Leishmania donovani activates uncoupling protein 2 transcription to suppress mitochondrial oxidative burst through differential modulation of SREBP2, Sp1 and USF1 transcription factors

Ball, Writoban Basu; Mukherjee, Madhuchhanda; Srivastav, Supriya; Das, Pritha

doi:10.1016/j.biocel.2014.01.004

Cited by 14 publications

(5 citation statements)

References 35 publications

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“…Although the details of the exact mechanism for this state in our study remains to be explored, the functioning of the iNOS pathway in immunized animals seems evident for their ability to clear in vitro reinfection such as the ROS pathway, which in turn, is connected to inflammasome activity in macrophages [102,103]. This is in agreement with previous studies where ROS generation has been shown in support of L. donovani clearance [104,105]. The protective response in our study is supported by a high level of inflammation and T cell activation in hamsters immunized with the designed multiepitope proteins.…”

Section: Discussionsupporting

confidence: 90%

A T-Cell Epitope-Based Multi-Epitope Vaccine Designed Using Human HLA Specific T Cell Epitopes Induces a Near-Sterile Immunity against Experimental Visceral Leishmaniasis in Hamsters

Arya

2021

Vaccines

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Visceral leishmaniasis is a neglected tropical disease affecting 12 million people annually. Even in the second decade of the 21st century, it has remained without an effective vaccine for human use. In the current study, we designed three multiepitope vaccine candidates by the selection of multiple IFN-γ inducing MHC-I and MHC-II binder T-cell specific epitopes from three previously identified antigen genes of Leishmania donovani from our lab by an immuno-informatic approach using IFNepitope, the Immune Epitope Database (IEDB) T cell epitope identification tools, NET-MHC-1, and NET MHC-2 webservers. We tested the protective potential of these three multiepitope proteins as a vaccine in a hamster model of visceral leishmaniasis. The immunization data revealed that the vaccine candidates induced a very high level of Th1 biased protective immune response in-vivo in a hamster model of experimental visceral leishmaniasis, with one of the candidates inducing a near-sterile immunity. The vaccinated animals displayed highly activated monocyte macrophages with the capability of clearing intracellular parasites due to increased respiratory burst. Additionally, these proteins induced activation of polyfunctional T cells secreting INF-γ, TNF-α, and IL-2 in an ex-vivo stimulation of human peripheral blood mononuclear cells, further supporting the protective nature of the designed candidates.

show abstract

Section: Discussionsupporting

confidence: 90%

A T-Cell Epitope-Based Multi-Epitope Vaccine Designed Using Human HLA Specific T Cell Epitopes Induces a Near-Sterile Immunity against Experimental Visceral Leishmaniasis in Hamsters

Arya

2021

Vaccines

View full text Add to dashboard Cite

show abstract

“…Although, the details of the exact mechanism for this state in our study remains to be explored, yet the functioning of the iNOS pathway in immunized animals seems evident for their ability to clear in-vitro reinfection, as the ROS pathway, in turn, is connected to inflammasome activity in macrophage [102,103]. This is in coherence with previous studies where ROS generation has been shown in support of Leishmania donovani clearance [104,105]. The protective response in our study is supported by a high level of inflammation and T cell activation in hamsters immunized with the designed multiepitope proteins.…”

Section: Discussionsupporting

confidence: 89%

A T-Cell Epitope-Based Multi-Epitope Vaccine Designed Using Human HLA Specific T Cell Epitopes Induces Sterile Immunity against Experimental Visceral Leishmaniasis in Hamsters

Arya¹,

Arora²

2021

Preprint

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Visceral Leishmaniasis is a neglected tropical disease affecting 12 million people annually. Even in the second decade of the 21st century, it has remained without an effective vaccine for human use. In the current study, we have designed three multiepitope vaccine candidates by the selection of multiple IFN-γ inducing MHC-I and MHC-II binder T-cell specific epitopes from 3 previously identified antigen genes of Leishmania donovani from our lab, by immune-informatic approach using IFNepiotpe, NET-MHC-1 and NET MHC-2 webservers. We have tested the protective potential of these three multiepitope proteins as vaccine in a hamster model of visceral leishmaniasis. The immunization data revealed that the vaccine candidates induced a very high level of Th-1 biased protective immune response in-vivo in a hamster model of experimental visceral Leishmaniasis, with one of the candidates inducing a sterile immunity. The vaccinated animals displayed highly activated monocyte macrophages with the capability of clearing intracellular parasites due to increased respiratory burst. Additionally, these proteins induced activation of polyfunctional T cells secreting INF-γ, TNF-α, and IL-2 in ex-vivo stimulation of human peripheral blood mononuclear cells, further supporting the protective nature of designed candidates.

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“…Sp1 that belonged to the 24h_plum1 is involved in the evasion mechanisms of Leishmania . Different species can induce the binding of Sp1 on Il10 , Ucp2 , and Hdac1 promoters in macrophages, resulting in the production of the inhibitory IL-10 cytokine, the suppression of oxidative burst, and a decrease of iNOS expression, respectively ( Yang et al., 2007 ; Basu Ball et al., 2014 ; Calegari-Silva et al., 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Dissection of the macrophage response towards infection by the Leishmania-viral endosymbiont duo and dynamics of the type I interferon response

Bekkar

Isorce

Snäkä

et al. 2022

Front. Cell. Infect. Microbiol.

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Leishmania RNA virus 1 (LRV1) is a double-stranded RNA virus found in some strains of the human protozoan parasite Leishmania, the causative agent of leishmaniasis, a neglected tropical disease. Interestingly, the presence of LRV1 inside Leishmania constitutes an important virulence factor that worsens the leishmaniasis outcome in a type I interferon (IFN)–dependent manner and contributes to treatment failure. Understanding how macrophages respond toward Leishmania alone or in combination with LRV1 as well as the role that type I IFNs may play during infection is fundamental to oversee new therapeutic strategies. To dissect the macrophage response toward infection, RNA sequencing was performed on murine wild-type and Ifnar-deficient bone marrow–derived macrophages infected with Leishmania guyanensis (Lgy) devoid or not of LRV1. Additionally, macrophages were treated with poly I:C (mimetic virus) or with type I IFNs. By implementing a weighted gene correlation network analysis, the groups of genes (modules) with similar expression patterns, for example, functionally related, coregulated, or the members of the same functional pathway, were identified. These modules followed patterns dependent on Leishmania, LRV1, or Leishmania exacerbated by the presence of LRV1. Not only the visualization of how individual genes were embedded to form modules but also how different modules were related to each other were observed. Thus, in the context of the observed hyperinflammatory phenotype associated to the presence of LRV1, it was noted that the biomarkers tumor-necrosis factor α (TNF-α) and the interleukin 6 (IL-6) belonged to different modules and that their regulating specific Src-family kinases were segregated oppositely. In addition, this network approach revealed the strong and sustained effect of LRV1 on the macrophage response and genes that had an early, late, or sustained impact during infection, uncovering the dynamics of the IFN response. Overall, this study contributed to shed light and dissect the intricate macrophage response toward infection by the Leishmania-LRV1 duo and revealed the crosstalk between modules made of coregulated genes and provided a new resource that can be further explored to study the impact of Leishmania on the macrophage response.

show abstract

Leishmania donovani activates uncoupling protein 2 transcription to suppress mitochondrial oxidative burst through differential modulation of SREBP2, Sp1 and USF1 transcription factors

Cited by 14 publications

References 35 publications

A T-Cell Epitope-Based Multi-Epitope Vaccine Designed Using Human HLA Specific T Cell Epitopes Induces a Near-Sterile Immunity against Experimental Visceral Leishmaniasis in Hamsters

A T-Cell Epitope-Based Multi-Epitope Vaccine Designed Using Human HLA Specific T Cell Epitopes Induces a Near-Sterile Immunity against Experimental Visceral Leishmaniasis in Hamsters

A T-Cell Epitope-Based Multi-Epitope Vaccine Designed Using Human HLA Specific T Cell Epitopes Induces Sterile Immunity against Experimental Visceral Leishmaniasis in Hamsters

Dissection of the macrophage response towards infection by the Leishmania-viral endosymbiont duo and dynamics of the type I interferon response

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