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Deletion of MIF gene from live attenuated LdCen^-/- parasites enhances protective CD4⁺ T cell immunity.

ABSTRACT: Vaccination with live attenuated Leishmania parasites such as centrin deleted Leishmania donovani (LdCen^-/-) against visceral leishmaniasis has been reported extensively. The protection induced by LdCen^-/- parasites was mediated by both CD4⁺ and CD8⁺ T cells. While the host immune mediators of protection are known, parasite determinants that affect the CD4⁺ and CD8⁺ T cell populations remain unknown. Parasite encoded inflammatory cytokine MIF has been shown to modulate the T cell differentiation characteristics by altering the inflammation induced apoptosis during contraction phase in experimental infections with Leishmania or Plasmodium. Neutralization of parasite encoded MIF either by antibodies or gene deletion conferred protection in Plasmodium and Leishmania studies. We investigated if the immunogenicity and protection induced by LdCen^-/- parasites is affected by deleting MIF genes from this vaccine strain. Our results showed that LdCen^-/-MIF^-/- immunized group presented higher percentage of CD4⁺ and CD8⁺ central memory T cells, increased CD8⁺ T cell proliferation after challenge compared to LdCen^-/- immunization. LdCen^-/-MIF^-/- immunized group presented elevated production of IFN-γ⁺ and TNF-α⁺ CD4⁺ T cells concomitant with a reduced parasite load in spleen and liver compared to LdCen^-/-group following challenge with L. infantum. Our results demonstrate the role of parasite induced factors involved in protection and long-term immunity of vaccines against VL.

SUBMITTER: Fiuza JA

PROVIDER: S-EPMC10163264 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Deletion of MIF gene from live attenuated LdCen-/- parasites enhances protective CD4+ T cell immunity.

Fiuza Jacqueline Araújo JA Gannavaram Sreenivas S Gaze Soraya Torres ST de Ornellas Letícia Gambogi LG Alves Érica Alessandra ÉA Ismail Nevien N Nakhasi Hira Lal HL Correa-Oliveira Rodrigo R

Scientific reports 20230505 1

Vaccination with live attenuated Leishmania parasites such as centrin deleted Leishmania donovani (LdCen-/-) against visceral leishmaniasis has been reported extensively. The protection induced by LdCen-/- parasites was mediated by both CD4+ and CD8+ T cells. While the host immune mediators of protection are known, parasite determinants that affect the CD4+ and CD8+ T cell populations remain unknown. Parasite encoded inflammatory ...[more]

PMID: 37147351

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Project description:Currently, there is no vaccine against visceral leishmaniasis (VL). Toward developing an effective vaccine, we have reported extensively on the immunogenicity of live attenuated LdCentrin-/- mutants in naive animal models. In VL endemic areas, asymptomatic carriers outnumber symptomatic cases of VL and are considered to be a reservoir of infection. Vaccination of asymptomatic cases represents a viable strategy to eliminate VL. Immunological correlates of protection thus derived might have limited applicability in conditions where the immunized host has prior exposure to virulent infection. To examine whether LdCen-/- parasites can induce protective immunity in experimental hosts that have low-level parasitemia from a previous exposure mimicking an asymptomatic condition, we infected C57Bl/6 mice with wild-type Leishmania donovani parasites expressing LLO epitope (LdWT LLO 103, i.v.). After 3 weeks, the mice with low levels of parasitemia were immunized with LdCen-/- parasites expressing 2W epitope (LdCen-/-2W 3 × 106 i.v.) to characterize the immune responses in the same host. Antigen experienced CD4+ T cells from the asymptomatic (LdWT LLO infected) LdCen-/-2W immunized, and other control groups were enriched using LLO- and 2W-specific tetramers, followed by Flow cytometric analysis. Our analysis showed that comparable CD4+ T cell proliferation and CD4+ memory T cell responses (TCM) represented by CD62Lhi, CCR7+, and IL-7R+ T cell populations were induced with LdCen-/-2W in both asymptomatic and naive animals that received LdCen-/- immunization. Upon restimulation with peptide, TCM cells differentiated into effector T cells and there was no significant difference in the recall response in animals with asymptomatic infection. Following virulent challenge, comparable reduction in splenic parasite burden was observed in both asymptomatic and naive LdCen-/- immunized animals concomitant with the development of multifunctional CD4+ and CD8+ T cells. Further, LdCen-/-2W immunization resulted in complete clearance of the preexisting asymptomatic infection (LdWT LLO ). Our results demonstrate that LdCen-/-2W immunization could be efficacious for use in asymptomatic VL individuals. Further, immunization with LdCen-/- could help in reducing the parasite burden in the asymptomatic cases and aid in controlling the VL in endemic areas.

Dataset Information

Deletion of MIF gene from live attenuated LdCen^-/- parasites enhances protective CD4⁺ T cell immunity.

Publications

Deletion of MIF gene from live attenuated LdCen<sup>-/-</sup> parasites enhances protective CD4<sup>+</sup> T cell immunity.

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