Thermotolerance in the pathogen Cryptococcus neoformans is linked to antigen masking via mRNA decay-dependent reprogramming

Bloom, Amanda L. M.; Jin, Richard; Leipheimer, Jay; Bard, Jonathan; Yergeau, Donald; Wohlfert, Elizabeth A.; Panepinto, John C.

doi:10.1038/s41467-019-12907-x

Cited by 48 publications

(66 citation statements)

References 38 publications

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“…Another environmental Cryptococcus species, C. amylolentus, is deficient in thermotolerance, and like our ccr4D mutant, also unmasks b-1,3-glucan at 37 o C (Bloom et al, 2019). In addition, C. amylolentus fails to repress abundant ribosomal protein (RP) transcripts, which is necessary for reprogramming the translatome in response to temperature stress.…”

Section: Introductionmentioning

confidence: 73%

“…One of these traits, thermotolerance, is required for mammalian infection. Previous work in our laboratory has implicated deadenylation-dependent mRNA decay mediated by Ccr4 in promoting adaptation to host temperature (Havel et al, 2011;Bloom et al, 2013;Bloom et al, 2019). This work suggests that reprogramming of the mRNAs associated with translating ribosomes, the translatome, is a prerequisite for temperature adaptation (Bloom et al, 2019).…”

Section: Introductionmentioning

confidence: 75%

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Glucan unmasking identifies regulators of temperature-induced translatome reprogramming inC. neoformans

Bloom

Goich

Knowles

et al. 2020

Preprint

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The cell walls of fungi are critical for cellular structure and rigidity, but also serve as a major communicator to alert the cell of the changing environment. In response to stresses encountered in human hosts pathogenic fungi remodel their cell walls. Masking the b-1,3-glucan component of the cell wall is critical to escape detection by innate immune cells. We previously demonstrated that b-1,3-glucan is unmasked in response to host temperature stress when translatome reprogramming is defective in C. neoformans. Here, we used b-1,3-glucan unmasking as an output to identify signaling modules involved both in masking and translatome reprogramming in response to host temperature stress. We reveal that the High Osmolarity Glycerol (HOG) MAPK pathway is involved in translatome reprogramming and that mutants in this pathway display moderate unmasking when grown at 37°C. Additionally, we show that mutants of the Cell Wall Integrity/Mpk1 MAPK pathway extensively unmask b-1,3-glucan. While the CWI pathway does not impact translatome reprogramming, our data suggest it may play a role in the post-translational regulation of transcription factors that govern masking.ImportanceCryptococcus neoformans is a fungal pathogen that causes devastating morbidity and mortality in immunocompromised individuals. It possesses several virulence factors that aid in its evasion from the host immune system including a large polysaccharide capsule that cloaks the antigenic cell wall. Studies investigating how the cell wall is remodeled to keep this pathogen disguised in response to stress have been limited. We previously found that host temperature stress results in translatome reprogramming that is necessary for keeping the highly antigenic β-(1,3)-glucan component masked. Our data reveals signaling modules that trigger these responses and suggest the points of regulations at which these pathways act in achieving masking. Understanding these mechanisms may allow for therapeutic manipulation that could promote immune recognition and clearance of this fungal pathogen.

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Section: Introductionmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 75%

Glucan unmasking identifies regulators of temperature-induced translatome reprogramming inC. neoformans

Bloom

Goich

Knowles

et al. 2020

Preprint

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“…These changes in the cell wall composition and exposure of different carbohydrates play meaningful roles in the immune recognition by the host and activate various signaling events in the host system (43). Another example is the enhanced recognition of the ccr4 Δ mutant by alveolar macrophages due to increased unmasking of the β -1,3-glucan (44). The importance of Ccr4, an mRNA deadenylase, in glucan masking is further evidence that post-transcriptional processes are essential for adaptation to a number of stressors, including caspofungin treatment.…”

Section: Discussionmentioning

confidence: 99%

Puf4 Mediates Post-transcriptional Regulation of Caspofungin Resistance inCryptococcus neoformans

Kalem

Subbiah

Leipheimer

et al. 2020

Preprint

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24Echinocandins have been on the market for 20 years, yet they are the newest class of 25 antifungal drugs. The human fungal pathogen Cryptococcus neoformans is intrinsically resistant 26 to the echinocandin antifungal drug caspofungin, which targets the b-1,3-glucan synthase 27 encoded by the FKS1. Analysis of a C. neoformans puf4∆ mutant, lacking the pumilio/FBF RNA 28 binding protein family member Puf4, revealed exacerbated caspofungin resistance. In contrast, 29 overexpression of PUF4 resulted in caspofungin sensitivity. The FKS1 mRNA contains three 30 Puf4-binding elements (PBEs) in its 5' untranslated region. Puf4 binds with specificity to this 31 region of the FKS1. The FKS1 mRNA was destabilized in the puf4∆ mutant, and the abundance 32 of the FKS1 mRNA was reduced compared to wild type, suggesting that Puf4 is a positive 33 regulator FKS1 mRNA stability. In addition to FKS1, the abundance of additional cell wall 34 biosynthesis genes, including chitin synthases (CHS3, CHS4, CHS6) and deacetylases (CDA1, 35 CDA2, CDA3) as well as a b-1,6-glucan synthase gene (SKN1) was regulated by Puf4 during a 36 caspofungin time course. The use of fluorescent dyes to quantify cell wall components revealed 37 that the puf4∆ mutant had increased chitin content, suggesting a cell wall composition that is 38 less reliant on b-1,3-glucan. Overall, our findings suggest a mechanism by which caspofungin 39 resistance, and more broadly, cell wall biogenesis, is regulated post-transcriptionally by Puf4. 40 41 Importance 42 Cryptococcus neoformans is an environmental fungus that causes pulmonary and central 43 nervous system infections. It is also responsible for 15% of AIDS-related deaths. A major 44 contributor to the high morbidity and mortality statistics is the lack of safe and effective 45 antifungal therapies, especially in resource-poor settings. Yet, antifungal drug development has 46 stalled in the pharmaceutical industry. Therefore, it is of importance to understand the mechanism by which C. neoformans is resistant to caspofungin in order to design adjunctive 48 therapies to potentiate its activity toward this important pathogen. 50 Introduction 51Invasive deep mycoses primarily impact immunocompromised populations causing high rates of 52 morbidity and mortality (1, 2). The pathogenic fungus Cryptococcus neoformans is the causative 53 agent of fatal meningitis most often in patients with defects in cell mediated immunity, including 54 transplant recipients and those living with HIV/AIDS (3-6). C. neoformans is responsible of the 55 15% of AIDS-related deaths (6). Treatment of cryptococcosis is difficult and therapeutic options 56 are limited. Even the best combination treatment using Amphotericin B with 5-fluorocytosine (5-57 FC) is not well tolerated, and 5-FC is often unavailable in resource-poor areas (7). Some of the 58 largest clinal challenges to invasive fungal infections are poor efficacy of the drugs, emerging 59 resistance issues, narrow selection and availability of antifungals especially in the areas where...

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“…It increases the expression of other cell wall components such that the β-glucans, which activate host macrophages are concealed. 28,40 3.1.2 | Immune alteration and cytotoxicity by C. neoformans C. neoformans infection usually begins with inhalation of spores from the environment. 4 Invasion of C. neoformans in the host cells leads to damaging effects associated with the alteration of cellular compartments.…”

Section: Proteasesmentioning

confidence: 99%

“…C. amylolentus is also considered an important model for analyzing the molecular processes that are essential for host-temperature adjustment by genus Cryptococcus. 40…”

Section: Cryptococcus Gattiimentioning

confidence: 99%

Diverse species in the genus Cryptococcus: Pathogens and their non‐pathogenic ancestors

2020

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The genus Cryptococcus comprises of more than 30 species. It consists of clinically significant pathogenic Cryptococcus neoformans/Cryptococcus gattii species complex comprising of a minimum of seven species. These pathogens cost more than 200,000 lives annually by causing cryptococcal meningoencephalitis. The evolution of the pathogenic species from closely related nonpathogenic species of the Cryptococcus amylolentus complex is of particular importance and several advances have been made to understand their phylogenetic and genomic relationships. The current review briefly describes the sexual reproduction process followed by an individual description of the members focusing on their key attributes and virulence mechanisms of the pathogenic species. A special section on phylogenetic studies is aimed at understanding the evolutionary divergence of pathogens from non-pathogens. Recent findings from our group pertaining to parameters affecting codon usage bias in six pathogenic and three non-pathogenic ancestral species and their corroboration with existing phylogenetic reports are also included in the current review.

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Thermotolerance in the pathogen Cryptococcus neoformans is linked to antigen masking via mRNA decay-dependent reprogramming

Cited by 48 publications

References 38 publications

Glucan unmasking identifies regulators of temperature-induced translatome reprogramming inC. neoformans

Glucan unmasking identifies regulators of temperature-induced translatome reprogramming inC. neoformans

Puf4 Mediates Post-transcriptional Regulation of Caspofungin Resistance inCryptococcus neoformans

Diverse species in the genus Cryptococcus: Pathogens and their non‐pathogenic ancestors

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