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Written by | November
Invasive fungal pathogens kill an estimated 1.
5 million people each year and cause diseases known as "neglected epidemics"
.
New drug-resistant pathogens are constantly emerging, and existing drugs have very limited efficacy and high
toxic side effects.
However, it is not fully understood
how fungal pathogens evade the host immune system to replicate and cause disease.
Recently, the Hiten D.
Madhani research group at the University of California, San Francisco, co-published a paper entitled Secreted fungal virulence effector triggers allergic inflammation via TLR4, discovering Cryptococcus neoformans The effector protein CPL1 secreted by Cryptococcus neoformans drives macrophage activation by enhancing Toll-like receptor TLR4, which causes infection in mice
.
Invasive fungal pathogens are a major cause of death and morbidity in humans, and Cryptococcus neoformans is an environmental yeast that enters the body through respiration and subsequently causes fatal meningitis in immunocompromised individuals [1
。 This is the most common cause of fungal meningitis, causing death
in 10% to 70% of cases each year.
During infection in mice, Cryptococcus neoformans causes a type II immune response, but how it promotes the inflammatory response is unknown
.
Previous studies have shown that Polysaccharide capsules formed by Cryptococcus neoformans help pathogens escape macrophages [2].
Thus, polysaccharide capsular membranes may have additional immunomodulatory functions
.
To test whether polysaccharide capsules help promote macrophage activation, the authors generated a polysaccharide capsule-deficient cryptococcus, using wild-type controls in mouse bone marrow-derived macrophages (BMDMs).
Medium detection stimulates the production
of tumor necrosis factor TNF.
Through this experiment, the authors found that polysaccharide capsular defective cryptococci do not cause TNF production
.
To study the global response of BMDM, the authors performed RNA-seq on lipopolysaccharides, enzymes, Saccharomyces cerevisiae, and cells stimulated by wild-type or polysaccharide capsular-deficient Cryptococcus, and found that the marker Arg1 associated with macrophage polarization activation was significantly increased in wild-type or polysaccharide capsular-deficient Cryptococcus, but the expression of Arg1 was less
increased after the loss of polysaccharide capsule.
These results suggest that Cryptococcus neoformans relies on polysaccharide capsules for macrophage activation
.
Subsequently, through the Transwell experiment, in which Cryptococcus neoformans were in direct contact with or separation of macrophages, the authors found that the stimulation effect on macrophages was similar, suggesting that Cryptococcus neoformans stimulates macrophage activation dependent on certain secreted factors
.
To analyze the specific molecular mechanisms by which Cryptococcus neoformans affects macrophages, the authors performed a forward genetic screening
of Cryptococcus neoformans.
Through this screening, the authors found a factor of unknown function, CPL1, which is presumed to be a secreted factor and has a cysteine-enriched domain
at the C-terminus.
The authors found that knocking out CPL1 in Cryptococcus neoformans resulted in a significant reduction in the number of ARG1+ macrophages, while the ability of Cryptococcus neoformans to activate macrophages was restored
after supplementing CPL1.
To further elucidate the molecular mechanism by which CPL1 stimulates macrophages, the authors directly express the CPL1 recombinant protein and process
the macrophages.
The authors found that CPL1 promotes the stimulation of macrophages by IL-4, which contributes to the growth
of pathogens in vitro.
Further, the authors explored how CPL1 and IL-4 systematically amplify the transcriptional signature of IL-4, and through time-course analysis experiments, the authors found that CPL1 promotes increased
STAT3 phosphorylation in macrophages.
By looking for the surface receptor for CPL1 on macrophages, the authors found that CPL1 activates the macrophage surface receptor TLR4
.
In addition, the authors transferred the experimental system to mice and found that CPL1 also triggered a similar type II immune response
.
Overall, the authors' work found that CPL1 of Cryptococcus neoformans is a secreted effector factor that promotes pathogen toxicity
by enhancing the immune inflammatory response.
The molecular biology model identified by the authors is that CPL1 activates TLR4 signaling, driving phosphorylation of STAT3 in macrophages; In vivo, CPL1 is necessary for the virulence of Cryptococcus neoformans and also promotes macrophage induction of Arg1
.
This work provides new possibilities
for understanding the molecular mechanism of Cryptococcus neoformans and providing possible drug development targets.
Original link:
https://doi.
org/10.
1038/s41586-022-05005-4
Platemaker: Eleven
References
1.
Zhao, Y.
, Lin, J.
, Fan, Y.
& Lin, X.
Life cycle of Cryptococcus neoformans.
Annu.
Rev.
Microbiol.
73, 17–42 (2019)2.
Vecchiarelli, A.
Immunoregulation by capsular components of Cryptococcus neoformans.
Med.
Mycol.
38, 407–417 (2000)
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