The mechanisms of latency in the context of C. neoformans infection remain poorly understood. Two reasons for this gap in knowledge are: 1) the lack of standardized criteria for defining latent cryptococcosis in animal models and 2) limited genetic and immunological tools available for studying host parameters against C. neoformans in non-murine models of persistent infection. In this study, we defined criteria required for latency in C. neoformans infection models and used these criteria to develop a murine model of persistent C. neoformans infection using clinical isolates. We analyzed infections with two clinical C. neoformans strains, UgCl223 and UgCl552, isolated from advanced HIV patients with cryptococcal meningitis. Our data show that the majority of C57BL/6 mice infected with the clinical C. neoformans isolates had persistent, stable infections with low fungal burden, survived beyond 90 days-post infection, exhibited weight gain, had no clinical signs of disease, and had yeast cells contained within pulmonary granulomas with no generalized alveolar inflammation. Infected mice exhibited stable relative frequencies of pulmonary immune cells during the course of the infection. Upon CD4+ T-cell depletion, the CD4DTR mice had significantly increased lung and brain fungal burden that resulted in lethal infection, indicating that CD4+ T-cells are important for control of the pulmonary infection and to prevent dissemination. Cells expressing the Tbet transcription factor were the predominant activated CD4 T-cell subset in the lungs during the latent infection. These Tbet-expressing T-cells had decreased IFNγ production, which may have implications in the capacity of the cells to orchestrate the pulmonary immune response. Altogether, these results indicate that clinical C. neoformans isolates can establish a persistent controlled infection that meets most criteria for latency; highlighting the utility of this new mouse model system for studies of host immune responses that control C. neoformans infections.
|Original language||English (US)|
|Journal||Frontiers in Cellular and Infection Microbiology|
|State||Published - Feb 2 2022|
Bibliographical noteFunding Information:
We thank J. Marina Yoder for technical assistance on this study. We thank Dr. Zhonghai Ding for mathematical assistance related to this study. We thank Dr. Marc Jenkins and Jennifer Walter for their help with the experiments performed using the Tbet-zsGreen FoxP3-RFP mice. We thank Virginia Godfrey for pathology consultation. Animal histopathology was performed by the Animal Histopathology & Laboratory Medicine Core at the University of North Carolina, which is supported in part by an NCI Center Core Support Grant (5P30CA016086-41) to the UNC Lineberger Comprehensive Cancer Center. We also thank the University of Minnesota Flow Cytometry Resource (UFCR) for technical assistance on this study.
This work was supported by the National Institutes of Health [R01AI134636, R01NS118538, and R21AI150303 to KN]. MD was supported by the National Institutes of Health [F30AI155292], a University of Minnesota Medical Student Training Program [T32GM008244], and a University of Minnesota Lung Biology Dinnaken Fellowship. DW was supported by a Center for Immunology Training Program [T32AI007313], a University of Minnesota Department of Microbiology Watson Fellowship, and a University of Minnesota Doctoral Dissertation Fellowship. KJ was supported by the National Institutes of Health [F31AI148047].
Copyright © 2022 Ding, Smith, Wiesner, Nielsen, Jackson and Nielsen.
- Cryptococcus neoformans
- adaptive immunity
- cryptococcal meningitis
- latent fungal infections
- pulmonary granulomas
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't