumulated exclusively in the absence of either TNF or TNFR1 in the draining lymph node. The capacity for these CD11b+, iNOS-, ,Ly6G-, Ly6Clow, CCR2low cells to become highly parasitised did not result from any intrinsic deficit of TNFR signalling. Rather, mixed bone marrow chimeras showed that this sensitivity to L. major parasitism results from external cues generated upstream of monocyte and macrophage activation that renders these cells susceptible to infection.

These data demonstrate a unique role for TNF in the coupling of innate and adaptive immune responses through modulating the development of infiltrating myeloid cells that have different leishmanicidal potentials and reflect a state of susceptibility to intracellular infection to L. major rather than promoting direct leishmanicidal functions in vivo.

Item ID: 19036
Item Type: Thesis (PhD)
Keywords: Leishmania major, leishmaniasis, tumor necrosis factor, TNF, nitric oxide, infectious tropical diseases, monocytes, T cells, interferon gamma, adaptive immune responses, medical parasitology, knockout models, knock out mice, autoimmune diseases, inflammatory diseases, immunogenetics
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Publications arising from this thesis are available from the Related URLs field. The publications are:

Roomberg, A., Kling, J., Fromm, P., and Korner, H. (2010) Tumor necrosis factor negative bone marrow-derived dendritic cells exhibit deficient IL-10 expression. Immunology and Cell Biology 88(8): 842-845.

Wiede, F., Roomberg, A., Cretney, E., Lechner, A., Fromm, P., Wren, L., Smyth, M.J., and Korner, H. (2009) Age-dependent, polyclonal hyperactivation of T cells is reduced in TNF-negative gld/gld mice. Journal of Leukocyte Biology 85(1): 108-116.

Hansen, E., Krautwald, M., E., M.A., Stuchbury, G., Fromm, P., Steele, M.S., Schulz, O., Garcia, O.B., Castillo, J., Körner, H., and Münch, G. (2010) A versatile high throughput screening system for the simultaneous identification of anti-inflammatory and neuroprotective compounds. Journal of Alzheimer's Disease, 19(2): 451-464.

Chapter 2: Korner, H., McMorran, B., Schluter, D., and Fromm, P. (2010) The role of TNF in parasitic diseases: still more questions than answers. International Journal for Parasitology 40(8): 879-888.

Date Deposited: 28 Nov 2011 22:56
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110704 Cellular Immunology @ 33%
11 MEDICAL AND HEALTH SCIENCES > 1108 Medical Microbiology > 110803 Medical Parasitology @ 34%
06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060199 Biochemistry and Cell Biology not elsewhere classified @ 33%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 33%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 34%
97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 33%
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