Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response

Oljuskin, Timur; Azodi, Nazli; Volpedo, Greta; Bhattacharya, Parna; Markle, Hannah L.; Hamano, Shinjiro; Matlashewski, Greg; Satoskar, Abhay R.; Gannavaram, Sreenivas; Nakhasi, Hira L.

doi:10.1016/j.isci.2023.107593

Cited by 4 publications

(1 citation statement)

References 116 publications

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“…This cannot be attributed to the presence of Leishmania RNA Virus (LRV) [ 35 ], as the strain of L. braziliensis used in this study does not carry LRV (unpublished). While immunization with LmexCen −/− promotes changes in the host cell leading to M1 polarization [ 36 ], LmajorCen −/− modulates tryptophan metabolism, promoting the production of IL-12 rather than IL-10 and TGF-β [ 37 ]. It remains to be investigated if the metabolic immune regulation in LbCen −/− infection disfavors the replication of parasites, rapidly clearing the infection.…”

Section: Discussionmentioning

confidence: 99%

Immunization with centrin-Deficient Leishmania braziliensis Does Not Protect against Homologous Challenge

Avendaño-Rangel,

Agra-Duarte,

Borba

et al. 2024

Vaccines

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Immunization with various Leishmania species lacking centrin induces robust immunity against a homologous and heterologous virulent challenge, making centrin mutants a putative candidate for a leishmaniasis vaccine. Centrin is a calcium-binding cytoskeletal protein involved in centrosome duplication in higher eukaryotes and Leishmania spp. lacking centrin are unable to replicate in vivo and are non-pathogenic. We developed a centrin-deficient Leishmania braziliensis (LbCen−/−) cell line and confirmed its impaired survival following phagocytosis by macrophages. Upon experimental inoculation into BALB/c mice, LbCen−/− failed to induce lesions and parasites were rapidly eliminated. The immune response following inoculation with LbCen−/− was characterized by a mixed IFN-γ, IL-4, and IL-10 response and did not confer protection against L. braziliensis infection, distinct from L. major, L. donovani, and L mexicana centrin-deficient mutants. A prime-boost strategy also did not lead to a protective immune response against homologous challenge. On the contrary, immunization with centrin-deficient L. donovani (LdonCen−/−) cross-protected against L. braziliensis challenge, illustrating the ability of LdonCen−/− to induce the Th1-dominant protective immunity needed for leishmaniasis control. In conclusion, while centrin deficiency in L. braziliensis causes attenuation of virulence, and disrupts the ability to cause disease, it fails to stimulate a protective immune response.

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Section: Discussionmentioning

confidence: 99%

Immunization with centrin-Deficient Leishmania braziliensis Does Not Protect against Homologous Challenge

Avendaño-Rangel,

Agra-Duarte,

Borba

et al. 2024

Vaccines

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The β-Carboline Harmine Has a Protective Immunomodulatory Role in Nonhealing Cutaneous Leishmaniasis

Peyvandi,

Lan,

Chabloz

et al. 2024

Journal of Investigative Dermatology

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Downregulation of IRF7-mediated type-I interferon response by LmCen–/– parasites is necessary for protective immunity

Sepahpour,

Alshaweesh,

Azodi

et al. 2024

npj Vaccines

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Leishmaniasis is a tropical disease caused by Leishmania parasites and currently has no licensed vaccines. We developed a dermotropic Leishmania major centrin gene-deleted strain (LmCen–/–) as a live attenuated vaccine. Recent studies have shown that type I interferons (IFNs) play important roles in immunity to parasitic and viral pathogens. However, their relevance in protective immunity following vaccination is not understood. We found that immunization with LmCen–/– induces a transient increase in type I IFN response along with its regulatory factor IRF7 that is downregulated 7–21 days post-immunization, coincided with the induction of a robust Th1 adaptive immune response. Challenge infection with virulent L. donovani parasites showed a significant reduction of splenic and hepatic parasite burden in IRF7–/– mice than wild type mice following immunization with LmCen–/–, suggesting that ablation of type I IFN response is a pre-requisite for the induction of LmCen–/– mediated Th1 immunity against L. donovani infection.

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Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response

Cited by 4 publications

References 116 publications

Immunization with centrin-Deficient Leishmania braziliensis Does Not Protect against Homologous Challenge

Immunization with centrin-Deficient Leishmania braziliensis Does Not Protect against Homologous Challenge

The β-Carboline Harmine Has a Protective Immunomodulatory Role in Nonhealing Cutaneous Leishmaniasis

Downregulation of IRF7-mediated type-I interferon response by LmCen–/– parasites is necessary for protective immunity

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