The Role of microRNAs and Cell-Free DNAs in Fungal Infections: Systematic Review and Meta-Analysis of the Literature
Abstract
1. Introduction
2. Materials and Methods
2.1. The Literature Search, Selection Process and Data Extraction
2.2. Data Synthesis and Statistical Analysis
2.3. Final Step Analysis Protocol
3. Results
3.1. Search Results
3.2. cfDNA Analyses
Study (Year) | Country | Design | Sample Size | miRNA(s) Investigated | Main Finding | Diagnostic Performance |
---|---|---|---|---|---|---|
Wang 2010 [29] | China | Case–control | Sepsis: 50, SIRS: 30 | miR-146a, miR-223, miR-126, miR-15b, miR-132, miR-155, and let-7i | miR-146a and miR-223 significantly lower in sepsis; miR-126 lower in sepsis and SIRS vs. controls | miR-223: AUC 0.858 (Sens 80%, Spec 100%); miR-146a: AUC 0.804 (Sens 63.3%, Spec 100%) |
Da Lacorta Singulani 2017 [30] | Brazil | Case–control | PCM: 4 | 752 miRNAs | Several miRNAs overexpressed (e.g., miR1323p, miR604, miR29b3p); one miRNA underexpressed (miR4233p) | - |
Attia 2020 [31] | Egypt | Case–control | Sepsis: 50, Control: 20 | miR-146a and miR-150 | Significant correlation between miR-146a and miR-150 expression (r = 0.489, p < 0.001) | - |
Wei 2020 [32] | China | Case–control | Sepsis: 121, Control: 60 | miR-545 | miR-545 significantly higher in sepsis vs. controls | AUC 0.942 for sepsis diagnosis; AUC 0.740 for 28-day mortality |
Esawy 2021 [33] | Egypt | Case–control | Asthma: 30, SAFS: 30, ABPA: 30, Control: 30 | miR-21 and miR-132 | miR-21 elevated in all patient groups vs. controls; miR-132 highest in ABPA | ABPA vs. control: Sens 93.3%, Spec 100%; ABPA vs. asthma: Sens 90%, Spec 100%; SAFS: Sens 86.7%, Spec 80% |
Fidler 2022 [34] | Hungary | Retrospective cohort | IA: 26, Control: 24 | Multiple (incl. hsa-miR-191-5p, hsa-miR-106b-5p, and hsa-miR-15a-5p) | 8 miRNAs downregulated in confirmed IA; 5 miRNAs had perfect discrimination (AUC 1.0) | 5 miRNAs: AUC 1.0; 3 miRNAs: AUC > 0.98 |
3.3. miRNA Analyses
4. Discussion
- (1)
- The role of miRNA and cfDNA in fungal pathogenesis;
- (2)
- Diagnostic options;
- (3)
- Advances in therapeutic strategies;
- (4)
- Future directions and recommendations.
4.1. Role of miRNA and cfDNA in Fungal Pathogenesis
4.2. Diagnostic Options
4.3. Advances in Therapeutic Strategies
4.4. Future Directions and Recommendations
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
miRNA | Micro RNA |
cfDNA | Cell free DNA |
MVBs | Multivesicular bodies |
HSP | Heat shock protein |
PRISMA | Preferred Reporting Items for Systematic Reviews and Meta-Analyses |
PROSPERO | Prospective Register of Systematic Reviews |
CD | Cluster of differentiation |
IFD | Invasive fungal disease |
ID | Infectious Disease |
NOS | Newcastle–Ottawa Scale |
JBI | Joanna Briggs Institute (JBI) Critical Appraisal Checklist |
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miRNA | Disease/Condition | Regulation | Reported/Predicted Function |
---|---|---|---|
miR-146a | Sepsis, Invasive aspergillosis | Downregulated | Regulates TLR signaling, controls inflammation and pathogen recognition |
miR-223 | Sepsis, Aspergillosis | Downregulated | Neutrophil activation, cytokine regulation, pathogen clearance |
miR-132 | ABPA, Invasive aspergillosis | Upregulated | Th2 immune response, inflammation modulation |
miR-155 | Candida albicans, Aspergillus spp. | Upregulated | Macrophage polarization, enhances fungal clearance |
miR-21 | ABPA, Asthma, Aspergillosis (in vitro) | Upregulated | Suppresses IL-6/TNF-α, promotes immune evasion |
miR-545 | Sepsis | Upregulated | Associated with severity and mortality prediction |
miR-191-5p, miR-106b-5p, miR-15a-5p | Invasive aspergillosis (hematology/oncology patients) | Downregulated | High discriminatory power for diagnosis in immunocompromised patients |
miR-21-5p, miR-145-5p, miR-583, miR-3978, miR-4488, miR-4454 | Aspergillus fumigatus infection (A549 in vitro) | Downregulated | Differential expression associated with host response in epithelial cells |
miR-186-5p, miR-490-5p, miR-26a-5p, miR-26b-5p, miR-424-5p, miR-548d-3p, miR-196a-5p, miR-150-5p, miR-17-5p, miR-99b-5p | Aspergillus fumigatus infection (A549 in vitro) | Upregulated | Differential expression associated with host response in epithelial cells |
Study (Author, Year) | Design | Tool Used | Risk of Bias/Quality Score | Comments |
---|---|---|---|---|
Armstrong, 2019 [28] | Prospective cohort (IFD) | QUADAS-2 | Moderate risk | Small sample size, Standardized test protocol |
Balks, 2025 [23] | Prospective cohort (Sepsis) | QUADAS-2 | Low risk | Clear patient selection; appropriate index test |
Chen, 2024 [21] | Prospective cohort (Suspected infectious diseases) | QUADAS-2 | Moderate risk | Sample location differences, temporal variations in treatment protocols |
Gracia, 2024 [17] | Case series (Mucormycosis) | QUADAS-2 | Moderate risk | Small sample size, Clear patient selection |
Hogan, 2021 [24] | Retrospective cohort (ID) | QUADAS-2 | Low risk | Standardized test protocol, Multicenter |
Hong, 2018 [27] | Retrospective (IFD) | QUADAS-2 | Moderate risk | Small sample size, Standardized test protocol |
Kushner, 2024 [16] | Retrospective (IFD) | QUADAS-2 | Low risk | Clear patient selection; appropriate index test |
Pang, 2024 [26] | Retrospective cohort (ID) | QUADAS-2 | Low risk | Clear patient selection; Multicenter |
Park, 2023 [20] | Descriptive (ID) | STROBE | Moderate/High Reporting Quality | Standardized test, Multicenter, Big sample size |
Shah, 2024 [25] | Retrospective (ID) | NOS | 6/9 stars | Clear patient selection, Standardized test |
Tang, 2025 [22] | Cross-sectional (ID) | QUADAS-2 | Low risk | Standardized test, Clear sample selection |
Vissichelli, 2023 [15] | Retrospective observational study (ID) | NOS | 6/9 stars | Limited sample size, Sample location differences |
Wang, 2021 [14] | Prospective cohort (Sepsis) | QUADAS-2 | Low risk | Strong design, Clear sample selection |
Weiss, 2023 [19] | Retrospective cohort (ID) | JBI | Moderate risk | Small sample size, appropriate index test |
Xu, 2023 [18] | Retrospective cohort (ID) | QUADAS-2 | Low risk | Clear patient selection; appropriate index test |
Zhang, 2024 [12] | Retrospective cohort (ID) | QUADAS-2 | Moderate risk | |
Wang, 2010 [29] | Case–control (Sepsis) | QUADAS-2 | Low risk | Clear patient selection; appropriate index test |
Attia, 2020 [31] | Case–control (Sepsis) | QUADAS-2 | Moderate risk | Small sample size; unclear blinding |
Wei, 2020 [32] | Case–control (Sepsis) | NOS | 7/9 stars | Good selection and comparability; limited outcome follow-up |
Esawy, 2021 [33] | Case–control (ABPA) | NOS | 6/9 stars | Adequate selection; limited sample size |
Fidler, 2022 [34] | Retrospective cohort (IA) | NOS | 8/9 stars | Strong design; potential retrospective bias |
Da Lacorta Singulani, 2017 [30] | Case–control (PCM) | NOS | 5/9 stars | Very small sample; exploratory findings |
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Kalkanci, A.; Bozdag, F.; Fidan, I.; Guzel Tunccan, O.; Cetintepe, S.P.; Ilhan, M.N. The Role of microRNAs and Cell-Free DNAs in Fungal Infections: Systematic Review and Meta-Analysis of the Literature. J. Fungi 2025, 11, 718. https://doi.org/10.3390/jof11100718
Kalkanci A, Bozdag F, Fidan I, Guzel Tunccan O, Cetintepe SP, Ilhan MN. The Role of microRNAs and Cell-Free DNAs in Fungal Infections: Systematic Review and Meta-Analysis of the Literature. Journal of Fungi. 2025; 11(10):718. https://doi.org/10.3390/jof11100718
Chicago/Turabian StyleKalkanci, Ayse, Fatma Bozdag, Isil Fidan, Ozlem Guzel Tunccan, Sultan Pinar Cetintepe, and Mustafa Necmi Ilhan. 2025. "The Role of microRNAs and Cell-Free DNAs in Fungal Infections: Systematic Review and Meta-Analysis of the Literature" Journal of Fungi 11, no. 10: 718. https://doi.org/10.3390/jof11100718
APA StyleKalkanci, A., Bozdag, F., Fidan, I., Guzel Tunccan, O., Cetintepe, S. P., & Ilhan, M. N. (2025). The Role of microRNAs and Cell-Free DNAs in Fungal Infections: Systematic Review and Meta-Analysis of the Literature. Journal of Fungi, 11(10), 718. https://doi.org/10.3390/jof11100718