Population genomics confirms acquisition of drug-resistant Aspergillus fumigatus infection by humans from the environment

Johanna Rhodes; Alireza Abdolrasouli; Katie Dunne; Thomas R. Sewell; Yuyi Zhang; Eloise Ballard; Amelie P. Brackin; Norman van Rhijn; Harry Chown; Alexandra Tsitsopoulou; Raquel B. Posso; Sanjay H. Chotirmall; Noel G. McElvaney; Philip G. Murphy; Alida Fe Talento; Julie Renwick; Paul S. Dyer; Adrien Szekely; Paul Bowyer; Michael J. Bromley; Elizabeth M. Johnson; P. Lewis White; Adilia Warris; Richard C. Barton; Silke Schelenz; Thomas R. Rogers; Darius Armstrong-James; Matthew C. Fisher

doi:10.1038/s41564-022-01091-2

Population genomics confirms acquisition of drug-resistant Aspergillus fumigatus infection by humans from the environment

Johanna Rhodes^*, Alireza Abdolrasouli, Katie Dunne, Thomas R. Sewell, Yuyi Zhang, Eloise Ballard, Amelie P. Brackin, Norman van Rhijn, Harry Chown, Alexandra Tsitsopoulou, Raquel B. Posso, Sanjay H. Chotirmall, Noel G. McElvaney, Philip G. Murphy, Alida Fe Talento, Julie Renwick, Paul S. Dyer, Adrien Szekely, Paul Bowyer, Michael J. BromleyElizabeth M. Johnson, P. Lewis White, Adilia Warris, Richard C. Barton, Silke Schelenz, Thomas R. Rogers, Darius Armstrong-James, Matthew C. Fisher

^*Corresponding author for this work

UK Health Security Agency

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Abstract

Infections caused by the fungal pathogen Aspergillus fumigatus are increasingly resistant to first-line azole antifungal drugs. However, despite its clinical importance, little is known about how susceptible patients acquire infection from drug-resistant genotypes in the environment. Here, we present a population genomic analysis of 218 A. fumigatus isolates from across the UK and Ireland (comprising 153 clinical isolates from 143 patients and 65 environmental isolates). First, phylogenomic analysis shows strong genetic structuring into two clades (A and B) with little interclade recombination and the majority of environmental azole resistance found within clade A. Second, we show occurrences where azole-resistant isolates of near-identical genotypes were obtained from both environmental and clinical sources, indicating with high confidence the infection of patients with resistant isolates transmitted from the environment. Third, genome-wide scans identified selective sweeps across multiple regions indicating a polygenic basis to the trait in some genetic backgrounds. These signatures of positive selection are seen for loci containing the canonical genes encoding fungicide resistance in the ergosterol biosynthetic pathway, while other regions under selection have no defined function. Lastly, pan-genome analysis identified genes linked to azole resistance and previously unknown resistance mechanisms. Understanding the environmental drivers and genetic basis of evolving fungal drug resistance needs urgent attention, especially in light of increasing numbers of patients with severe viral respiratory tract infections who are susceptible to opportunistic fungal superinfections.

Original language	English
Pages (from-to)	663-674
Number of pages	12
Journal	Nature Microbiology
Volume	7
Issue number	5
DOIs	https://doi.org/10.1038/s41564-022-01091-2
Publication status	Published - 25 Apr 2022

Bibliographical note

Funding Information: This study was partially supported by an unrestricted education grant from Gilead Sciences through their investigator sponsored research programme. J. Rhodes, T.S., A.P.B., P.S.D., D.A.J. and M.C.F. were supported by grants from the NERC (nos. NE/P001165/1 and NE/P000916/1), the UK Medical Research Council (MRC) (no. MR/R015600/1) and Wellcome Trust (no. 219551/Z/19/Z). D.A.J. is also funded by the Medical Research Council (grant no. MR/V037315/1) and Cystic Fibrosis Trust (grant no. SRC015). D.A.J. is funded by the Department of Health and Social Care (DHSC) Centre for Antimicrobial Optimisation (CAMO), Imperial College London. The views expressed in this publication are those of the authors and not necessarily those of the DHSC, National Health Service or National Institute for Health Research (NIHR). M.C.F. is a CIFAR Fellow in the Fungal Kingdom programme. K.D. was supported by a PhD studentship awarded by the School of Medicine, Trinity College Dublin. P.G.M. and J. Renwick (Dublin) received a project grant from the National Children’s Hospital, Tallaght University Hospital, which in part supported this work. A.W. and E.B. are supported by the Wellcome Trust Strategic Award (grant no. 097377), MRC Centre for Medical Mycology (grant no. MR/N006364/2) at the University of Exeter and a Biotechnology and Biological Sciences Research Council EASTBIO grant (no. BB/M010996/1). The authors also acknowledge the Imperial College London Cystic Fibrosis Strategic Research Centre and NIHR CAMO.

Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Publisher Copyright: © The Author(s) 2022.

Citation: Rhodes, J., Abdolrasouli, A., Dunne, K. et al. Population genomics confirms acquisition of drug-resistant Aspergillus fumigatus infection by humans from the environment. Nat Microbiol 7, 663–674 (2022).

DOI: https://doi.org/10.1038/s41564-022-01091-2

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Rhodes, J., Abdolrasouli, A., Dunne, K., Sewell, T. R., Zhang, Y., Ballard, E., Brackin, A. P., van Rhijn, N., Chown, H., Tsitsopoulou, A., Posso, R. B., Chotirmall, S. H., McElvaney, N. G., Murphy, P. G., Talento, A. F., Renwick, J., Dyer, P. S., Szekely, A., Bowyer, P., ... Fisher, M. C. (2022). Population genomics confirms acquisition of drug-resistant Aspergillus fumigatus infection by humans from the environment. Nature Microbiology, 7(5), 663-674. https://doi.org/10.1038/s41564-022-01091-2

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abstract = "Infections caused by the fungal pathogen Aspergillus fumigatus are increasingly resistant to first-line azole antifungal drugs. However, despite its clinical importance, little is known about how susceptible patients acquire infection from drug-resistant genotypes in the environment. Here, we present a population genomic analysis of 218 A. fumigatus isolates from across the UK and Ireland (comprising 153 clinical isolates from 143 patients and 65 environmental isolates). First, phylogenomic analysis shows strong genetic structuring into two clades (A and B) with little interclade recombination and the majority of environmental azole resistance found within clade A. Second, we show occurrences where azole-resistant isolates of near-identical genotypes were obtained from both environmental and clinical sources, indicating with high confidence the infection of patients with resistant isolates transmitted from the environment. Third, genome-wide scans identified selective sweeps across multiple regions indicating a polygenic basis to the trait in some genetic backgrounds. These signatures of positive selection are seen for loci containing the canonical genes encoding fungicide resistance in the ergosterol biosynthetic pathway, while other regions under selection have no defined function. Lastly, pan-genome analysis identified genes linked to azole resistance and previously unknown resistance mechanisms. Understanding the environmental drivers and genetic basis of evolving fungal drug resistance needs urgent attention, especially in light of increasing numbers of patients with severe viral respiratory tract infections who are susceptible to opportunistic fungal superinfections.",

author = "Johanna Rhodes and Alireza Abdolrasouli and Katie Dunne and Sewell, {Thomas R.} and Yuyi Zhang and Eloise Ballard and Brackin, {Amelie P.} and {van Rhijn}, Norman and Harry Chown and Alexandra Tsitsopoulou and Posso, {Raquel B.} and Chotirmall, {Sanjay H.} and McElvaney, {Noel G.} and Murphy, {Philip G.} and Talento, {Alida Fe} and Julie Renwick and Dyer, {Paul S.} and Adrien Szekely and Paul Bowyer and Bromley, {Michael J.} and Johnson, {Elizabeth M.} and {Lewis White}, P. and Adilia Warris and Barton, {Richard C.} and Silke Schelenz and Rogers, {Thomas R.} and Darius Armstrong-James and Fisher, {Matthew C.}",

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Rhodes, J, Abdolrasouli, A, Dunne, K, Sewell, TR, Zhang, Y, Ballard, E, Brackin, AP, van Rhijn, N, Chown, H, Tsitsopoulou, A, Posso, RB, Chotirmall, SH, McElvaney, NG, Murphy, PG, Talento, AF, Renwick, J, Dyer, PS, Szekely, A, Bowyer, P, Bromley, MJ, Johnson, EM, Lewis White, P, Warris, A, Barton, RC, Schelenz, S, Rogers, TR, Armstrong-James, D & Fisher, MC 2022, 'Population genomics confirms acquisition of drug-resistant Aspergillus fumigatus infection by humans from the environment', Nature Microbiology, vol. 7, no. 5, pp. 663-674. https://doi.org/10.1038/s41564-022-01091-2

TY - JOUR

T1 - Population genomics confirms acquisition of drug-resistant Aspergillus fumigatus infection by humans from the environment

AU - Rhodes, Johanna

AU - Abdolrasouli, Alireza

AU - Dunne, Katie

AU - Sewell, Thomas R.

AU - Zhang, Yuyi

AU - Ballard, Eloise

AU - Brackin, Amelie P.

AU - van Rhijn, Norman

AU - Chown, Harry

AU - Tsitsopoulou, Alexandra

AU - Posso, Raquel B.

AU - Chotirmall, Sanjay H.

AU - McElvaney, Noel G.

AU - Murphy, Philip G.

AU - Talento, Alida Fe

AU - Renwick, Julie

AU - Dyer, Paul S.

AU - Szekely, Adrien

AU - Bowyer, Paul

AU - Bromley, Michael J.

AU - Johnson, Elizabeth M.

AU - Lewis White, P.

AU - Warris, Adilia

AU - Barton, Richard C.

AU - Schelenz, Silke

AU - Rogers, Thomas R.

AU - Armstrong-James, Darius

AU - Fisher, Matthew C.

N1 - Funding Information: This study was partially supported by an unrestricted education grant from Gilead Sciences through their investigator sponsored research programme. J. Rhodes, T.S., A.P.B., P.S.D., D.A.J. and M.C.F. were supported by grants from the NERC (nos. NE/P001165/1 and NE/P000916/1), the UK Medical Research Council (MRC) (no. MR/R015600/1) and Wellcome Trust (no. 219551/Z/19/Z). D.A.J. is also funded by the Medical Research Council (grant no. MR/V037315/1) and Cystic Fibrosis Trust (grant no. SRC015). D.A.J. is funded by the Department of Health and Social Care (DHSC) Centre for Antimicrobial Optimisation (CAMO), Imperial College London. The views expressed in this publication are those of the authors and not necessarily those of the DHSC, National Health Service or National Institute for Health Research (NIHR). M.C.F. is a CIFAR Fellow in the Fungal Kingdom programme. K.D. was supported by a PhD studentship awarded by the School of Medicine, Trinity College Dublin. P.G.M. and J. Renwick (Dublin) received a project grant from the National Children’s Hospital, Tallaght University Hospital, which in part supported this work. A.W. and E.B. are supported by the Wellcome Trust Strategic Award (grant no. 097377), MRC Centre for Medical Mycology (grant no. MR/N006364/2) at the University of Exeter and a Biotechnology and Biological Sciences Research Council EASTBIO grant (no. BB/M010996/1). The authors also acknowledge the Imperial College London Cystic Fibrosis Strategic Research Centre and NIHR CAMO. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Publisher Copyright: © The Author(s) 2022. Citation: Rhodes, J., Abdolrasouli, A., Dunne, K. et al. Population genomics confirms acquisition of drug-resistant Aspergillus fumigatus infection by humans from the environment. Nat Microbiol 7, 663–674 (2022). DOI: https://doi.org/10.1038/s41564-022-01091-2

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N2 - Infections caused by the fungal pathogen Aspergillus fumigatus are increasingly resistant to first-line azole antifungal drugs. However, despite its clinical importance, little is known about how susceptible patients acquire infection from drug-resistant genotypes in the environment. Here, we present a population genomic analysis of 218 A. fumigatus isolates from across the UK and Ireland (comprising 153 clinical isolates from 143 patients and 65 environmental isolates). First, phylogenomic analysis shows strong genetic structuring into two clades (A and B) with little interclade recombination and the majority of environmental azole resistance found within clade A. Second, we show occurrences where azole-resistant isolates of near-identical genotypes were obtained from both environmental and clinical sources, indicating with high confidence the infection of patients with resistant isolates transmitted from the environment. Third, genome-wide scans identified selective sweeps across multiple regions indicating a polygenic basis to the trait in some genetic backgrounds. These signatures of positive selection are seen for loci containing the canonical genes encoding fungicide resistance in the ergosterol biosynthetic pathway, while other regions under selection have no defined function. Lastly, pan-genome analysis identified genes linked to azole resistance and previously unknown resistance mechanisms. Understanding the environmental drivers and genetic basis of evolving fungal drug resistance needs urgent attention, especially in light of increasing numbers of patients with severe viral respiratory tract infections who are susceptible to opportunistic fungal superinfections.

AB - Infections caused by the fungal pathogen Aspergillus fumigatus are increasingly resistant to first-line azole antifungal drugs. However, despite its clinical importance, little is known about how susceptible patients acquire infection from drug-resistant genotypes in the environment. Here, we present a population genomic analysis of 218 A. fumigatus isolates from across the UK and Ireland (comprising 153 clinical isolates from 143 patients and 65 environmental isolates). First, phylogenomic analysis shows strong genetic structuring into two clades (A and B) with little interclade recombination and the majority of environmental azole resistance found within clade A. Second, we show occurrences where azole-resistant isolates of near-identical genotypes were obtained from both environmental and clinical sources, indicating with high confidence the infection of patients with resistant isolates transmitted from the environment. Third, genome-wide scans identified selective sweeps across multiple regions indicating a polygenic basis to the trait in some genetic backgrounds. These signatures of positive selection are seen for loci containing the canonical genes encoding fungicide resistance in the ergosterol biosynthetic pathway, while other regions under selection have no defined function. Lastly, pan-genome analysis identified genes linked to azole resistance and previously unknown resistance mechanisms. Understanding the environmental drivers and genetic basis of evolving fungal drug resistance needs urgent attention, especially in light of increasing numbers of patients with severe viral respiratory tract infections who are susceptible to opportunistic fungal superinfections.

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Population genomics confirms acquisition of drug-resistant Aspergillus fumigatus infection by humans from the environment

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