Drug Evasion by Important Microbial Pathogens and AI-Based Diagnostic & Treatment Technologies

PhD Institute of Microbiology
BS Shandong University

   

2014.12-present: Professor of IMCAS
2010.7-2014.12: Post Doctoral Fellow, Texas A&M University
2010.2-2010.7: Post Doctoral Fellow, New York University

2014 Faculty 1000 Member Travel Grant
2013 Faculty 1000 Member Travel Grant
2011 Eukaryotic Cell Outstanding Young Investigator Award,
American Society of Microbiology
2011 Nomination for One-hundred excellent PhD theses of China
2010 The Outstanding Doctoral Dissertation Award,
Chinese Academy of Sciences
2009 President Scholarship, Chinese Academy of Sciences

1. Huang J ^#, Hu P ^#, Ye L ^#, Shen Z, Chen X, Liu F, Xie Y, Yu J, Fan X, Xiao M, Clement K M Tsui, Wang W, Li Y, Zhang G, Koon Ho Wong, Cai L, Bai F, Xu Y*, Wang L* (2024) Pan-drug resistance and hypervirulence in a human fungal pathogen are enabled by mutagenesis induced by mammalian body temperature. Nature Microbiology. DOI: 10.1038/s41564-024-01720-y. (Nature Microbiology Featured Article）

2. Chen L^#, Tian X^#, Zhang L^#, Wang W, Hu P, Ma Z, Li Y, Li S, Shen Z, Fan X, Ye L, Ke W, Wu Y, Shui G, Xiao M, He G, Yang Y, Fang W, Bai F, Liao G, Chen M, Lin X, Li C, Wang L* (2024) Brain glucose induces tolerance of Cryptococcus neoformans to amphotericin B during meningitis. Nature Microbiology. DOI: 10.1038/s41564-023-01561-1.（Nature Microbiology Featured Article）

3. Tian X^#, He G^#, Hu P^#, Chen L, Tao C, Cui YL, Shen L, Ke W, Xu H, Zhao Y, Xu Q, Bai F, Wu B, Yang E, Lin X, Wang L* (2018) Cryptococcus neoformans sexual reproduction is controlled by a quorum sensing peptide. Nature Microbiology. DOI: 10.1038/s41564-018-0160-4.（Nature Microbiology Hero Image Article）

4. Ke W^#, Xie Y^#, Chen Y^#, Ding H, Ye L, Qiu H, Li H, Zhang L, Chen L, Tian X, Shen Z, Song Z, Fan X, Zong J, Guo Z, Ma X, Xiao M, Liao G, Liu CH, Yin W, Dong Z, Yang F, Jiang Y, Perlin DS, Chen Y, Fu Y*, Wang L* （2024）Fungicide-tolerant persister formation during cryptococcal pulmonary infection. Cell Host & Microbe. DOI: 10.1016/j.chom.2023.12.012.（Cell Host & Microbe Featured Article）

5. Hu P^#, Ding H^#, Liu H^#, Yang Y, Chen L, He G, Ke W, Ping Z, Tian X, Peng Y, Shen Z, Yao X, Tao C, Yang E, Liao G, Liu X, Wang L* (2022) Regulatory basis for reproductive flexibility in a meningitis-causing fungal pathogen. Nature Communications. DOI: 10.1038/s41467-022-35549-y. （Nature Communications Featured Article）

6. Fan X^#, Chen L^#, Chen M^#, Zhang N, Chang H, He M, Shen Z, Zhang L, Ding H, Xie Y, Huang Y, Ke W, Xiao M, Zang X, Xu H, Fang W, Li S, Cao C, Xu Y, Shan S,Wu W, Chen C*, Xue X*, Wang L* (2024) Pan-omics-based characterization and prediction of highly multidrug-adapted strains from an outbreak fungal species complex. The Innovation. DOI: 10.1016/j.xinn.2024.100681

7. Tian X^#, Ding H^#, Ke W, Wang L* (2021) Quorum Sensing in Fungal Species. Annual Review of Microbiology. DOI: 10.1146/annurev-micro-060321-045510. 

8. Hu P^#, Ding H^#, Shen L^#, He G, Liu H, Tian X, Tao C, Bai X, Liang J, Jin C, Xu X, Yang E, Wang L* (2021) A unique cell wall synthetic response evoked by glucosamine determines pathogenicity-associated fungal cellular differentiation. PLoS Genetics. DOI: 10.1371/journal.pgen.1009817.（Highlighted by F1000）

9. Hu P^#, Liu L^#, Ke W, Tian X, Wang L* (2021) A cyclin protein governs the infectious and sexual life cycles of Cryptococcus neoformans. Science China Life Sciences. DOI: 10.1007/s11427-020-1697-3.

10. Liu L^#, He G^#, Chen L#, Zheng J, Chen Y, Shen L, Tian X, Li E, Yang E, Liao G, Wang L* (2018) Genetic basis for coordination of meiosis and sexual structure maturation in Cryptococcus neoformans. eLife. DOI: 10.7554/eLife.38683. （Highlighted by F1000）

11. Ke W, Xie Y, Hu Y, Ding H, Fan X, Huang J, Tian X, Zhang B, Xu Y, Liu X, Yang Y*, Wang L* (2022) A forkhead transcription factor contributes to the regulatory differences of pathogenicity in closely related fungal pathogens. mLife. DOI：10.1002/mlf2.12011

12. Chen L^#, Zhang L^#, Xie Y, Wang Y, Tian X, Fang W, Xue X, Wang L* (2023) Confronting antifungal resistance, tolerance, and persistence: advances in drug target discovery and delivery systems. Advanced Drug Delivery Reviews. DOI: 10.1016/j.addr.2023.115007. 

Fungi cause over 3.75 million deaths annually, with case fatality rates for many pathogenic fungal infections exceeding 40%. Since both fungi and human hosts are eukaryotes, their key molecular machines are highly similar, and antifungal drugs obtained through traditional screening methods often exhibit high toxicity, rendering them unsuitable for clinical use (Denning et al., Science, 2015). Therefore, exploring unique pathogenic biological processes in fungi can help identify novel drug targets and provide a theoretical basis for developing highly effective, low-toxicity antifungal drugs. However, current research in this area remains generally insufficient. To address the above clinical problems and research bottlenecks, our research group has developed fungal systems biology techniques combined with single‑cell imaging, multi‑omics analysis, and artificial intelligence (The Innovation 2024, corresponding author). We discovered cell‑density‑driven sexual reproduction in pathogenic fungi (Nature Microbiology 2018, corresponding author, Hero Image; Annual Review of Microbiology 2021, corresponding author), mapped the spatiotemporal regulatory landscape of different reproductive strategies across the full life cycle of major pathogenic fungi (Nature Communications 2022, sole corresponding author, Featured Article), established the field of phenotypic antifungal resistance linked to host mortality (Nature Microbiology 2024a, corresponding author, Featured Article), reported a new multidrug‑resistant fungal pathogen — Rhodotorula sporidioboli (Nature Microbiology 2024b, corresponding author, Featured Article), developed a drug combination with significantly better cure rates than clinically recommended treatments for fungal meningitis in animals, and identified the first FDA‑approved drug with activity against fungal persister cells using a “drug repurposing” strategy (Cell Host & Microbe 2024, corresponding author, Featured Article), as well as an FDA‑approved drug with activity against fully drug‑resistant fungal strains. These achievements have been incorporated into the national 14th Five‑Year Plan undergraduate textbook Microbiology, were pre‑released to the media by the Nature portfolio, and have been reported by Xinhua Net, CGTN, Science News, Forbes, and as a front‑page headline by China Science Daily. The research objectives of our group are as follows:

Scientific research: Focusing on key pathogenic biological processes of fungi (evolution, infection, drug resistance)

(1) Evolution: At the kingdom scale, how do host and ecological factors influence the emergence and alteration of fungal pathogenic traits?

(2) Infection: What are the fundamental pathogenic biological rules during co‑infection of fungi with other microorganisms?

(3) Drug resistance: What are the spatiotemporal interaction rules among fungi, host, and drugs in the real‑world clinical setting?

Technological research: Developing novel diagnostic and therapeutic strategies for fungal infections (phenotype, target, diagnosis & treatment)

(1) Phenotype: Development of high‑throughput digital phenotyping technologies for fungi and artificial intelligence techniques adapted to fungal phenotypes

(2) Target: Technologies for target discovery, evaluation, and application based on DNA barcoded mutant libraries

(3) Diagnosis & treatment: Novel diagnostic and therapeutic approaches targeting genetic and phenotypic antifungal resistance.