Biology subjects

Sheta, D.

Publications and source records attributed to Sheta, D..

2 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↗