Biology subjects

Dey, N. S.

Publications and source records attributed to Dey, N. S..

5 recordsLinked to original sources

bioRxiv2025

Ontogeny-independent expression of LPCAT2 in granuloma macrophages during experimental visceral leishmaniasis

Granulomas are organized inflammatory lesions that form in response to persistent stimuli such as infections. Murine infection with Leishmania donovani results in the formation of granulomas around infected Kupffer cells in the liver and serves as a well-defined model of immune granuloma formation. The formation and resolution of granulomatous inflammation requires dynamic shifts in immune cell activation states, imposing significant metabolic demands. As mediators of energy homeostasis and cell signaling, lipids and lipid metabolism play a key role in regulating immune cell function during inflammation and the response to infection. However, the extent to which alterations in lipids are spatially linked to altered immune cell transcription has yet to be resolved. In this study, we performed a multimodal imaging analysis combining MALDI mass spectrometry, spatial and single cell transcriptomics, proteomics of flow-sorted macrophages and histopathology of L. donovani induced hepatic granulomas. Using this spatially-integrated approach, we identified LPCAT2-mediated membrane re-modelling of myeloid cells as a novel feature of these granulomas. Our study provides new insights into local immunometabolic changes associated with granuloma formation and macrophage activation.

immunology↗

bioRxiv2023

UVB modifies skin immune-stroma cross-talk and promotes effector T cell recruitment during cryptic Leishmania donovani infection

Many parasites of significant public health importance assume skin residency without causing overt pathlogy. How immune and stromal cells respond to such "cryptic" infections and how exposure to UVB alters such responses in poorly understood. We combined scRNA-seq, spatial transcriptomics and inferential network analysis to address these questions in a model of cryptic skin infection by Leishmania donovani. In infected C57BL/6 mice, p-selectin and CXCL12 interactions dominate intercellular communication between leucocytes, fibroblast and endothelial cells, but effector T cell function remains muted. Following UVB exposure, increased numbers of IFN{gamma}+ CD4+ Th1 cells and NK cells enter the skin, communicating with stromal cells via CCL5-CCR5 and LFA-1-ICAM1/2. However, spatial mapping indicated that Th1 cells and macrophages occupied distinct niches after UVB exposure, likely limiting effector function. Our data provide the first holistic view of the immune landscape during cryptic L. donovani infection and demonstrate how UVB exposure fundamentally reshapes this response. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/526940v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1238cbaorg.highwire.dtl.DTLVardef@ec350eorg.highwire.dtl.DTLVardef@18f412corg.highwire.dtl.DTLVardef@1ffd468_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

Interferon-γ-producing CD4+ T cells drive monocyte activation in the bone marrow during experimental Leishmania donovani infection.

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 IFN-{gamma} 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 IFN-{gamma} 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 IFN-{gamma} 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.

immunology↗

bioRxiv2021

Relish plays a dynamic role in the niche to modulate Drosophila bloodprogenitor homeostasis in development and infection.

Immune challenges demand the gearing up of basal hematopoiesis to combat infection. Little is known about how during development, this switch is achieved to take care of the insult. Here, we show that the hematopoietic niche of the larval lymph gland of Drosophila senses immune challenge and reacts to it quickly through the nuclear factor-{kappa}B (NF-{kappa}B), Relish, a component of the immune deficiency (Imd) pathway. During development, Relish is triggered by ecdysone signaling in the hematopoietic niche to maintain the blood progenitors. Loss of Relish causes an alteration in the cytoskeletal architecture of the niche cells in a Jun Kinase dependent manner, resulting in the trapping of Hh implicated in progenitor maintenance. Notably, during infection, downregulation of Relish in the niche tilts the maintenance program towards precocious differentiation, thereby bolstering the cellular arm of the immune response.

developmental biology↗

bioRxiv2020

Reduced expression of PD-L1 and IDO1 characterises early response to antimonial therapy in cutaneous leishmaniasis patients.

Cutaneous leishmaniasis (CL) is a chronic skin disease caused by Leishmania parasites and in Sri Lanka, CL is caused by L. donovani. Pentavalent antimonials (e.g. sodium stibogluconate; SSG) are first line drugs for CL, despite protracted and painful treatment regimens. Data from animal models indicate that the effectiveness of SSG requires drug-immune synergy, but mechanistic insight from patients is lacking. We studied whole blood and lesion transcriptomes from CL patients in Sri Lanka at presentation and during SSG treatment. In lesions, we identified differential expression of immune-related genes, including immune checkpoint molecules, after the onset of treatment whereas no differentially expressed genes were identified in whole blood. We confirmed reduced lesional PD-L1 and IDO1 protein expression on treatment in a second validation cohort, using digital spatial profiling and quantitative immunohistochemistry. Dual IHC-FISH revealed significantly higher expression of these immune checkpoint molecules on parasite-infected compared to non-infected lesional CD68+ monocytes / macrophages. Crucially, early reduction in PD-L1 but not IDO1 expression was predictive of rate of clinical cure and occurred in parallel with a reduction in parasite load. A multivariate cox proportional hazard model showed that patients with lower PD-L1 expression on treatment were more likely to cure earlier (HR= 4.88). Our data support a model whereby the initial anti-leishmanial activity of antimonial drugs alleviates checkpoint inhibition of T cell immunity, facilitating immune-drug synergism and clinical cure. Our findings demonstrate that PD-L1 expression can be used as an early predictor of clinical response to SSG treatment and support the use of PD-L1 inhibition as adjunct host directed therapy in Sri Lankan CL.

immunology↗