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Cryptococcus gattii (Cg) is a facultative intracellular pathogen that can replicate and disseminate in mammalian macrophages, causing life-threatening cryptococcosis in both immunocompetent and immunocompromised individuals. Cryptococcus-macrophage interactions are crucial for cryptococcosis prognosis. However, the relationship between Cg pathogenicity and phagocytosis by macrophages has not yet been investigated in depth. In this study, a series of in vitro and in vivo experiments were conducted to investigate the interaction between macrophages and Cg. Flow cytometry was used to detect the phagocytic phenotypes of the Cg strains within macrophages. Scanning electron microscopy, transmission electron microscopy, and immunofluorescence were used to observe phagocytosis and proliferation, respectively. Survival and lung fungal burden tests were also performed. Our results show that Cg cells display different phagocytosis phenotypes, which are independent of the molecular type. Within macrophages, the high phagocytosis phenotype (HP) strains obtain higher intracellular proliferation than the low phagocytosis phenotype (LP) strains. At the early stage of infection in vivo, HP-inducing permissive granulomas within the lungs seldom limit the dissemination of cryptococci. In addition, HP strains could inhibit the formation of M1-type macrophages, proliferate intracellularly and disseminate extracellularly, and cause hypoxia induced by mucus and acidic polysaccharide accumulation in pulmonary alveoli much earlier than LP strains in vivo. Our work reveals that Cg displays diverse interactions with macrophages, which may enhance our understanding of the pathogenicity of this life-threatening pathogen.

Objective To investigate the potential pathogenesis and therapeutic targets for diabetic kidney disease (DKD) using renal genomic expression profile and the bioinformatics methods. Methods Genomic data of kidney from diabetic kidney disease patients and diabetic kidney disease mice model were selected from NCBI-GEO database. The data was analyzed by bioinformatics software to find differentially expressed genes (DEG). Gene ontology and ingenuity pathway analysis (IPA) were performed to find potential targets for DKD for elucidating the possible molecular mechanisms in DKD. Results Eighty-nine common DEG were identified from the human and mouse diabetic kidney disease database. Most of the DEG were mainly enriched in metabolism-related enzymes, transporters, nucleic acid binding proteins, and cell proliferation and extracellular matrix. The bioinformatics analysis of IPA showed that the common differentially expressed genes were mainly concentrated in the complement system, the primary immunodeficiency signaling and the B cell development, among them, the complement system is one of important regulatory pathways in diabetic kidney disease. Disease and biological function enrichment analysis showed that DKD was closely related to diabetes mellitu, glucose metabolism disorder, cell movement of blood cells, activation of blood cells and leukocyte migration. IPA regulatory network analysis revealed that proto-oncogene ETS1 and integrin β2 (ITGB) were two crucial sites identified by IPA bioinformatics analysis. Conclusion The potential site of diabetic kidney disease can be screened by using different species genomic data of diabetic kidney disease. Bioinformatics analysis shows that transcription factor ETS1 and ITGB might play a role in the pathogenesis of diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Managing renal fibrosis is challenging owing to the complex cell signaling redundancy in diseased kidneys. Renal fibrosis involves an immune response dominated by macrophages, which activates myofibroblasts in fibrotic niches. However, macrophages exhibit high heterogeneity, hindering their potential as therapeutic cell targets. Herein, we aimed to eliminate specific macrophage subsets that drive the profibrotic immune response in the kidney both temporally and spatially. We identified the major profibrotic macrophage subset (Fn1 + Spp1 + Arg1 + ) in the kidney and then constructed a 12-mer glycopeptide that was designated as bioactivated in vivo assembly PK (BIVA-PK) to deplete these cells. BIVA-PK specifically binds to and is internalized by profibrotic macrophages. By inducing macrophage cell death, BIVA-PK reshaped the renal microenvironment and suppressed profibrotic immune responses. The robust efficacy of BIVA-PK in ameliorating renal fibrosis and preserving kidney function highlights the value of targeting macrophage subsets as a potential therapy for patients with CKD., (© 2024. The Author(s), under exclusive licence to CSI and USTC.)

Cryptococcus gattii (Cg) is a facultative intracellular pathogen that can replicate and disseminate in mammalian macrophages, causing life-threatening cryptococcosis in both immunocompetent and immunocompromised individuals. Cryptococcus- macrophage interactions are crucial for cryptococcosis prognosis. However, the relationship between Cg pathogenicity and phagocytosis by macrophages has not yet been investigated in depth. In this study, a series of in vitro and in vivo experiments were conducted to investigate the interaction between macrophages and Cg. Flow cytometry was used to detect the phagocytic phenotypes of the Cg strains within macrophages. Scanning electron microscopy, transmission electron microscopy, and immunofluorescence were used to observe phagocytosis and proliferation, respectively. Survival and lung fungal burden tests were also performed. Our results show that Cg cells display different phagocytosis phenotypes, which are independent of the molecular type. Within macrophages, the high phagocytosis phenotype (HP) strains obtain higher intracellular proliferation than the low phagocytosis phenotype (LP) strains. At the early stage of infection in vivo , HP-inducing permissive granulomas within the lungs seldom limit the dissemination of cryptococci. In addition, HP strains could inhibit the formation of M1-type macrophages, proliferate intracellularly and disseminate extracellularly, and cause hypoxia induced by mucus and acidic polysaccharide accumulation in pulmonary alveoli much earlier than LP strains in vivo . Our work reveals that Cg displays diverse interactions with macrophages, which may enhance our understanding of the pathogenicity of this life-threatening pathogen.