Dataset Information

Increased amphiregulin expression by CD4⁺ T cells from individuals with asymptomatic Leishmania donovani infection.

ABSTRACT:

Objectives

There is an urgent need to be able to identify individuals with asymptomatic Leishmania donovani infection, so their risk of progressing to VL and transmitting parasites can be managed. This study examined transcriptional markers expressed by CD4⁺ T cells that could distinguish asymptomatic individuals from endemic controls and visceral leishmaniasis (VL) patients.

Methods

CD4⁺ T cells were isolated from individuals with asymptomatic L. donovani infection, endemic controls and VL patients. RNA was extracted and RNAseq employed to identify differentially expressed genes. The expression of one gene and its protein product during asymptomatic infection were evaluated.

Results

Amphiregulin (AREG) was identified as a distinguishing gene product in CD4⁺ T cells from individuals with asymptomatic L. donovani infection, compared to VL patients and healthy endemic control individuals. AREG levels in plasma and antigen-stimulated whole-blood assay cell culture supernatants were significantly elevated in asymptomatic individuals, compared to endemic controls and VL patients. Regulatory T (Treg) cells were identified as an important source of AREG amongst CD4⁺ T-cell subsets in asymptomatic individuals.

Conclusion

Increased Treg cell AREG expression was identified in individuals with asymptomatic L. donovani infection, suggesting the presence of an ongoing inflammatory response in these individuals required for controlling infection and that AREG may play an important role in preventing inflammation-induced tissue damage and subsequent disease in asymptomatic individuals.

SUBMITTER: Singh SS

PROVIDER: S-EPMC9136704 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Increased amphiregulin expression by CD4<sup>+</sup> T cells from individuals with asymptomatic <i>Leishmania donovani</i> infection.

Singh Siddharth Sankar SS Chauhan Shashi Bhushan SB Ng Susanna Ss SS Corvino Dillon D de Labastida Rivera Fabian F Engel Jessica A JA Waddell Nic N Mukhopadhay Pamela P Johnston Rebecca L RL Koufariotis Lambros T LT Nylen Susanne S Prakash Singh Om O Engwerda Christian R CR Kumar Rajiv R Sundar Shyam S

Clinical & translational immunology 20220527 6

<h4>Objectives</h4>There is an urgent need to be able to identify individuals with asymptomatic <i>Leishmania donovani</i> infection, so their risk of progressing to VL and transmitting parasites can be managed. This study examined transcriptional markers expressed by CD4<sup>+</sup> T cells that could distinguish asymptomatic individuals from endemic controls and visceral leishmaniasis (VL) patients.<h4>Methods</h4>CD4<sup>+</sup> T cells were isolated from individuals with asymptomatic <i>L</i ...[more]

PMID: 35663920

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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.

Project description:BackgroundVisceral leishmaniasis is endemic in Ethiopia and caused by Leishmania donovani. Although the disease manifests with significant clinical variability, a substantial number of individuals are asymptomatic. These individuals can serve as reservoirs, complicating control efforts. However, comprehensive data on asymptomatic L. donovani infections in Ethiopia are lacking, highlighting the need for a systematic review and meta-analysis to consolidate evidence and understand the distribution and determinants of this infection.MethodsPRISMA guidelines followed and registered with PROSPERO (CRD42024531454). Systematically searched electronic databases and grey literature sources up to April 13, 2024. Original research articles in English considered. Statistical analyses performed using STATA version 16. Publication bias evaluated using funnel plots and Egger's regression tests. Pooled estimate of asymptomatic L. donovani infection derived using a random effects model. Study heterogeneity assessed using Chi-square (χ²)-based Q test (p < 0.1) and I² subgroup analysis and meta-regression conducted with significance set at p < 0.05.ResultA total of 1,288 articles were identified, with 11 studies met inclusion criteria. These studies, published between 2012 and 2024, reported data from 17 districts across six regions. Sample sizes ranged from 185 to 1,682, with a total of 7,288. Six types of laboratory testing methods were employed. Prevalence of asymptomatic L. donovani infection per individual study ranged from 0.9 to 15.8%, while district-level prevalence varied from 0 to 31.1%. The overall pooled estimate of asymptomatic L. donovani infection in Ethiopia was 9.0% (95% CI: 6.0-11.0%). The pooled estimate in the Amhara region was 9.0% (95% CI: 8.0-11.0%), compared to 7.0% (95% CI: 3.0-12.0%) in other regions. Living in a household with domestic animals (OR: 2.54; 95% CI: 1.43-3.64) and being male (OR: 2.22; 95% CI: 1.21-3.23) were significantly associated with higher asymptomatic L. donovani infection.ConclusionA considerable number of asymptomatic L. donovani infections were reported in Ethiopia. Close contact with domestic animals and being male were identified as significant risk factors. Regular screening of people living in close contact with animals. This will minimize role of man as reservoir host of asymptomatic L. donovani infection VL and hence aid in disease control and management.

Project description:Ly6Chi inflammatory monocytes develop in the bone marrow and migrate to the site of infection during inflammation. Upon recruitment, Ly6Chi monocytes can differentiate into dendritic cells or macrophages. According to the tissue environment they can also acquire different functions. Several studies have described pre-activation of Ly6Chi monocytes in the bone marrow during parasitic infection, but whether this process occurs during experimental visceral leishmaniasis and, if so, the mechanisms contributing to their activation are yet to be established. In wild type C57BL/6 (B6) mice infected with Leishmania donovani, the number of bone marrow Ly6Chi monocytes increased over time. Ly6Chi monocytes displayed a highly activated phenotype from 28 days to 5 months post infection (p.i), with >90% expressing MHCII and >20% expressing iNOS. In comparison, in B6.Rag2 -/- mice <10% of bone marrow monocytes were MHCII+ at day 28 p.i., an activation deficiency that was reversed by adoptive transfer of CD4+ T cells. Depletion of CD4+ T cells in B6 mice and the use of mixed bone marrow chimeras further indicated that monocyte activation was driven by IFNγ produced by CD4+ T cells. In B6.Il10 -/- mice, L. donovani infection induced a faster but transient activation of bone marrow monocytes, which correlated with the magnitude of CD4+ T cell production of IFNγ and resolution of the infection. Under all of the above conditions, monocyte activation was associated with greater control of parasite load in the bone marrow. Through reinfection studies in B6.Il10 -/- mice and drug (AmBisome®) treatment of B6 mice, we also show the dependence of monocyte activation on parasite load. In summary, these data demonstrate that during L. donovani infection, Ly6Chi monocytes are primed in the bone marrow in a process driven by CD4+ T cells and whereby IFNγ promotes and IL-10 limits monocyte activation and that the presence of parasites/parasite antigen plays a crucial role in maintaining bone marrow monocyte activation.

Dataset Information

Increased amphiregulin expression by CD4⁺ T cells from individuals with asymptomatic Leishmania donovani infection.

Objectives

Methods

Results

Conclusion

Publications

Increased amphiregulin expression by CD4<sup>+</sup> T cells from individuals with asymptomatic <i>Leishmania donovani</i> infection.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Increased amphiregulin expression by CD4+ T cells from individuals with asymptomatic Leishmania donovani infection.

Objectives

Methods

Results

Conclusion

Publications

Increased amphiregulin expression by CD4<sup>+</sup> T cells from individuals with asymptomatic <i>Leishmania donovani</i> infection.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Increased amphiregulin expression by CD4⁺ T cells from individuals with asymptomatic Leishmania donovani infection.