The main pathogen taxa of fungal meningitis are endemic to the regulatory basis and evolutionary pathways of the main pathogen taxa

On December 24, 2022, the research team of Wang Linqi, State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, published an article entitled "Regulatory basis for reproductive flexibility in a meningitis-causing fungal pathogen" in Nature Communications.
New advances
in the regulation of the specific reproductive patterns of the main pathogen groups of fungal meningitis and the research on evolutionary pathways are reported online.

The Catalogue of Pathogenic Microorganisms Transmitted to Humans (Draft for Comments) (2021 edition) points out that the number of fungal pathogenic microorganisms has increased from 59 in the 2006 edition to 166, revealing that fungal infections have become one of the key factors threatening the
health and security of Chinese people.
Based on the growing threat of pathogenic fungi, on 25 October 2022, the World Health Organization issued the first list of key pathogens for fungi for invasive mycoses, including pathogenic fungi of the Cryptococcaceae family
.

Cryptococcal fungi are the main pathogen group that causes fungal meningitis, causing hundreds of thousands of deaths every year, and its infection fatality rate in China exceeds 30%.

Sexual reproduction, including bisex and α α unisex, promotes infection, virulence evolution, and drug-resistant variants of this pathogen taxa
.
Among them, α same-sex reproduction is a unique reproductive strategy for cryptococcal pathogens, which promotes the production of highly virulent strains by creating genetic material and karyotype diversification, resulting in severe Cryptococcal fulminant infections
in North America.
The previous work of the research team revealed the important signaling molecules and molecular cell mechanisms that drive the sexual reproductive differentiation of Cryptococcus, which laid the foundation
for this study.

In this study, Cryptococcus deneoformans (a model pathogen for the study of sexual reproduction of fungi in the family Cryptococcaceae) was used as a research model to construct the first library of transcription factor gene deletion strains in this pathogen
.
Through the development of systems biology methods, quantitative and semi-quantitative evaluation strategies were established for eight spatiotemporal developmental traits of sexual reproduction, revealing 374 molecular regulatory-phenotypic associations associated with sexual reproduction of Cryptococcus (Figures 2A and 2B).

With the help of gene evolutionary age analysis, it is found that the molecular regulatory network of intersex reproduction is relatively old
.
In this regulatory network, Fmp1, a component of an unreported conserved fungal mating pathway (pheromone MAPK pathway) was identified (Figure 2C
).
Unlike intersex reproduction, a recently evolved regulatory pathway stimulates and coordinates five successive developmental processes
in the same-sex reproductive cycle α Cryptococcus.
The underlying component of this pathway, Cua1, was found to be a novel spindle polar body associated protein, most of its functional domains are derived from viruses (Figures 2D and 2E), and the gene encoding Cua1 homologous protein is only present
in Cryptococcaceae fungi with α homosexual reproductive ability.
These results show that ancient and recent evolutionary regulatory pathways control the intersex reproductive and α homosexual reproductive processes of Cryptococcus, respectively, suggesting that the unique reproductive mode of Cryptococcus, α same-sex reproduction, is a recent evolutionary event, and the acquisition of this reproductive mode may be related to
viral infection and horizontal gene transfer.

This research was supported
by the National Key Research and Development Program of China (2021YFC2300400), the National Natural Science Foundation of China, and the "Interdisciplinary and Cooperative Team" of Science and Technology Innovation of the Chinese Academy of Sciences.
Researcher Wang Linqi of the Institute of Microbiology is the corresponding author of this paper, and Dr.
Pengjie Hu, special research assistant, and doctoral students Ding Hao and Liu Huimin are co-first authors
.
Liu Xiao's research group of the Institute of Microbiology, Liao Guojian Research Group of Southwest University, and Yang Ence Research Group of Peking University Health Science Center have given important support
for this work.