Biology subjects

Aufiero, M. A.

Publications and source records attributed to Aufiero, M. A..

3 recordsLinked to original sources

bioRxiv2024

An IFN-STAT1-CYBB Axis Defines Protective Plasmacytoid DC to Neutrophil Crosstalk During Aspergillus fumigatus Infection.

Aspergillus fumigatus is the most common cause of invasive aspergillosis (IA), a devastating infection in immunocompromised patients. Plasmacytoid dendritic cells (pDCs) regulate host defense against IA by enhancing neutrophil antifungal properties in the lung. Here, we define the pDC activation trajectory during A. fumigatus infection and the molecular events that underlie the protective pDC - neutrophil crosstalk. Fungus-induced pDC activation begins after bone marrow egress and results in pDC-dependent regulation of lung type I and type III IFN levels. These pDC-derived products act on type I and type III IFN receptor-expressing neutrophils and control neutrophil fungicidal activity and reactive oxygen species production via STAT1 signaling in a cell-intrinsic manner. Mechanistically, neutrophil STAT1 signaling regulates the transcription and expression of Cybb, which encodes one of five NADPH oxidase subunits. Thus, pDCs regulate neutrophil-dependent immunity against inhaled molds by controlling the local expression of a subunit required for NADPH oxidase assembly and activity in the lung. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/620079v2_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1394ccforg.highwire.dtl.DTLVardef@e1bb13org.highwire.dtl.DTLVardef@1c0f991org.highwire.dtl.DTLVardef@40d5db_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

GM-CSF-mediated epithelial-immune cell crosstalk orchestrates pulmonary immunity to Aspergillus fumigatus

Aspergillus fumigatus causes life-threatening mold pneumonia in immune compromised patients, particularly in those with quantitative or qualitative defects in neutrophils. While innate immune cell crosstalk licenses neutrophil antifungal activity in the lung, the role of epithelial cells in this process is unknown. Here, we find that that surfactant protein C (SPC)-expressing lung epithelial cells integrate infection-induced IL-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. Using in vivo models that distinguish the role of GM-CSF during acute infection from its homeostatic function in alveolar macrophage survival and surfactant catabolism, we demonstrate that epithelial-derived GM-CSF increases the accumulation and fungicidal activity of GM-CSF-responsive neutrophils, with the latter being essential for host survival. Our findings establish SPC+ epithelial cells as a central player in regulating the quality and strength of neutrophil-dependent immunity against inhaled mold pathogens. HIGHLIGHTSO_LIGM-CSF is essential for host defense against A. fumigatus in the lung C_LIO_LIIL-1 and IFN-{lambda} promote GM-CSF production by lung epithelial cells in parallel C_LIO_LIEpithelial cell-derived GM-CSF increases neutrophil accumulation and fungal killing capacity C_LIO_LIEpithelial cells preferentially upregulate GM-CSF in local sites of inflammation C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/574062v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@708497org.highwire.dtl.DTLVardef@11106f7org.highwire.dtl.DTLVardef@e08140org.highwire.dtl.DTLVardef@1459e89_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2020

During Aspergillus infection, neutrophil, monocyte-derived DC, and plasmacytoid DC enhance innate immune defense through CXCR3-dependent crosstalk

Aspergillus fumigatus, a ubiquitous mold, is a common cause of invasive aspergillosis (IA) in immunocompromised patients. Host defense against IA relies on lung-infiltrating neutrophils and monocyte-derived dendritic cells (Mo-DCs). Here, we demonstrate that plasmacytoid dendritic cells (pDCs), which are prototypically anti-viral cells, participate in innate immune crosstalk underlying mucosal antifungal immunity. Aspergillus-infected murine Mo-DCs and neutrophils recruited pDCs to the lung by releasing the CXCR3 ligands, CXCL9 and CXCL10, in a Dectin-1/Card9- and type I and III interferon-signaling dependent manner, respectively. During aspergillosis, circulating pDCs entered the lung in response to CXCR3-dependent signals. Via targeted pDC ablation, we found that pDCs were essential for host defense in the presence of normal neutrophil and Mo-DC numbers. Although interactions between pDC and fungal cells were not detected, pDCs regulated neutrophil NADPH oxidase activity and conidial killing. Thus, pDCs act as positive feedback amplifiers of neutrophil effector activity against inhaled mold conidia.

immunology↗