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Pho4 Is Essential for Dissemination of to the Host Brain by Promoting Phosphate Uptake and Growth at Alkaline pH. | LitMetric

Pho4 Is Essential for Dissemination of to the Host Brain by Promoting Phosphate Uptake and Growth at Alkaline pH.

mSphere

Fungal Pathogenesis Laboratory, Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, Westmead, NSW, Australia; Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Sydney, NSW, Australia; The Westmead Clinical School, Sydney Medical School, The University of Sydney, Westmead, NSW, Australia.

Published: January 2017

AI Article Synopsis

  • - The PHO signaling pathway regulates how fungi, specifically Cryptococcus, acquire phosphate, which is crucial for their survival and virulence, especially in the context of meningitis.
  • - A knockout strain of Cryptococcus with defective phosphate acquisition displayed growth issues and reduced ability to spread in mouse models, indicating the importance of phosphate for fungal dissemination and pathogenicity.
  • - Phosphate acquisition is essential for efficient infection and stress tolerance in Cryptococcus, particularly under alkaline conditions, highlighting the necessity of the Pho4 protein in these processes.

Article Abstract

Phosphate acquisition by fungi is regulated by the phosphate-sensing and acquisition (PHO) signaling pathway. disseminates from the lung to the brain and is the commonest cause of fungal meningitis worldwide. To investigate the contribution of PHO signaling to cryptococcal dissemination, we characterized a transcription factor knockout strain () defective in phosphate acquisition. Despite little similarity with other fungal Pho4 proteins, Hlh3/Pho4 functioned like a typical phosphate-responsive transcription factor in phosphate-deprived cryptococci, accumulating in nuclei and triggering expression of genes involved in phosphate acquisition. The Δ mutant strain was susceptible to a number of stresses, the effect of which, except for alkaline pH, was alleviated by phosphate supplementation. Even in the presence of phosphate, the PHO pathway was activated in wild-type cryptococci at or above physiological pH, and under these conditions, the Δ mutant had a growth defect and compromised phosphate uptake. The mutant was hypovirulent in a mouse inhalation model, where dissemination to the brain was reduced dramatically, and markedly hypovirulent in an intravenous dissemination model. The mutant was not detected in blood, nor did it proliferate significantly when cultured with peripheral blood monocytes. In conclusion, dissemination of infection and the pathogenesis of meningitis are dependent on cryptococcal phosphate uptake and stress tolerance at alkaline pH, both of which are Pho4 dependent. Cryptococcal meningitis is fatal without treatment and responsible for more than 500,000 deaths annually. To be a successful pathogen, must obtain an adequate supply of essential nutrients, including phosphate, from various host niches. Phosphate acquisition in fungi is regulated by the PHO signaling cascade, which is activated when intracellular phosphate decreases below a critical level. Induction of phosphate acquisition genes leads to the uptake of free phosphate via transporters. By blocking the PHO pathway using a Pho4 transcription factor mutant ( mutant), we demonstrate the importance of the pathway for cryptococcal dissemination and the establishment of brain infection in murine models. Specifically, we show that reduced dissemination of the mutant to the brain is due to an alkaline pH tolerance defect, as alkaline pH mimics the conditions of phosphate deprivation. The end result is inhibited proliferation in host tissues, particularly in blood.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266496PMC
http://dx.doi.org/10.1128/mSphere.00381-16DOI Listing

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