Elsevier

Current Opinion in Microbiology

Volume 40, December 2017, Pages 88-94
Current Opinion in Microbiology

The cause and effect of Cryptococcus interactions with the host

https://doi.org/10.1016/j.mib.2017.10.012Get rights and content

Upon Cryptococcus neoformans infection of the host lung, the fungus enters a nutrient poor environment and must adapt to a variety of host-specific stress conditions (temperature, nutrient limitation, pH, CO2). Fungal spores enter this milieu with limited nutritional reserves, germinate, and begin proliferating by budding as yeast. Although relatively little is known about the initial stages of infection, recent work has characterized changes that occur upon germination. This program and subsequent yeast-phase proliferation progress in a dynamic environment as host nutrient immunity responds to the infection via toxic accumulation or sequestration of essential micronutrients and innate immune cells are recruited to the site of infection. Adaptation to the host environment and evasion of the immune response through pathogenicity factor expression allows proliferation and dissemination to multiple sites throughout the body, including, most significantly for human disease, the central nervous system. Here we will discuss recent insights into mechanisms underlying C. neoformans interactions with the host during infection.

Section snippets

Initiation of infection by cryptococcal spores

Cryptococcus neoformans infection occurs via inhalation of desiccated yeast or spores, which germinate in the host lung (Figure 1) [1, 2, 3, 4]. Two recent studies from the Hull lab have significantly improved overall understanding of this transition [5, 6]. Barkal et al. developed a high throughput, computational method for in vitro spore germination and analysis [5]. They show that C. neoformans germination, defined as a switch from ovoid spores to round yeast, is a synchronous process

Cell cycle control in yeast phase virulence

While the importance of capsule and melanin for host evasion, immunomodulation, and stress resistance is well established, an emerging theme is the role of the cell cycle in regulating pathogenicity factor expression. The fundamental observation that, unlike model yeast, C. neoformans bud emergence can be uncoupled from DNA synthesis during host stress or nutrient limiting conditions (summarized in [11]) has clear morphological consequences. For example, Fu et al. showed that G2 arrested cells

Host condition dependent changes in C. neoformans

The question of how pathogenicity factor expression became integrated into cell cycle control remains unexplored, however the conserved role of Usv101 in regulating cell wall synthesis genes (AGS1 (α-glucan), CHS5 (chitin), and SKO1 (β-gucan)) in C. neoformans and the distantly related, non-periodic S. cerevisiae Usv1 suggest that Usv101 is a cell wall transcription factor that has co-opted pathogenicity factor expression pathways and been incorporated into cell cycle regulation. This link may

Surviving the warm-blooded host

Thermotolerance is essential to C. neoformans virulence, and recent findings have emphasized the requirement for calcineurin-Crz1 signalling [28], the unfolded protein response [29], and amino acid permeases [30]. Capsule synthesis induction by differences in temperature varies between C. neoformans strains [31]. Analysis of the signalling networks responsible for the increased thermotolerance of the SCH9 protein kinase mutant identified the heat shock transcription factor HSF1 to have both

The immune response and interaction with cryptococci

How the different aspects of the host immune system protect against cryptococcal infection is highly complex, and our understanding of normal immunity, and the defects in immuno-compromise, are still incomplete (reviewed in [36]). A critical area of investigation is pro-inflammatory activation of macrophages. Recent clinical studies have highlighted the complexity of the immunology associated with cryptococcal meningitis in HIV positive patients (reviewed in [37]) and increased clarity on the

Initiation of cryptococcal meningitis

Cryptococcal meningitis is the life-threatening form of cryptococcosis and requires the invasion of the central nervous system (CNS) by cryptococcal yeast. Three different mechanisms for CNS invasion have been identified: first, disruption of the blood vessel endothelium integrity, second, uptake and expulsion by blood vessel cells and third, Trojan horse invasion via host macrophages. The cryptococcal matrixmetalloprotease MPR1 has been implicated in CNS invasion and adherence to endothelia in

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

ERB is supported by an Anniversary Future Leaders Fellowship from the UK Biotechnology and Biological Research Council (BB/M014525/1). SAJ is supported by a Medical Research Council and Department for International Development Career Development Award Fellowship MR/J009156 and a Krebs Institute Fellowship.

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