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Updated: Sep 22, 2025
Passive Administration of Monoclonal Antibodies Against H. capsulatum and Others Fungal Pathogens
Published on: February 14, 2011
Notch regulates Histoplasma capsulatum clearance in mouse lungs during innate and adaptive immune response phases in
Shuo Huang1,2, George S Deepe2
1Department of Internal Medicine and Department of Pathology, Pathobiology and Molecular Medicine Program, University of Cincinnati College of Medicine, Cincinnati, USA.
Abstract:
The clearance of the pathogenic fungus, Histoplasma capsulatum, requires cooperation between innate and adaptive immunity. Since this organism is inhaled, lung macrophages and dendritic cells (DCs) are the first lines of defense. Moreover, DCs act as APCs to drive the education of type 1 Th cells to produce IFNγ, which contributes to the final elimination of H. capsulatum. In this study, we explored the importance of Notch signaling in host defenses using a mouse model of pulmonary histoplasmosis. We found up-regulation of Notch ligands (NLs) and Notch receptors (NRs) on phagocytes and IFNγ+ CD4+ T cells upon infection in lungs and lymph nodes. To ascertain the influence of Notch on the course of infection, we used a gamma-secretase inhibitor (GSI), LY-411,575, which inhibits NR downstream signaling. This compound impaired fungal clearance when given at the time of infection or 7 days after infection. However, GSI did not impact fungal clearance in mice with preexisting immunity. The dampened host defenses were associated with reduced differentiation and maturation of monocyte-derived DCs and elevatmonocyte-derived macrophage and alveolar macrophage polarization to M2. Our study reveals the critical nature of Notch signaling in maintaining control of this infectious agent.
Insights
Notch signaling is crucial for controlling Histoplasma capsulatum infection. Inhibiting this pathway impairs fungal clearance by affecting immune cell development and function.
Area of Science:
- Immunology
- Mycology
- Cell Biology
Background:
- Pulmonary histoplasmosis is caused by the inhaled fungus Histoplasma capsulatum.
- Effective clearance relies on innate and adaptive immune responses, particularly lung macrophages, dendritic cells (DCs), and T helper 1 (Th1) cells producing IFNγ.
- The role of Notch signaling in host defense against H. capsulatum was previously unclear.
Purpose of the Study:
- To investigate the role of Notch signaling in host defense during pulmonary histoplasmosis.
- To determine the impact of inhibiting Notch signaling on fungal clearance and immune cell function.
Main Methods:
- Utilized a mouse model of pulmonary histoplasmosis.
- Administered a gamma-secretase inhibitor (GSI) LY-411,575 to block Notch receptor signaling.
- Analyzed fungal burden, immune cell populations (macrophages, DCs), and T cell responses (IFNγ production).
Main Results:
- Notch ligands and receptors were upregulated on immune cells in infected lungs and lymph nodes.
- GSI treatment impaired H. capsulatum clearance when administered during active infection.
- Inhibition of Notch signaling led to reduced DC differentiation/maturation and increased M2 polarization of macrophages.
- Notch inhibition did not affect fungal clearance in mice with pre-existing immunity.
Conclusions:
- Notch signaling is essential for effective host defense against H. capsulatum.
- Disruption of Notch signaling compromises immune cell function, leading to impaired fungal clearance.
- Targeting Notch signaling may offer therapeutic strategies for histoplasmosis, particularly in early infection stages.
