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Passive Administration of Monoclonal Antibodies Against H. capsulatum and Others Fungal Pathogens
Published on: February 14, 2011
Histoplasma capsulatum manifests preferential invasion of phagocytic subpopulations in murine lungs
George S Deepe1, Reta S Gibbons, A George Smulian
1Veterans Affairs Hospital , Cincinnati, OH, USA. george.deepe@uc.edu
Abstract:
Numerous in vitro studies have demonstrated that Histoplasma capsulatum is engulfed by the diverse populations of phagocytic cells including monocytes/macrophages (Mphi), immature dendritic cells (DC), and neutrophils. The in vivo distribution of H. capsulatum has yet to be examined following an intrapulmonary challenge. To accomplish this goal, we engineered GFP into two genetically dissimilar strains of H. capsulatum, G217B and 186R. C57BL/6 mice were infected with each of these strains, and we analyzed the distribution of this fungus in the three major phagocytic populations on successive days. Yeast cells were found in all three populations of cells from Days 1 through 7. Proportionally, DC dominated at Day 1, whereas the majority of yeast cells was detected in neutrophils thereafter. Yeast cells were present in inflammatory and resident Mphi on Day 3, but on Day 7, they were chiefly in inflammatory Mphi. Yeast cells were predominantly in a CD11c(+intermediate/high), F4/80(-), CD11b(+), Ly-6C(+), CD205(+) DC population. Neutralization of TNF-alpha or IFN-gamma produced a significant redistribution of yeast cells. These results reveal the complex nature of intracellular residence of this fungus. Moreover, the findings demonstrate that there is a skewing in the subpopulations of cells that are infected, especially DC.
Insights
Histoplasma capsulatum yeast cells infect various immune cells in mice. Dendritic cells initially host the fungus, followed by neutrophils and macrophages, revealing complex fungal distribution.
Area of Science:
- Immunology
- Mycology
- Infectious Diseases
Background:
- In vitro studies show Histoplasma capsulatum is phagocytosed by monocytes/macrophages, dendritic cells, and neutrophils.
- The in vivo distribution of H. capsulatum within phagocytic populations after lung infection remains unexamined.
Purpose of the Study:
- To investigate the in vivo distribution of Histoplasma capsulatum within key phagocytic cell populations following an intrapulmonary challenge in mice.
- To characterize the specific subpopulations of infected cells, particularly dendritic cells.
Main Methods:
- Engineered two H. capsulatum strains (G217B, 186R) with GFP.
- Infected C57BL/6 mice and analyzed fungal distribution in monocytes/macrophages, dendritic cells, and neutrophils over seven days.
- Utilized flow cytometry to identify infected cell populations, including specific markers like CD11c, F4/80, CD11b, Ly-6C, and CD205.
- Neutralized TNF-alpha and IFN-gamma to assess their impact on fungal distribution.
Main Results:
- Yeast cells were detected in all three phagocytic populations from Day 1 to Day 7.
- Dendritic cells predominated on Day 1, with neutrophils becoming the primary host thereafter.
- Yeast cells were found in both inflammatory and resident macrophages on Day 3, shifting to predominantly inflammatory macrophages by Day 7.
- A specific dendritic cell population (CD11c(intermediate/high), F4/80(-), CD11b(+), Ly-6C(+), CD205(+)) was the main site of yeast cells.
- Neutralization of TNF-alpha and IFN-gamma significantly altered the distribution of yeast cells.
Conclusions:
- Histoplasma capsulatum exhibits complex intracellular residence patterns in vivo.
- There is a dynamic skewing in the subpopulations of phagocytic cells infected by H. capsulatum, with a notable preference for specific dendritic cell subsets.
