期刊
CELL COMMUNICATION AND SIGNALING
卷 12, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s12964-014-0051-0
关键词
Cryptococcus neoformans; Cryptococcal meningoencephalitis; Host immune response; Glucuronoxylomannan; Capsule production; Inositol transporters; Genome-wide transcriptome; Quantitative real-time PCR; Cellular networks; Immune pathways
类别
资金
- National Institute of Health [AI113368]
- American Heart Association grant [12SDG9110034]
- National Basic Research Program of China [2013CB531606]
- Chinese Natural Science Fund [31270180]
- Shanghai Key Laboratory of Molecular Medical Mycology Fund [20110001]
- National Natural Science Foundation [81371851, 81071316, 81271882]
- New Century Excellent Talents in Universities [NCET-11-0703]
Background: Cryptococcus neoformans is the most common cause of fungal meningitis among individuals with HIV/AIDS, which is uniformly fatal without proper treatment. The underlying mechanism of disease development in the brain that leads to cryptococcal meningoencephalitis remains incompletely understood. We have previously demonstrated that inositol transporters (ITR) are required for Cryptococcus virulence. The itr1a Delta itr3c Delta double mutant of C. neoformans was attenuated for virulence in a murine model of intra-cerebral infection; demonstrating that Itr1a and Itr3c are required for full virulence during brain infection, despite a similar growth rate between the mutant and wild type strains in the infected brain. Results: To understand the immune pathology associated with infection by the itr1a Delta itr3c Delta double mutant, we investigated the molecular correlates of host immune response during mouse brain infection. We used genome-wide transcriptome shotgun sequencing (RNA-Seq) and quantitative real-time PCR (qRT-PCR) methods to examine the host gene expression profile in the infected brain. Our results show that compared to the wild type, infection of mouse brains by the mutant leads to significant activation of cellular networks/pathways associated with host protective immunity. Most of the significantly differentially expressed genes (SDEG) are part of immune cell networks such as tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) regulon, indicating that infection by the mutant mounts a stronger host immune response compared to the wild type. Interestingly, a significant reduction in glucuronoxylomannan (GXM) secretion was observed in the itr1a Delta itr3c Delta mutant cells, indicating that inositol utilization pathways play a role in capsule production. Conclusions: Since capsule has been shown to impact the host response during Cryptococcus-host interactions, our results suggest that the reduced GXM production may contribute to the increased immune activation in the mutant-infected animals.
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