Abstract
Pathogens and hosts require rapid modulation of virulence and defense mechanisms at the infection axis, but monitoring such modulations is challenging. In studying the human fungal pathogen Cryptococcus neoformans, mouse and rabbit infection models are often employed to shed light on the disease mechanisms but that may not be clinically relevant. In this study, we developed an animal infection model using the non-human primate cynomolgus monkey Macaca fascicularis. In addition, we systematically profiled and compared transcriptional responses between the infected mice and the cynomolgus monkey, using simultaneous or dual RNA next-generation sequencing. We demonstrated that there are shared but distinct transcriptional profiles between the two models following C. neoformans infection. Specifically, genes involved in immune and inflammatory responses are all upregulated. Osteoclastogenesis and insulin signaling are also significantly co-regulated in both models and disrupting an osteoclastogenesis-associated gene (OC-STAMP) or the insulin-signaling process significantly altered the host tolerance to C. neoformans. Moreover, C. neoformans was shown to activate metal sequestration, dampen the sugar metabolism, and control cell morphology during infection. Taking together, we described the development of a non-human primate model of cryptococcosis that allowed us to perform an in-depth analysis and comparison of transcriptome profiles during infections of two animal models and conceptually identify host genes important in disease responses. This study provides new insights in understanding fungal pathogenesis mechanisms that potentially facilitate the identification of novel drug targets for the treatment of cryptococcal infection.
Highlights
Microbial pathogens including fungi have evolved rapid and precise yet complex gene expression regulatory mechanisms to colonize hosts during infections [1,2,3]
Current animal models for studying pathogenic fungi are limited in mimicking the responses from humans
The development of a new Cryptococcus neoformans infection model using nonhuman primates and the utilization of simultaneous RNA sequencing analysis provide fast and clinically relevant research data allowing the identification of novel critical players from both the invading fungus and the host
Summary
Microbial pathogens including fungi have evolved rapid and precise yet complex gene expression regulatory mechanisms to colonize hosts during infections [1,2,3]. In studying cryptococcal pathogenesis mechanisms, forward genetics and murine infection models are often employed to assess factors involved in infection Such efforts have resulted in the identification of virulence-modulating genes involved in capsule and melanin production, morphological switching, metal homeostasis, and others [6,7,8,9,10,11]. Fungal insertion gene disruption plus a murine infection model have revealed that fungal iron and copper homeostasis play reciprocal functions at various host niches [9, 12, 13]. Such studies indicated that host cells might differentially manipulate metals during fungal infection but further investigation is limited by the approach. Additional limitations include that the mouse model may not be clinically relevant
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