Unveil the transcriptional landscape at the Cryptococcus-host axis in mice and nonhuman primates

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.

Animal Models of Cryptococcus neoformans in Identifying Immune Parameters Associated With Primary Infection and Reactivation of Latent Infection

“…This is most likely due to the greater cost and housing requirements compared to other animal models ( 78 , 79 ). Most studies in non-human primates were conducted decades ago, but a recent 2019 study performed a transcriptome analysis of cynomolgus monkeys ( Macaca fascicularis ) and mice using RNA-Seq during acute C. neoformans infections ( 80 ). The authors found that only about 20 percent of the differentially expressed genes were shared between these two hosts during infection, and they suggested monkeys could be a better model than mice at recapitulating the human response to C. neoformans .…”

Immune Complex–Driven Generation of Human Macrophages with Anti-Inflammatory and Growth-Promoting Activity

“…Twelve of the top 30 transcripts induced by the addition of IC (Fig. 1B) have been reported to be associated with cell growth and differentiation, including AREG (42), LIF (38), DC-STAMP (39), INHBA (53), and OCSTAMP (54). The top 30 upregulated transcripts also included three MMPs (MMP1, MMP3, and MMP10) and five cytokine-like molecules (IL-10, LIF, CSF2, IL-36RN, and TSLP).…”

Reimagining the future of African brain health: Perspectives for basic research on the pathogenesis of cryptococcal meningitis

“…SnRNA-Seq offers a high resolution characterisation of the neuroimmune response different cell types, subtypes and activation states. A few studies have described successful characterisation of cell-type specific transcriptomic changes that occur in host cells during fungal infections, including C. neoformans ( Li et al., 2019 ; Liu et al., 2014 , 2015 ; Niemiec et al., 2017 ). A recent prolific study used snRNA-Seq to characterise transcriptomic biomarkers in patients who survived, against those who succumbed to cryptococcal immune reconstitution inflammatory syndrome ( Vlasova-St Louis et al., 2021b ).…”