Transforming Growth Factor-β in Leishmanial Infection: a Parasite Escape Mechanism

Barral‐Netto, Manoel; Barral, Aldina; Brownell, Cari E.; Skeiky, Yasir A. W.; Ellingsworth, Larry; Twardzik, Daniel R.; Reed, Steven G.

doi:10.1126/science.1636092

Cited by 411 publications

(282 citation statements)

References 19 publications

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“…5). Similar observations were made in which addition of recombinant TGF-b1 in vitro to murine peritonial macrophages or human macrophages increased the intracellular replication of L. braziliensis and T. cruzi, respectively [29,31].…”

Section: Discussionsupporting

confidence: 75%

Transforming growth factor-β expression in human retinal pigment epithelial cells is enhanced by Toxoplasma gondii: a possible role in the immunopathogenesis of retinochoroiditis

Nagineni

Detrick

Hooks

2002

Clinical and Experimental Immunology

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SUMMARYRetinochoroiditis caused by Toxoplasma gondii infection results in inflammation and necrosis of the retina. We have used human retinal pigment epithelial cultures (HRPE) as an in vitro model to investigate the role of TGF-b in T. gondii-induced retinochoroiditis. RT-PCR analyses showed enhanced steady state levels of TGF-b1 and TGF-b2 mRNA in T. gondii-infected HRPE. Uninfected HRPE secrete TGF-b1 in a latent form while 10-30% of the secreted TGF-b2 was in the active form. T. gondii infection induced a significant increase (P < 0·01) in total TGF-b1 and TGF-b2 secretion by HRPE. In addition, soluble extracts of T. gondii (ST) stimulated secretion of both TGF-b1 and TGF-b2 significantly (P < 0·01). Interestingly, T. gondii infection as well as ST of the parasites completely inhibited secretion of the active form of TGF-b2. Studies evaluating the effect of TGF-b on T. gondii replication in HRPE revealed that TGF-b enhanced parasite replication. The interactions between host retinal cells and T. gondii may play an active role in the pathogenesis of retinochoroiditis.

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Section: Discussionsupporting

confidence: 75%

Transforming growth factor-β expression in human retinal pigment epithelial cells is enhanced by Toxoplasma gondii: a possible role in the immunopathogenesis of retinochoroiditis

Nagineni

Detrick

Hooks

2002

Clinical and Experimental Immunology

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“…TGF-␤ has also been shown to suppress resistance to L. amazonensis infection in BALB/c mice (31), and during the early immune response, LN cells from L. major-infected BALB/c mice increased production of IFN-␥ when treated with anti-TGF-␤ (27). Similarly, IFN-␥ production was limited by TGF-␤ during the recall response of liver-derived immune cells from L. chagasi-infected mice (32).…”

Section: Discussionmentioning

confidence: 99%

IL-4-Independent Inhibition of IL-12 Responsiveness DuringLeishmania amazonensisInfection

Jones

Buxbaum

Scott

2000

The Journal of Immunology

124

139

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Leishmania amazonensis induces a nonhealing infection in C3H mice, whereas infection with Leishmania major is self-healing. We found that C3H mice infected with L. amazonensis exhibited decreased IL-12 production, which could account for the susceptibility to this organism. However, exogenous IL-12 administration failed to induce a healing immune response. The failure of L. amazonensis-infected C3H mice to respond to IL-12 was associated with a specific defect in IL-12 receptor β2 (IL-12Rβ2) mRNA expression by CD4+ T cells. Furthermore, decreased IL-12Rβ2 mRNA expression correlated with a decrease in the IL-12-signaling capacity of the lymph node (LN) cells. IL-4 did not contribute to susceptibility or down-regulation of the IL-12Rβ2 subunit, because IL-4−/− mice remained susceptible to L. amazonensis infection, even after IL-12 administration, and CD4+ cells from infected IL-4−/− mice also had reduced expression of IL-12Rβ2 mRNA. These results demonstrate that regulation of the IL-12 receptor, independent of IL-4, is a point of control for the immune response to leishmaniasis. In contrast to experimental L. major infections, where host genetics control susceptibility, these studies demonstrate that the lack of IL-12 responsiveness may be dictated by the pathogen, rather than the host.

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“…High levels of total TGF-b were detected in sera in one study 9 and levels similar to those in control individuals were detected in another ; TGF-b was also found to be highly expressed in bone marrow 26 and spleen 50 samples. Its macrophage deactivating effect was observed both in vitro and in vivo 6 and was found to affect NO production 41 .…”

Section: Immunoactivation In Lymphoid Organsmentioning

confidence: 99%

Immunoactivation and immunopathogeny during active visceral leishmaniasis

Goto

Prianti

2009

Rev. Inst. Med. trop. S. Paulo

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SUMMARYVisceral leishmaniasis is caused by protozoan parasites of the Leishmania donovani complex. During active disease in humans, high levels of IFN-g and TNF-a detected in blood serum, and high expression of IFN-g mRNA in samples of the lymphoid organs suggest that the immune system is highly activated. However, studies using peripheral blood mononuclear cells have found immunosuppression specific to Leishmania antigens; this poor immune response probably results from Leishmania antigen-engaged lymphocytes being trapped in the lymphoid organs. To allow the parasites to multiply, deactivating cytokines IL-10 and TGF-b may be acting on macrophages as well as anti-Leishmania antibodies that opsonize amastigotes and induce IL-10 production in macrophages. These high activation and deactivation processes are likely to occur mainly in the spleen and liver and can be confirmed through the examination of organ samples. However, an analysis of sequential data from studies of visceral leishmaniasis in hamsters suggests that factors outside of the immune system are responsible for the early inactivation of inducible nitric oxide synthase, which occurs before the expression of deactivating cytokines. In active visceral leishmaniasis, the immune system actively participates in non-lymphoid organ lesioning. While current views only consider immunocomplex deposition, macrophages, T cells, cytokines, and immunoglobulins by diverse mechanism also play important roles in the pathogenesis. KEYWORDS:Visceral leishmaniasis; Human; Immunosuppression; Immunoactivation; Cytokines; Immunopathogenesis.Visceral leishmaniasis is caused by protozoa of the genus Leishmania that are transmitted to mammalian hosts, including humans, by phlebotomine sandflies. The disease is present in 66 countries in tropical and subtropical regions, and 90% of cases occur in India, Sudan, Bangladesh, Nepal, and Brazil. It is estimated that there are 500,000 new cases a year worldwide 68 , and 3,000 new cases occur each year in Brazil 48 . Until recently, the disease was thought to be caused by three species of the Leishmania donovani complex: Leishmania (Leishmania) donovani, L. (L.) infantum, and Leishmania (L.) chagasi (a species present in Brazil). There is now debate, however, over whether L. (L). infantum and Leishmania (L.) chagasi are the same 44 or different 60 species. In this review, the names of the three species will be used as in the original publications. Leishmania (Leishmania) donovani is present in East Africa, India, and parts of the Middle East, while L. (L.) infantum in Europe, North Africa, and South and Central America. Human infections can be asymptomatic or can manifest as oligosymptomatic and progressive diseases; progressive cases can involve hepatosplenomegaly, fever, pancytopenia, hypergammaglobulinemia, and serious weight loss 4 . During active visceral leishmaniasis, the parasite multiplies within the cells of the mononuclear phagocyte system in the spleen, liver, and bone marrow, and the disease is fatal if untreated.Studies...

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Transforming Growth Factor-β in Leishmanial Infection: a Parasite Escape Mechanism

Cited by 411 publications

References 19 publications

Transforming growth factor-β expression in human retinal pigment epithelial cells is enhanced by Toxoplasma gondii: a possible role in the immunopathogenesis of retinochoroiditis

Transforming growth factor-β expression in human retinal pigment epithelial cells is enhanced by Toxoplasma gondii: a possible role in the immunopathogenesis of retinochoroiditis

IL-4-Independent Inhibition of IL-12 Responsiveness DuringLeishmania amazonensisInfection

Immunoactivation and immunopathogeny during active visceral leishmaniasis

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