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Published on: February 27, 2018
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Modulation of Replicative Lifespan in Cryptococcus neoformans: Implications for Virulence
Tejas Bouklas1, Neena Jain2, Bettina C Fries3
1Department of Medicine (Division of Infectious Diseases), Stony Brook University, Stony BrookNY, USA; Department of Biomedical Sciences, Long Island University-Post, BrookvilleNY, USA.
Frontiers in Microbiology
|February 15, 2017
Summary
Manipulating the aging process of the fungal pathogen Cryptococcus neoformans affects its virulence. Extending replicative lifespan (RLS) with Sir2p agonists decreased virulence, while shortening RLS with antagonists increased it.
Area of Science:
- Mycology
- Aging Biology
- Antimicrobial Research
Background:
- Cryptococcus neoformans exhibits replicative aging, with older cells showing increased resistance to host defenses and antifungal agents.
- This age-associated resilience contributes to the accumulation of C. neoformans during chronic infections.
- The SIR2 gene, encoding a histone deacetylase, is a key regulator of aging and a target for anti-aging drug development.
Purpose of the Study:
- To investigate the hypothesis that modulating the generational age of C. neoformans affects its virulence and susceptibility to host defenses.
- To determine the role of SIR2 in regulating the replicative lifespan (RLS) of C. neoformans.
- To evaluate the impact of SIR2-modulating drugs on C. neoformans virulence and antifungal efficacy.
Main Methods:
- Generation and characterization of a sir2Δ mutant strain of C. neoformans.
- Assessment of replicative lifespan (RLS) following treatment with Sir2p agonists and antagonists.
- Evaluation of C. neoformans virulence in a Galleria mellonella infection model after RLS modulation.
- Testing the combined effect of Sir2p agonists and antifungal therapy.
Main Results:
- The sir2Δ mutant exhibited a shortened RLS, confirming SIR2's role in aging.
- Sir2p agonists significantly prolonged RLS, while antagonists shortened it, effects dependent on SIR2.
- Prolonging RLS with agonists decreased C. neoformans virulence in G. mellonella, whereas shortening RLS with antagonists enhanced it.
- Combination therapy with Sir2p agonists and antifungals improved antifungal efficacy.
Conclusions:
- Modulating the replicative lifespan (RLS) of C. neoformans via SIR2 targeting alters its virulence.
- Sir2p agonists demonstrate potential as novel antifungal agents by reducing fungal virulence and enhancing existing antifungal therapies.
- Targeting fungal aging represents a promising strategy for developing new treatments against C. neoformans infections.
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