Lesional senescent CD4 T cells mediate bystander cytolysis and contribute to the skin pathology of human cutaneous leishmaniasis.

Cytotoxic activity is a hallmark of the immunopathogenesis in human cutaneous leishmaniasis (CL). In this study, we identified accumulation of CD4 granzyme B producing T cells with increased cytotoxic capacity in CL lesions. These cells showed enhanced expression of activating NK receptors (NKG2D and NKG2C), diminished expression of inhibitory NKG2A, along with the upregulation of the senescence marker CD57.

Senescence-related genes are associated with the immunopathology signature of American tegumentary leishmaniasis lesions and may predict progression to mucosal leishmaniasis.

The American tegumentary leishmaniasis (ATL) is caused by protozoans of the genus Leishmania and varies from mild localized cutaneous leishmaniasis (LCL) form to more severe manifestations such as the diffuse cutaneous leishmaniasis (DCL) form and the mucosal leishmaniasis (ML) form. Previously, we demonstrated the accumulation of senescent cells in skin lesions of patients with LCL. Moreover, lesional transcriptomic analyses revealed a robust co-induction of senescence and pro-inflammatory gene signatures, highlighting the critical role of senescent T cells in orchestrating pathology.

Canine Visceral Leishmaniasis: A Histological and Immunohistochemical Study of Fibropoiesis in Chronic Interstitial Pneumonitis.

We studied some fibrotic aspects of chronic interstitial pneumonitis in the lungs of dogs infected with . The lungs of eleven naturally infected dogs, twelve experimentally infected with two distinct strains of (BH401 and BH46), and six uninfected (controls) dogs, were analyzed by histological, parasitological, and immunohistochemical studies. Conventional histology (HE), collagen deposition (Gomori's silver staining for reticulin collagen fibers), and immunohistochemistry for myofibroblast characterization were carried out based on the cellular expression of alpha-smooth muscle actin, vimentin, cytokeratin, E-cadherin, snail antigen homologue 1 (SNAI1) (Snail), and the cytokine expression of transforming growth factor-beta (TGF-β).

NKG2C+CD57+ natural killer cells with senescent features are induced during cutaneous leishmaniasis and accumulate in patients with lesional healing impairment.

Natural killer (NK) cells include different subsets with diverse effector capacities that are poorly understood in the context of parasitic diseases. Here, we investigated inhibitory and activating receptor expression on NK cells in patients with cutaneous leishmaniasis (CL) and explored their phenotypic and functional heterogeneity based on CD57 and NKG2C expression. The expression of CD57 identified NK cells that accumulated in CL patients and exhibited features of senescence.

Isolation and Culture of Bone Marrow-Derived Macrophages from Mice.

Macrophages have important effector functions in homeostasis and inflammation. These cells are present in every tissue in the body and have the important ability to change their profile according to the stimuli present in the microenvironment. Cytokines can profoundly affect macrophage physiology, especially IFN-γ and interleukin 4, generating M1 and M2 types respectively.

Caspase-mediated cleavage of miRNA processing proteins Drosha, DGCR8, Dicer, and TRBP2 in heat-shocked cells and its inhibition by HSP70 overexpression.

Cells respond to stress through adaptive mechanisms that limit cellular damage and prevent cell death. MicroRNAs act as regulators of stress responses and stress can impact the functioning of miRNA biogenesis pathways. We were interested in the effect that severe proteotoxic stress capable of inducing apoptosis may have on miRNA biogenesis and the impact of the molecular chaperone protein HSP70 under these conditions.

Transcriptomic landscape of skin lesions in cutaneous leishmaniasis reveals a strong CD8 T cell immunosenescence signature linked to immunopathology.

The severity of lesions that develop in patients infected by Leishmania braziliensis is mainly associated with a highly cytotoxic and inflammatory cutaneous environment. Recently, we demonstrated that senescent T and NK cells play a role in the establishment and maintenance of this tissue inflammation. Here, we extended those findings using transcriptomic analyses that demonstrate a strong co-induction of senescence and pro-inflammatory gene signatures in cutaneous leishmaniasis (CL) lesions.

PD-1 Blockade Modulates Functional Activities of Exhausted-Like T Cell in Patients With Cutaneous Leishmaniasis.

Patients infected by develop debilitating skin lesions. The role of inhibitory checkpoint receptors (ICRs) that induce T cell exhaustion during this disease is not known. Transcriptional profiling identified increased expression of ICRs including PD-1, PDL-1, PDL-2, TIM-3, and CTLA-4 in skin lesions of patients that was confirmed by immunohistology where there was increased expression of PD-1, TIM-3, and CTLA-4 in both CD4 and CD8 T cell subsets.

Humoral immunity in leishmaniasis - Prevention or promotion of parasite growth?

Leishmaniasis can present as a "spectrum" of clinical outcomes. There is evidence that these divergent clinical outcomes are attributable to genetic differences in the human host [1] as well the species of infecting parasite [2]. The spectrum of disease has largely been described by defining the polar opposites of T cell immune responses.

High-Density-Immune-Complex Regulatory Macrophages Promote Recovery of Experimental Colitis in Mice.

Macrophages not only play a fundamental role in the pathogenesis of inflammatory bowel disease (IBD), but they also play a major role in preserving intestinal homeostasis. In this work, we evaluated the role of macrophages in IBD and investigated whether the functional reprogramming of macrophages to a very specific phenotype could decrease disease pathogenesis. Thus, macrophages were stimulated in the presence of high-density immune complexes which strongly upregulate their production of IL-10 and downregulate pro-inflammatory cytokines.

The transition of M-CSF-derived human macrophages to a growth-promoting phenotype.

Stimulated macrophages are potent producers of inflammatory mediators. This activity is highly regulated, in part, by resolving molecules to prevent tissue damage. In this study, we demonstrate that inflammation induced by Toll-like receptor stimulation is followed by the upregulation of receptors for adenosine (Ado) and prostaglandin E2 (PGE2), which help terminate macrophage activation and initiate tissue remodeling and angiogenesis.

Macrophages and the maintenance of homeostasis.

There have been many chapters written about macrophage polarization. These chapters generally focus on the role of macrophages in orchestrating immune responses by highlighting the T-cell-derived cytokines that shape these polarizing responses. This bias toward immunity is understandable, given the importance of macrophages to host defense.

Macrophage polarization in intestinal inflammation and gut homeostasis.

Gut homeostasis is a process that requires a prudent balance of host responses to the beneficial enteric microbial community and the pathogenic stimuli that can arise. The lack of this balance in the intestine can result in inflammatory bowel diseases, where the immune system dysfunctions leading to exacerbated inflammatory responses. In this process, macrophages are considered to play a pivotal role.

Immune Complex-Driven Generation of Human Macrophages with Anti-Inflammatory and Growth-Promoting Activity.

To maintain homeostasis, macrophages must be capable of assuming either an inflammatory or an anti-inflammatory phenotype. To better understand the latter, we stimulated human macrophages in vitro with TLR ligands in the presence of high-density immune complexes (IC). This combination of stimuli resulted in a broad suppression of inflammatory mediators and an upregulation of molecules involved in tissue remodeling and angiogenesis.

The dichotomous effects of caffeine on homologous recombination in mammalian cells.

This study was initiated to examine the effects of caffeine on the DNA damage response (DDR) and homologous recombination (HR) in mammalian cells. A 5 mM caffeine treatment caused the cell cycle to stall at G2/M and cells eventually underwent apoptosis. Caffeine exposure also induced a strong DDR along with subsequent activation of wildtype p53 protein.

Immunohistochemical study of renal fibropoiesis associated with dogs naturally and experimentally infected with two different strains of Leishmania (L.) infantum.

The objectives of this work were to study some pathological aspects of kidneys obtained from dogs naturally infected with Leishmania infantum and from dogs experimentally infected with two different strains of L infantum with special emphasis on fibrotic process. Seventy eight specimens of paraffin-embedded kidney fragments were collected as follows: (a) CNI group composed by 62 kidney samples of adult mongrel dogs, naturally infected with L infantum; (b) BH401 group composed by five kidney samples of adult Beagles experimentally infected with L infantum strain MCAN BR/2002/BH401; (c) BH400 group composed by eleven kidney samples of adult Beagles experimentally infected with L infantum strain MCAN/BR/2000/BH400, at the same dose and same route of the previous group, denominated group BH400; Control group (CC) composed by four kidney samples of adult Beagles. All animals revealed glomerular and interstitial fibropoiesis associated with different types of glomerulonephritis and chronic interstitial nephritis.

Regulatory Macrophages Inhibit Alternative Macrophage Activation and Attenuate Pathology Associated with Fibrosis.

Diversity and plasticity are the hallmarks of macrophages. The two most well-defined macrophage subsets are the classically activated macrophages (CAMϕs) and the IL-4-derived alternatively activated macrophages (AAMϕs). Through a series of studies, we previously identified and characterized a distinct population of macrophages with immunoregulatory functions, collectively termed regulatory macrophages (RMϕs).

Host and parasite responses in human diffuse cutaneous leishmaniasis caused by L. amazonensis.

Diffuse cutaneous leishmaniasis (DCL) is a rare form of leishmaniasis where parasites grow uncontrolled in diffuse lesions across the skin. Meta-transcriptomic analysis of biopsies from DCL patients infected with Leishmania amazonensis demonstrated an infiltration of atypical B cells producing a surprising preponderance of the IgG4 isotype. DCL lesions contained minimal CD8+ T cell transcripts and no evidence of persistent TH2 responses.

Monocyte subpopulations as important biomarkers of resistence and susceptibility during experimental infection with Leishmania (Leishmania) major.

Visceral Leishmaniasis is a chronic and lethal, parasitic disease. In the later infection stages, it is known that expressive hematological disorders can be observed, including changes in the frequency and phenotype of certain leukocytes. There is a lack of good prognostic indicators to characterize the on-goin clinical status of the patient.

Pro-inflammatory cytokine Interleukin-1β (IL-1β) controls Leishmania infection.

Leishmania is an obligate intracellular parasite uses low pH phagolysosomal compartments of host macrophages as their final abode. IL-1β is a pro inflammatory cytokine, which is secreted by immune cells to trigger inflammation and this has been found profoundly in the lesions caused by Leishmania pathogens. But the specific role of this cytokine on host cell macrophages during infection has not been fully explored.

Cardiolipin exposure on the outer mitochondrial membrane modulates α-synuclein.

Neuronal loss in Parkinson's disease (PD) is associated with aberrant mitochondrial function and impaired proteostasis. Identifying the mechanisms that link these pathologies is critical to furthering our understanding of PD pathogenesis. Using human pluripotent stem cells (hPSCs) that allow comparison of cells expressing mutant SNCA (encoding α-synuclein (α-syn)) with isogenic controls, or SNCA-transgenic mice, we show that SNCA-mutant neurons display fragmented mitochondria and accumulate α-syn deposits that cluster to mitochondrial membranes in response to exposure of cardiolipin on the mitochondrial surface.

Hepatic fibropoiesis in dogs naturally infected with Leishmania (Leishmania) infantum treated with liposome-encapsulated meglumine antimoniate and allopurinol.

Hepatic fibropoiesis in canine visceral leishmaniasis (CVL) were evaluated by histological (morphometrical collagen deposition) and immunohistochemical assays characterizing alpha-actin (α-SMA), vimentin, calprotectin (L1 antigen), and TGF-β in 46 naturally infected dogs with Leishmania infantum treated with liposome-encapsulated meglumine antimoniate and allopurinol separately and in combination. Six treatment groups were defined: meglumine antimoniate encapsulated in nanometric liposomes (LMA), allopurinol (ALLOP); liposome-encapsulated meglumine antomoniate combined with allopurinol (LMA+ALLOP); empty liposomes (LEMP); empty liposomes combined with allopurinol (LEMP+ALLOP) and saline. Relative liver weight was lower in LMA, LMA+ALLOP, and ALLOP groups compared to the LEMP control.

Using a Concept Inventory to Reveal Student Thinking Associated with Common Misconceptions about Antibiotic Resistance.

Misconceptions, also known as alternate conceptions, about key concepts often hinder the ability of students to learn new knowledge. Concept inventories (CIs) are designed to assess students' understanding of key concepts, especially those prone to misconceptions. Two-tiered CIs include prompts that ask students to explain the logic behind their answer choice.

Correction: Meta-transcriptome Profiling of the Human-Leishmania braziliensis Cutaneous Lesion.

[This corrects the article DOI: 10.1371/journal.pntd.