Analysis of chronic biological responses between host and fungus ball using a novel aspergilloma mouse model

Author:

R Hamashima1,2*, M Tashiro1,3, Y Nakano1, N Ashizawa4, K Takeda4, N Iwanaga4, K Nishi5, A Fujita3, T Takazono1,4, T Tanaka3, K Yamamoto4, H Liu9, Y Komohara8, A Furumoto6, K Yanagihara7, H Mukae4, SG Filler9, K Takayama2, K Izumikawa1,3

Author address:

1Department of Infectious Diseases, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

2Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

3Nagasaki University Infection Control and Education Center, Nagasaki University Hospital, Nagasaki, Japan

4Department of Respiratory Medicine, Nagasaki University Hospital, Nagasaki, Japan

5Department of Radioisotope Medicine, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan

6Nagasaki University Hospital Infectious Diseases Experts Training Center, Nagasaki University Hospital, Nagasaki, Japan

7Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan

8Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

9Division of Infectious Diseases, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance CA, United States of America

Full conference title:

10th Advances Against Aspergillosis and Mucormycosis

Date: 2 February 2022

Abstract:

Purpose:

The mechanism of the chronic biological responses against aspergilloma has been poorly understood due to the lack of appropriate animal models. Therefore, we attempted to create a new mouse model of aspergilloma and to analyze the chronic biological responses of the host to aspergilloma over a period of several months using this model.

 

Methods:

Live or heat-killed fungus ball which was prepared in vitro in advance was implanted in a subcutaneous air-filled cavity created in the back of the ICR mouse. Pre-immunization to Aspergillus fumigatus was performed in some mice by intraperitoneal administration of the homogenized solution of live fungus ball to mice for 1 month before implantation. Longitudinal histopathological and immunohistological examinations of the fungus ball and surrounding tissues were performed over a period of up to 5 months. We measured the concentration of galactomannan (GM) of fungus balls to quantify the changes in fungal load over time. To determine the extent of host cell damage by A. fumigatus dead hyphae, the 51Cr release assay was used. The characteristics of the macrophages (RAW 264.7 cell line) that phagocytosed the dead hyphae were examined with Oil-red-O stain in vitro.

 

Results:

We found that implantation of a live fungus ball resulted in tissue invasion even in the immunocompetent and immunized mouse. In contrast, implantation of a dead fungus ball

persisted for more than 3 months and showed pathological findings that mimic those of human aspergilloma, such as inflammatory cell infiltration to the fungus ball and angiogenesis in the cavity wall. The macrophages around the fungus ball were swollen with phagocytosis of the dead hyphae fragments. Consistent with the results of pathological observations, GM was continuously detected in the fungus balls for 3 months, although the fungal burden gradually decreased. The 51Cr release assay in vitro showed that bone marrow-derived macrophages in direct contact with dead A. fumigatus hyphae were damaged. Lipid staining using Oil-red-O revealed that RAW264.7 cells phagocytosed the dead hyphae were converted into foam cells.

 

Conclusion:

We have developed a novel aspergilloma mouse model in which the fungus ball can persist for more than 3 months. Using this model, we were able to observe part of the chronic biological responses to aspergilloma, which is composed of dead hyphae. We believe that this mouse model will be useful for understanding the elimination mechanisms of aspergilloma.

Abstract Number: 71

Conference Year: 2022

Link to conference website: https://aaam2022.org/

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