Leishmania major Strain-Dependent Macrophage Activation Contributes to Pathogenicity in the Absence of Lymphocytes

Alshaweesh, Jalal; Nakamura, Ryô; Tanaka, Yuka; Hayashishita, Mizuki; Musa, Abu; Kikuchi, Mihoko; Inaoka, Daniel Ken; Hamano, Shinjiro

doi:10.1128/spectrum.01126-22

Cited by 7 publications

(4 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly a recent experimental study of CL by L . major has shown macrophage differentiation into different functional types in a strain dependent manner in the absence of lymphocytes, thus with direct implications on the innate response elicited [ 60 ]. It is likely that the local parasite also has such antigenic differences when compared to the typical isolates of the species, which has resulted in altered pathogenicity.…”

Section: Discussionmentioning

confidence: 99%

Cytokine and phenotypic cell profiles in human cutaneous leishmaniasis caused by Leishmania donovani

2023

View full text Add to dashboard Cite

Background The innate immune mediators are likely to influence the clinical phenotype of leishmaniasis by primary responses which limit or facilitate the spread of the parasite, as well as by modulating adaptive immunity. This study investigated the response of key innate immune cells in a focus which regularly reports localised cutaneous leishmaniasis (LCL) caused by Leishmania donovani, a species which typically causes visceral disease. Methods Peripheral blood mononuclear cell (PBMC) derived macrophages and dendritic cells from patients with LCL and healthy controls from endemic and non-endemic areas, were stimulated with soluble Leishmania antigen (SLA). Inflammatory mediators produced by macrophages (TNF-α/TGF-β/IL-10, ELISA; NO, Griess method) and dendritic cells (IL-12p70, IL-10, flowcytometry) and macrophage expression of surface markers of polarization, activation and maturation (flowcytometry) were determined at 24h, 48h and 72h and compared. Study was conducted prospectively from 2015–2019. Results Patient derived macrophages and dendritic cells produced higher levels of both pro and anti-inflammatory mediators compared to controls (p<0.05) with the best discrimination for active disease observed at 72h. Data demonstrated an early activation of macrophages and a subsequent pro-inflammatory bias, as indicated by temporal profiles of TNF-α/TGF-β and TNF-α/IL-10 ratios and higher proportions of classical (M1) macrophages. Higher TGF-β levels were observed in cells from patients with ulcerated or persistent lesions. Immune responses by cells derived from controls in endemic and non-endemic regions did not differ significantly from each other. Conclusions The overall immunophenotypic profile suggests that LCL observed in the country is the result of a balancing immune response between pro-inflammatory and regulatory mediators. The mediators which showed distinct profiles in patients warrant further investigation as potential candidates for immunotherapeutic approaches. A comparison with visceral leishmaniasis caused by the same species, would provide further evidence on the differential role of these mediators in the resulting clinical phenotype.

show abstract

Section: Discussionmentioning

confidence: 99%

Cytokine and phenotypic cell profiles in human cutaneous leishmaniasis caused by Leishmania donovani

2023

View full text Add to dashboard Cite

show abstract

“…The percentage of infection was determined by the equation . The infection index was determined by multiplying the percentage of infected macrophages by the mean of intracellular amastigotes per infected macrophage [114].…”

Section: Methodsmentioning

confidence: 99%

Ablation of telomerase reverse transcriptase inLeishmania majorresults in a senescent-like phenotype and loss of infectivity

Shiburah,

de Oliveira,

Bisetegn

et al. 2023

Preprint

View full text Add to dashboard Cite

The lack of efficient human vaccines and effective nontoxic drugs for leishmaniasis necessitates a search for new therapeutic targets. The telomere environment could provide potential targets against leishmaniasis. TERT, the telomerase reverse transcriptase component, has been on the radar for new therapeutic options against several diseases for more than two decades. In this study, we constructed a full deletion (LmTERT-/-) and an ORF disruption (LmN420) of the gene encoding the TERT component ofLeishmania major.LmTERT-/- andLmN420 parasites showed replicative and proliferative defects, growth impairment, cell cycle alterations, increased DNA damage, and progressive telomere shortening. Blockage of parasite altruism and the presence of autophagosomes characteristic of a senescent-like phenotype were also detected.LmTERT-/- andLmN420 parasites caused either micro lesion development or no visible lesions in mouse footpads and reduced infectivity in macrophages. While our checks to see if telomere erosion had reached theSCGgenes involved in lipophosphoglycan modification showed no changes, our proteomic assessment revealed a downregulation of a metacyclic-associated protein. Complementation of the knockout lineages using the WTLmTERT restored some of the lost phenotypes. Therefore, we speculate that the pleiotropic effects of the loss ofLmTERT advance the case for using it as a drug target against the parasite.

show abstract

“…IL-17A signaling induces macrophage activation in a unique manner that differs from other T cell-derived cytokines but also has an essential role in promoting skin inflammation alongside tissue resident nonimmune cells [ 85 , 86 ]. Furthermore, even without T cells, ILCs and NK cells appear involved in an IL-17-mediated neutrophil accumulation and classical macrophage activation in cutaneous leishmaniasis [ 87 ].…”

Section: Leishmaniasis: Immune Cells Crosstalk In Macrophage Polariza...mentioning

confidence: 99%

Leishmaniasis: Immune Cells Crosstalk in Macrophage Polarization

et al. 2023

View full text Add to dashboard Cite

Leishmaniasis is a complex infectious parasitic disease caused by protozoa of the genus Leishmania, belonging to a group of neglected tropical diseases. It establishes significant global health challenges, particularly in socio-economically disadvantaged regions. Macrophages, as innate immune cells, play a crucial role in initiating the inflammatory response against the pathogens responsible for this disease. Macrophage polarization, the process of differentiating macrophages into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes, is essential for the immune response in leishmaniasis. The M1 phenotype is associated with resistance to Leishmania infection, while the M2 phenotype is predominant in susceptible environments. Notably, various immune cells, including T cells, play a significant role in modulating macrophage polarization by releasing cytokines that influence macrophage maturation and function. Furthermore, other immune cells can also impact macrophage polarization in a T-cell-independent manner. Therefore, this review comprehensively examines macrophage polarization’s role in leishmaniasis and other immune cells’ potential involvement in this intricate process.

show abstract

Leishmania major Strain-Dependent Macrophage Activation Contributes to Pathogenicity in the Absence of Lymphocytes

Cited by 7 publications

References 90 publications

Cytokine and phenotypic cell profiles in human cutaneous leishmaniasis caused by Leishmania donovani

Cytokine and phenotypic cell profiles in human cutaneous leishmaniasis caused by Leishmania donovani

Ablation of telomerase reverse transcriptase inLeishmania majorresults in a senescent-like phenotype and loss of infectivity

Leishmaniasis: Immune Cells Crosstalk in Macrophage Polarization

Contact Info

Product

Resources

About