<scp>STAT</scp>4 is critical for immunity but not for antileishmanial activity of antimonials in experimental visceral leishmaniasis

Oghumu, Steve; Gupta, Gaurav; Snider, Heidi; Terrazas, César; Papenfuss, Tracey L.; Kaplan, Mark H.; Satoskar, Abhay R.

doi:10.1002/eji.201343477

Cited by 19 publications

(22 citation statements)

References 41 publications

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“…Consistent with the increased gene expression of IFN-␥ in the liver of miR155KO mice, we observed increased expression of iNOS at chronic stages of the infection. It is well known that IFN-␥ and nitric oxide play an important role in protective Th1 immunity during VL (23,33,34). Surprisingly, the spleens of miR155KO-infected mice also expressed higher iNOS levels at 90 and 120 dpi than WT mice despite the decrease in IFN-␥ production.…”

Section: Discussionmentioning

confidence: 88%

MicroRNA 155 Contributes to Host Immunity against Leishmania donovani but Is Not Essential for Resolution of Infection

et al. 2019

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CD4 ϩ T helper 1 (Th1) cells producing interferon gamma (IFN-␥) are critical for the resolution of visceral leishmaniasis (VL). MicroRNA 155 (miR155) promotes CD4 ϩ Th1 responses and IFN-␥ production by targeting suppressor of cytokine signaling-1 (SOCS1) and Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP-1) and therefore could play a role in the resolution of VL. To determine the role of miR155 in VL, we monitored the course of Leishmania donovani infection in miR155 knockout (miR155KO) and wild-type (WT) C57BL/6 mice. miR155KO mice displayed significantly higher liver and spleen parasite loads than WT controls and showed impaired hepatic granuloma formation. However, parasite growth eventually declined in miR155KO mice, suggesting the induction of a compensatory miR155-independent antileishmanial pathway. Leishmania antigen-stimulated splenocytes from miR155KO mice produced significantly lower levels of Th1-associated IFN-␥ than controls. Interestingly, at later time points, levels of Th2-associated interleukin-4 (IL-4) and IL-10 were also lower in miR155KO splenocyte supernatants than in WT mice. On the other hand, miR155KO mice displayed significantly higher levels of IFN-␥, iNOS, and TNF-␣ gene transcripts in their livers than WT mice, indicating that distinct organspecific antiparasitic mechanisms were involved in control of L. donovani infection in miR155KO mice. Throughout the course of infection, organs of miR155KO mice showed significantly more PDL1-expressing Ly6C hi inflammatory monocytes than WT mice. Conversely, blockade of Ly6C hi inflammatory monocyte recruitment in miR155KO mice significantly reduced parasitic loads, indicating that these cells contributed to disease susceptibility. In conclusion, we found that miR155 contributes to the control of L. donovani but is not essential for infection resolution.

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Section: Discussionmentioning

confidence: 88%

MicroRNA 155 Contributes to Host Immunity against Leishmania donovani but Is Not Essential for Resolution of Infection

et al. 2019

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“…In such a setting, drug efficacy is preserved in early infection in (i) B6 and BALB/c mice deficient in signaling (6,49), granular proteins (31), cytokine secretion (13,50), macrophage activation (34), and/or individual intracellular antileishmanial mechanisms (12,14) and (ii) in innately resistant mice (31). However, even if they are not microscopically in situ at the time that treatment is given, host T cells are nevertheless required to convert Sb from an inactive to leishmanicidal form (36), likely via endogenous IFN-␥, which is required for expression of Sb's intracellular killing action (12).…”

Section: Discussionmentioning

confidence: 99%

Gamma Interferon-Regulated Chemokines in Leishmania donovani Infection in the Liver

et al. 2017

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In the livers of C57BL/6 mice, gamma interferon (IFN-␥) controls intracellular Leishmania donovani infection and the efficacy of antimony (Sb) chemotherapy. Since both responses usually correlate with granulomatous inflammation, we tested six prominently expressed, IFN-␥-regulated chemokines-CXCL9, CXCL10, CXCL13, CXCL16, CCL2, and CCL5-for their roles in (i) mononuclear cell recruitment and granuloma assembly and maturation, (ii) initial control of infection and self-cure, and (iii) responsiveness to Sb treatment. Together, the results for the L. donovani-infected livers of chemokine-deficient mice (CXCR6 Ϫ/Ϫ mice were used as CXCL16-deficient surrogates) indicated that individual IFN-␥-induced chemokines have diverse affects and (i) may be entirely dispensable (CXCL13, CXCL16), (ii) may promote (CXCL10, CCL2, CCL5) or downregulate (CXCL9) initial granuloma assembly, (iii) may enhance (CCL2, CCL5) or hinder (CXCL10) early parasite control, (iv) may promote granuloma maturation (CCL2, CCL5), (v) may exert a granuloma-independent action that enables self-cure (CCL5), and (vi) may have no role in responsiveness to chemotherapy. Despite the near absence of tissue inflammation in early-stage infection, parasite replication could be controlled (in CXCL10 Ϫ/Ϫ mice) and Sb was fully active (in CXCL10 Ϫ/Ϫ , CCL2 Ϫ/Ϫ , and CCL5 Ϫ/Ϫ mice). These results characterize chemokine action in the response to L. donovani and also reemphasize that (i) recruited mononuclear cells and granulomas are not required to control infection or respond to Sb chemotherapy, (ii) granuloma assembly, control of infection, and Sb's efficacy are not invariably linked expressions of the same T cell-dependent, cytokine-mediated antileishmanial mechanism, and (iii) granulomas are not necessarily hallmarks of protective antileishmanial immunity.KEYWORDS chemokines, visceral leishmaniasis, Leishmania donovani, granuloma, pentavalent antimony I n visceral leishmaniasis, a disseminated protozoal infection, tissue macrophages in the liver, spleen, and bone marrow are targeted and support intracellular parasite replication. In the susceptible host, experimental Leishmania donovani infection in the liver does not come under control nor are parasites killed until either chemotherapy is given or T cell-dependent, multi-cytokine-driven mechanisms emerge and macrophage activation is induced. In the livers of infected wild-type (WT) C57BL/6 (B6) and BALB/c mice, this immunoinflammatory response is usually associated with mononuclear cell recruitment to and granuloma assembly at parasitized Kupffer cells (1-8). In the granulomatous environment, this T cell-and cytokine-mediated response also directs self-cure in initially susceptible B6 and BALB/c mice and, in addition, regulates the intracellular efficacy of conventional antileishmanial chemotherapy, pentavalent antimony (Sb) (2, 4, 6, 7, 9-11).

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“…Leishmania donovani (LV82 strain) was maintained as described previously by serial passage of amastigotes in Golden Syrian hamsters [12]. L. donovani amastigotes were isolated from the spleen of sick hamsters and experimental mice were injected with 10 7 L. donovani amastigotes prepared in 100 μl volume by tail vein injection.…”

Section: Methodsmentioning

confidence: 99%

“…At 60 days post-infection, infected mice were sacrificed to harvest spleens and livers and parasite burdens were determined as described previously [12]. Briefly, organs were weighed and sectioned to prepare impression smears on microscopic slides.…”

Section: Methodsmentioning

confidence: 99%

Transgenic T cell-specific expression of CXCR3 enhances splenic and hepatic T cell accumulation but does not affect the outcome of visceral leishmaniasis

Natarajan

Oghumu

Sperling

et al. 2016

Cellular Immunology

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The outcome of visceral leishmaniasis, caused by parasite Leishmania donovani, depends on the recruitment of leishmanicidal Th1 cells. Chemokine receptor CXCR3, preferentially expressed by Th1 cells, is critical for migration of these T cells during infection. During chronic VL, there is a decrease in the presence of CXCR3-expressing CD4 + T cells in the spleen, which is associated with high parasitic burden in this organ. We therefore examined whether T cell-specific expression of CXCR3 in mice (CXCR3 Tg ) would promote resistance to VL. L. donovani infected CXCR3 Tg mice showed increased accumulation of T cells in the spleens compared to WT littermates (CXCR3 +/+ ). However, CXCR3 + T cells from CXCR3 Tg mice showed low CD69 expression and these mice developed fewer granulomas. Additionally, both groups of mice showed similar cytokine profiles and parasitic burdens during the course of infection. In summary, although T cell-specific expression of CXCR3 promoted the accumulation of CXCR3-expressing T cells during L. donovani infection, this did not enhance resistance to VL.

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STAT4 is critical for immunity but not for antileishmanial activity of antimonials in experimental visceral leishmaniasis

Cited by 19 publications

References 41 publications

MicroRNA 155 Contributes to Host Immunity against Leishmania donovani but Is Not Essential for Resolution of Infection

MicroRNA 155 Contributes to Host Immunity against Leishmania donovani but Is Not Essential for Resolution of Infection

Gamma Interferon-Regulated Chemokines in Leishmania donovani Infection in the Liver

Transgenic T cell-specific expression of CXCR3 enhances splenic and hepatic T cell accumulation but does not affect the outcome of visceral leishmaniasis

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