Relevance of heterokaryosis for adaptation and azole-resistance development in Aspergillus fumigatus

Jianhua Zhang*, Eveline E. Snelders, Bas J. Zwaan, Sijmen E. Schoustra, Ed J. Kuijper, Maiken C. Arendrup, Willem J.G. Melchers, Paul E. Verweij, Alfons J.M. Debets

*Corresponding author for this work

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Abstract

Aspergillus fumigatus causes a range of diseases in humans, some of which are characterized by fungal persistence. Aspergillus fumigatus, being a generalist saprotroph, may initially establish lung colonization due to its physiological versatility and subsequently adapt through genetic changes to the human lung environment and antifungal treatments. Human lung-adapted genotypes can arise by spontaneous mutation and/or recombination and subsequent selection of the fittest genotypes. Sexual and asexual spores are considered crucial contributors to the genetic diversity and adaptive potential of aspergilli by recombination and mutation supply, respectively. However, in certain Aspergillus diseases, such as cystic fibrosis and chronic pulmonary aspergillosis, A. fumigatus may not sporulate but persist as a network of fungal mycelium. During azole therapy, such mycelia may develop patient-acquired resistance and become heterokaryotic by mutations in one of the nuclei. We investigated the relevance of heterokaryosis for azole-resistance development in A. fumigatus. We found evidence for heterokaryosis of A. fumigatus in patients with chronic Aspergillus diseases. Mycelium from patient-tissue biopsies segregated different homokaryons, from which heterokaryons could be reconstructed. Whereas all variant homokaryons recovered from the same patient were capable of forming a heterokaryon, those from different patients were heterokaryon-incompatible. We furthermore compared heterokaryons and heterozygous diploids constructed from environmental isolates with different levels of azole resistance. When exposed to azole, the heterokaryons revealed remarkable shifts in their nuclear ratio, and the resistance level of heterokaryons exceeded that of the corresponding heterozygous diploids.
Original languageEnglish
Article number20182886
JournalProceedings of the Royal Society B: Biological Sciences
Volume286
Issue number1896
DOIs
Publication statusPublished - 13 Feb 2019

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heterokaryon
azoles
Azoles
Aspergillus fumigatus
Aspergillus
mutation
Mycelium
recombination
genotype
lungs
mycelium
Diploidy
Lung
Mutation
Genetic Recombination
generalist
Genotype
spore
Pulmonary Aspergillosis
diploidy

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title = "Relevance of heterokaryosis for adaptation and azole-resistance development in Aspergillus fumigatus",
abstract = "Aspergillus fumigatus causes a range of diseases in humans, some of which are characterized by fungal persistence. Aspergillus fumigatus, being a generalist saprotroph, may initially establish lung colonization due to its physiological versatility and subsequently adapt through genetic changes to the human lung environment and antifungal treatments. Human lung-adapted genotypes can arise by spontaneous mutation and/or recombination and subsequent selection of the fittest genotypes. Sexual and asexual spores are considered crucial contributors to the genetic diversity and adaptive potential of aspergilli by recombination and mutation supply, respectively. However, in certain Aspergillus diseases, such as cystic fibrosis and chronic pulmonary aspergillosis, A. fumigatus may not sporulate but persist as a network of fungal mycelium. During azole therapy, such mycelia may develop patient-acquired resistance and become heterokaryotic by mutations in one of the nuclei. We investigated the relevance of heterokaryosis for azole-resistance development in A. fumigatus. We found evidence for heterokaryosis of A. fumigatus in patients with chronic Aspergillus diseases. Mycelium from patient-tissue biopsies segregated different homokaryons, from which heterokaryons could be reconstructed. Whereas all variant homokaryons recovered from the same patient were capable of forming a heterokaryon, those from different patients were heterokaryon-incompatible. We furthermore compared heterokaryons and heterozygous diploids constructed from environmental isolates with different levels of azole resistance. When exposed to azole, the heterokaryons revealed remarkable shifts in their nuclear ratio, and the resistance level of heterokaryons exceeded that of the corresponding heterozygous diploids.",
author = "Jianhua Zhang and Snelders, {Eveline E.} and Zwaan, {Bas J.} and Schoustra, {Sijmen E.} and Kuijper, {Ed J.} and Arendrup, {Maiken C.} and Melchers, {Willem J.G.} and Verweij, {Paul E.} and Debets, {Alfons J.M.}",
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language = "English",
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journal = "Proceedings of the Royal Society. B: Biological Sciences",
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Relevance of heterokaryosis for adaptation and azole-resistance development in Aspergillus fumigatus. / Zhang, Jianhua; Snelders, Eveline E.; Zwaan, Bas J.; Schoustra, Sijmen E.; Kuijper, Ed J.; Arendrup, Maiken C.; Melchers, Willem J.G.; Verweij, Paul E.; Debets, Alfons J.M.

In: Proceedings of the Royal Society B: Biological Sciences, Vol. 286, No. 1896, 20182886, 13.02.2019.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Relevance of heterokaryosis for adaptation and azole-resistance development in Aspergillus fumigatus

AU - Zhang, Jianhua

AU - Snelders, Eveline E.

AU - Zwaan, Bas J.

AU - Schoustra, Sijmen E.

AU - Kuijper, Ed J.

AU - Arendrup, Maiken C.

AU - Melchers, Willem J.G.

AU - Verweij, Paul E.

AU - Debets, Alfons J.M.

PY - 2019/2/13

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N2 - Aspergillus fumigatus causes a range of diseases in humans, some of which are characterized by fungal persistence. Aspergillus fumigatus, being a generalist saprotroph, may initially establish lung colonization due to its physiological versatility and subsequently adapt through genetic changes to the human lung environment and antifungal treatments. Human lung-adapted genotypes can arise by spontaneous mutation and/or recombination and subsequent selection of the fittest genotypes. Sexual and asexual spores are considered crucial contributors to the genetic diversity and adaptive potential of aspergilli by recombination and mutation supply, respectively. However, in certain Aspergillus diseases, such as cystic fibrosis and chronic pulmonary aspergillosis, A. fumigatus may not sporulate but persist as a network of fungal mycelium. During azole therapy, such mycelia may develop patient-acquired resistance and become heterokaryotic by mutations in one of the nuclei. We investigated the relevance of heterokaryosis for azole-resistance development in A. fumigatus. We found evidence for heterokaryosis of A. fumigatus in patients with chronic Aspergillus diseases. Mycelium from patient-tissue biopsies segregated different homokaryons, from which heterokaryons could be reconstructed. Whereas all variant homokaryons recovered from the same patient were capable of forming a heterokaryon, those from different patients were heterokaryon-incompatible. We furthermore compared heterokaryons and heterozygous diploids constructed from environmental isolates with different levels of azole resistance. When exposed to azole, the heterokaryons revealed remarkable shifts in their nuclear ratio, and the resistance level of heterokaryons exceeded that of the corresponding heterozygous diploids.

AB - Aspergillus fumigatus causes a range of diseases in humans, some of which are characterized by fungal persistence. Aspergillus fumigatus, being a generalist saprotroph, may initially establish lung colonization due to its physiological versatility and subsequently adapt through genetic changes to the human lung environment and antifungal treatments. Human lung-adapted genotypes can arise by spontaneous mutation and/or recombination and subsequent selection of the fittest genotypes. Sexual and asexual spores are considered crucial contributors to the genetic diversity and adaptive potential of aspergilli by recombination and mutation supply, respectively. However, in certain Aspergillus diseases, such as cystic fibrosis and chronic pulmonary aspergillosis, A. fumigatus may not sporulate but persist as a network of fungal mycelium. During azole therapy, such mycelia may develop patient-acquired resistance and become heterokaryotic by mutations in one of the nuclei. We investigated the relevance of heterokaryosis for azole-resistance development in A. fumigatus. We found evidence for heterokaryosis of A. fumigatus in patients with chronic Aspergillus diseases. Mycelium from patient-tissue biopsies segregated different homokaryons, from which heterokaryons could be reconstructed. Whereas all variant homokaryons recovered from the same patient were capable of forming a heterokaryon, those from different patients were heterokaryon-incompatible. We furthermore compared heterokaryons and heterozygous diploids constructed from environmental isolates with different levels of azole resistance. When exposed to azole, the heterokaryons revealed remarkable shifts in their nuclear ratio, and the resistance level of heterokaryons exceeded that of the corresponding heterozygous diploids.

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DO - 10.1098/rspb.2018.2886

M3 - Article

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JF - Proceedings of the Royal Society. B: Biological Sciences

SN - 0962-8452

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