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Clinical epidemiology of pulmonary aspergillosis in hospitalized patients and contribution of Cyp51A, Yap1, and Cdr1B mutations to voriconazole resistance in etiologic Aspergillus species

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Abstract

Pulmonary aspergillosis is a life-threatening fungal infection with worldwide distribution. In the present study, clinical epidemiology of pulmonary aspergillosis and antifungal susceptibility of etiologic Aspergillus species were evaluated in one-hundred fifty patients with special focus on the frequency of voriconazole resistance. All the cases were confirmed by the clinical pictures, laboratory findings, and isolation of etiologic Aspergillus species which belonged to two major species, i.e., A. flavus and A. fumigatus. Seventeen isolates displayed voriconazole MIC greater than or equal to the epidemiological cutoff value. Expression of cyp51A, Cdr1B, and Yap1 genes was analyzed in voriconazole-intermediate/resistant isolates. In A. flavus, Cyp51A protein sequencing showed the substitutions T335A and D282E. In the Yap1 gene, A78C replacement led to Q26H amino acid substitution that was not reported previously in A. flavus resistant to voriconazole. No mutations associated with voriconazole resistance were found in the three genes of A. fumigatus. The expression of Yap1 was higher than that of two other genes in both A. flavus and A. fumigatus. Overall, voriconazole-resistant strains of both A. fumigatus and A. flavus demonstrated overexpression of Cdr1B, Cyp51A, and Yap1 genes compared to voriconazole-susceptible strains. Although there are still ambiguous points about the mechanisms of azole resistance, our results showed that mutations were not present in majority of resistant and intermediate isolates, while all of these isolates showed overexpression in all three genes studied. As a conclusion, it seems that the main reason of the emergence of mutation in voriconazole-resistant isolates of A. flavus and A. fumigatus is previous or prolonged exposure to azoles.

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Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was financially supported by the Research Deputy of the Pasteur Institute of Iran.

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Authors and Affiliations

  1. Department of Mycology, Pasteur Institute of Iran, Tehran, 1316943551, Iran

    Zahra Salehi, Fatemehsadat Jamzivar & Mehdi Razzaghi-Abyaneh

  2. Clinical Tuberculosis and Epidemiology Research Center, NRITLD, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Somayeh Sharifynia, Zahra Abtahian, Majid Marjani, Afshin Moniri & Payam Tabarsi

  3. Department of Mycology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Masoomeh Shams-Ghahfarokhi

  4. Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mihan Poorabdollah

  5. HIV/STI Surveillance Research Center, and WHO Collaborating Center for HIV Surveillance, Institute for Futures Studies in Health, Kerman University of Medical Sciences, Kerman, Iran

    Naser Nasiri

  6. Research Center for Antibiotic Stewardship & Antimicrobial Resistance, Department of Infectious Diseases, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran

    Mohammadreza Salehi

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  1. Zahra Salehi
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Contributions

Zahra Salehi and Mehdi Razzaghi-Abyaneh designed and conceived the study; Zahra Salehi performed the experiments and wrote the manuscript draft; Somayeh Sharifynia cultured patient samples; Zahra Abtahian recruited all patients and conducted all interviews; Payam Tabarsi, Majid Marjani, and Afshin Moniri handled the patients and collected patient samples; Naser Nasiri performed statistical analyses; Mihan Poorabdollah performed pathology examination; Masoomeh Shams-Ghahfarokhi and Fatemehsadat Jamzivar assisted in molecular analyses and interpretation of the molecular data; Mohammadreza Salehi prepared the patient questionnaire. Mehdi Razzaghi-Abyaneh supervised the study. All authors read and approved the final manuscript.

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Correspondence to Mehdi Razzaghi-Abyaneh.

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Salehi, Z., Sharifynia, S., Jamzivar, F. et al. Clinical epidemiology of pulmonary aspergillosis in hospitalized patients and contribution of Cyp51A, Yap1, and Cdr1B mutations to voriconazole resistance in etiologic Aspergillus species. Eur J Clin Microbiol Infect Dis 42, 853–864 (2023). https://doi.org/10.1007/s10096-023-04608-7

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