Biology subjects

Abboud, Z.

Publications and source records attributed to Abboud, Z..

3 recordsLinked to original sources

bioRxiv2026

M-CSF stimulated alveolar macrophages safeguard from invasive aspergillosis

Invasive pulmonary aspergillosis (IPA) is a life-threatening complication in immunocompromised individuals, including recipients of allogeneic hematopoietic cell transplantation (allo-HCT). While systemic neutropenia is traditionally considered the primary risk factor for IPA, we demonstrate that tissue-resident alveolar macrophages (AMs), rather than recruited neutrophils, dictate survival during the critical early window after transplantation. Utilizing an ultra-low dose Aspergillus fumigatus infection model that mimics physiological exposure, we identify alveolar macrophages (AMs) as key players in pulmonary antifungal defense. In immunocompromised mice, AMs conferred protection against lethal invasive aspergillosis by day 6, but not day 4 post-allo-HCT. To enhance AM function at the earlier time point, we tested cytokine-based interventions and show that M-CSF, but not IL-34, which both bind to the CSF-1 receptor, promotes migratory activity, phagolysosomal function and fungal killing in both mouse and human primary tissue-resident AMs. In allo-HCT recipient mice, M-CSF treatment preserved lung tissue integrity, suppressed pro-inflammatory cytokines, and protected mice from lethal invasive aspergillosis. The M-CSF-driven protective effect was abrogated upon AM depletion. Our findings demonstrate a critical role of tissue-resident AMs in pulmonary antifungal immunity and suggest that therapeutic modulation of AM activity via M-CSF may offer a promising strategy to combat severe fungal infections in immunocompromised patients. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=107 SRC="FIGDIR/small/736478v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@49ba37org.highwire.dtl.DTLVardef@607c4forg.highwire.dtl.DTLVardef@814894org.highwire.dtl.DTLVardef@1c413c9_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Integrative phenotypic and transcriptomic validation of an alveolar-like macrophage model reveals early host-pathogen dynamics during Aspergillus fumigatus infection

Primary alveolar macrophages (pAMs) are essential for the rapid clearance of conidia and maintenance of pulmonary homeostasis. However, Aspergillus fumigatus remains the leading cause of invasive pulmonary aspergillosis in immunocompromised patients, and the mechanisms governing fungal clearance versus invasion remain poorly understood. Although, pAMs can be isolated from human donors, their broader application in in vitro infection studies is limited by their low availability and technical challenges with their maintenance in culture. In this study, we successfully adapted a previously established monocyte-derived alveolar-like macrophage (ALM) model to investigate early host-pathogen interactions upon A. fumigatus challenge. Given the requirement of GM-CSF for maintaining alveolar macrophage identity and function, we included GM-CSF differentiated macrophages (GM-M), as a widely employed reference model. Primary alveolar macrophages (pAM), isolated from human lung biopsies were utilized to validate the physiological relevance of the ALM model. Combined phenotypic, transcriptomic and functional analyses demonstrated that ALMs closely resemble pAMs under both steady-state and infection conditions across multiple time points and fungal burdens. Notably, fungal dual RNA-sequencing revealed a significant upregulation of fungal virulence-associated factors during interaction with ALM, which was not observed in our GM-M co-cultures. Collectively, these findings support the use of ALMs as a robust, experimentally accessible and physiologically relevant in vitro model for investigating early A. fumigatus infection, providing new insights into host-pathogen dynamics at the alveolar interface.

microbiology↗

bioRxiv2025

Secondary lymphoid organ endothelial cells prime alloreactive CD4+ T cells to trigger acute graft-versus-host disease

Donor CD4 T cell priming is a pivotal determinant of acute graft-versus-host disease (aGvHD) after allogeneic hematopoietic cell transplantation (allo-HCT). While professional hematopoietic antigen-presenting cells (APCs) have long been implicated in the pathogenesis of aGvHD, the contribution of non-hematopoietic APCs has remained unclear. Here, we show that naive alloreactive CD4 T cells initially localize and activate specifically within secondary lymphoid organs (SLOs) before infiltrating target tissues. Using genetic models to selectively ablate MHC class II on endothelial cells (ECs) or hematopoietic cells, we demonstrate that blood endothelial cells (BECs) in SLOs function as APCs, efficiently processing and presenting antigen to prime donor CD4 T cells. Deletion of MHC class II (MHCII) specifically in ECs substantially attenuates T cell activation and protects mice from lethal aGvHD, whereas selective deletion of MHCII in lymphatic ECs has no effect. Likewise, selective deletion of MHCII in hematopoietic cells also protects mice against aGvHD, suggesting that both cell types contribute to pathogenic allogeneic T cells activation after allo-HCT. Mechanistically, IL-12/IFN{gamma} signaling upregulates MHC class II expression on BECs. These findings identify BECs in SLOs as initiators of alloreactive CD4 T cell responses and highlight a potential target for preventing aGvHD. HighlightsO_LIBlood endothelial cells in secondary lymphoid organs prime naive CD4 T cells to trigger acute GvHD. C_LIO_LIT cell activation occurs exclusively in secondary lymphoid organs before tissue infiltration. C_LIO_LIExpression of MHC class II only on endothelial cells is sufficient to drive lethal GvHD, independent of other antigen presenting cells. C_LIO_LIRegulation of MHC class II expression in blood endothelial cells by IL-12/IFN{gamma} offers the potential for new therapeutic targets and corroborates findings for existing therapeutics. C_LI

immunology↗