Neutralizing GM-CSF autoantibodies impair neutrophil antifungal effector function in a patient with aspergillosis.

Objectives: To present a putatively immunocompetent patient with locally invasive aspergillosis and neutralizing autoantibodies (Aabs) against granulocyte-macrophage colony-stimulating factor (GM-CSF) and to characterize GM-CSF Aab-mediated impairments in neutrophil anti-Aspergillus effector function.

Methods: Imaging studies and histological analyses of infected tissue were employed to diagnose sino-orbital aspergillosis and monitor antifungal treatment responses. Whole genome sequencing (WGS), dihydrorhodamine testing, and particle-based Aab detection were employed to assess for the underlying etiology of fungal disease.

GM-CSF-mediated epithelial-immune cell cross-talk orchestrates pulmonary immunity to .

causes life-threatening mold pneumonia in immunocompromised patients, particularly in those with quantitative or qualitative defects in neutrophils. Whereas innate immune cell cross-talk licenses neutrophil antifungal activity in the lung, the role of epithelial cells in this process is unknown. Here, we find that surfactant protein C (SPC)-expressing lung epithelial cells integrate infection-induced interleukin-1 and type III interferon signaling to produce granulocyte-macrophage colony-stimulating factor (GM-CSF) preferentially at local sites of fungal infection and neutrophil influx.

The Gcn5 lysine acetyltransferase mediates cell wall remodeling, antifungal drug resistance, and virulence of .

Unlabelled: has emerged as a multidrug-resistant human fungal pathogen that causes infections of high morbidity and mortality. However, the molecular mechanisms underlying pronounced multidrug resistance and host-pathogen interactions are poorly understood. Here, we show that lysine acetyltransferase is essential for cell wall remodeling, antifungal drug resistance, and virulence.

mSphere of Influence: Complement activity beyond systemic circulation-implications in the context of infections.

Jigar V. Desai works in the field of immunology, studying the mucosal and systemic complement systems and their roles in regulating the immune response. In this mSphere of Influence article, he reflects on how the papers by the Kemper, Kulkarni, and Kasper laboratories made an impact on his ongoing work investigating the cell-intrinsic and extrinsic regulation of complement and studying its impacts on mucosal and systemic immunity.

A multidimensional assessment of in-host fitness costs of drug resistance in the opportunistic fungal pathogen Candida glabrata.

Drug-resistant microbes typically carry mutations in genes involved in critical cellular functions and may therefore be less fit under drug-free conditions than susceptible strains. Candida glabrata is a prevalent opportunistic yeast pathogen with a high rate of fluconazole resistance (FLZR), echinocandin resistance (ECR), and multidrug resistance (MDR) relative to other Candida. However, the fitness of C.

The Hog1 MAP kinase is essential for the colonization of murine skin and intradermal persistence.

Unlabelled: , a multidrug-resistant human fungal pathogen, was first identified in 2009 in Japan. Since then, systemic infections have now been reported in more than 50 countries, with mortality rates of 30%-60%. A major contributing factor to its high inter- and intrahospital clonal transmission is that unlike most species, displays unique skin tropism and can stay on human skin for a prolonged period.

The Influence of Body Fat Dynamics on Pulmonary Immune Responses in Murine Tuberculosis: Unraveling Sex-Specific Insights.

The World Health Organization (WHO) highlights a greater susceptibility of males to tuberculosis (TB), a vulnerability attributed to sex-specific variations in body fat and dietary factors. Our study delves into the unexplored terrain of how alterations in body fat influence () burden, lung pathology, immune responses, and gene expression, with a focus on sex-specific dynamics. Utilizing a low-dose -HN878 clinical strain infection model, we employ transgenic FAT-ATTAC mice with modulable body fat to explore the impact of fat loss (via fat ablation) and fat gain (via a medium-fat diet, MFD).

BTK drives neutrophil activation for sterilizing antifungal immunity.

We describe a previously unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used for treating B cell lymphoid malignancies. We studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, patients who were treated with BTKi, and X-linked agammaglobulinemia patients. Upon fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcγR-dependent manner, triggering the oxidative burst.

The Hog1 MAP kinase is essential for the colonization of murine skin and intradermal persistence.

Unlabelled: , a multidrug-resistant human fungal pathogen, was first identified in 2009 in Japan. Since then, systemic infections have now been reported in more than 50 countries, with mortality rates of 30-60%. A major contributing factor to its high inter- and intrahospital clonal transmission is that unlike most species, displays unique skin tropism and can stay on human skin for a prolonged period.

Evaluation of murine renal phagocyte-fungal interactions using intravital confocal microscopy and flow cytometry.

Myeloid phagocytes are essential for antifungal host defense during systemic candidiasis. Here, we present a protocol for assessing phagocyte-fungal interactions in vivo in the kidney, the primary target organ of the murine systemic candidiasis model. We describe steps for intravital confocal microscopy and flow cytometry.

Overlooked petites are echinocandin tolerant, induce host inflammatory responses, and display poor fitness.

is a major fungal pathogen, which is able to lose mitochondria and form small and slow-growing colonies, called "petite." This attenuated growth rate has created controversies and questioned the clinical importance of petiteness. Herein, we have employed multiple omics technologies and mouse models to critically assess the clinical importance of petite phenotype.

Overlooked petites are echinocandin tolerant, induce host inflammatory responses, and display poor fitness.

Unlabelled: Small colony variants (SCVs) are relatively common among some bacterial species and are associated with poor prognosis and recalcitrant infections. Similarly, - a major intracellular fungal pathogen - produces small and slow-growing respiratory-deficient colonies, termed "petite." Despite reports of clinical petite .

C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection.

Systemic candidiasis is a common, high-mortality, nosocomial fungal infection. Unexpectedly, it has emerged as a complication of anti-complement C5-targeted monoclonal antibody treatment, indicating a critical niche for C5 in antifungal immunity. We identified transcription of complement system genes as the top biological pathway induced in candidemic patients and as predictive of candidemia.

pDC-like cells are pre-DC2 and require KLF4 to control homeostatic CD4 T cells.

Plasmacytoid dendritic cells (pDCs) have been shown to play an important role during immune responses, ranging from initial viral control through the production of type I interferons to antigen presentation. However, recent studies uncovered unexpected heterogeneity among pDCs. We identified a previously uncharacterized immune subset, referred to as pDC-like cells, that not only resembles pDCs but also shares conventional DC (cDC) features.

Network analysis of large-scale ImmGen and Tabula Muris datasets highlights metabolic diversity of tissue mononuclear phagocytes.

The diversity of mononuclear phagocyte (MNP) subpopulations across tissues is one of the key physiological characteristics of the immune system. Here, we focus on understanding the metabolic variability of MNPs through metabolic network analysis applied to three large-scale transcriptional datasets: we introduce (1) an ImmGen MNP open-source dataset of 337 samples across 26 tissues; (2) a myeloid subset of ImmGen Phase I dataset (202 MNP samples); and (3) a myeloid mouse single-cell RNA sequencing (scRNA-seq) dataset (51,364 cells) assembled based on Tabula Muris Senis. To analyze such large-scale datasets, we develop a network-based computational approach, genes and metabolites (GAM) clustering, for unbiased identification of the key metabolic subnetworks based on transcriptional profiles.

Efficacy of Cochleated Amphotericin B in Mouse and Human Mucocutaneous Candidiasis.

Candida albicans causes debilitating, often azole-resistant, infections in patients with chronic mucocutaneous candidiasis (CMC). Amphotericin B (AMB) resistance is rare, but AMB use is limited by parenteral administration and nephrotoxicity. In this study, we evaluated cochleated AMB (CAMB), a new oral AMB formulation, in mouse models of oropharyngeal candidiasis (OPC) and vulvovaginal candidiasis (VVC) and in patients with azole-resistant CMC.

Long-term antibiotic exposure promotes mortality after systemic fungal infection by driving lymphocyte dysfunction and systemic escape of commensal bacteria.

Antibiotics are a modifiable iatrogenic risk factor for the most common human nosocomial fungal infection, invasive candidiasis, yet the underlying mechanisms remain elusive. We found that antibiotics enhanced the susceptibility to murine invasive candidiasis due to impaired lymphocyte-dependent IL-17A- and GM-CSF-mediated antifungal immunity within the gut. This led to non-inflammatory bacterial escape and systemic bacterial co-infection, which could be ameliorated by IL-17A or GM-CSF immunotherapy.

Mitochondrial C5aR1 activity in macrophages controls IL-1β production underlying sterile inflammation.

While serum-circulating complement destroys invading pathogens, intracellularly active complement, termed the “complosome,” functions as a vital orchestrator of cell-metabolic events underlying T cell effector responses. Whether intracellular complement is also nonredundant for the activity of myeloid immune cells is currently unknown. Here, we show that monocytes and macrophages constitutively express complement component (C) 5 and generate autocrine C5a via formation of an intracellular C5 convertase.

Response to Comments on "Aberrant type 1 immunity drives susceptibility to mucosal fungal infections".

Puel and Casanova and Kisand . challenge our conclusions that interferonopathy and not IL-17/IL-22 autoantibodies promote candidiasis in autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy. We acknowledge that conclusive evidence for causation is difficult to obtain in complex human diseases.