Pho4 is essential for dissemination of Cryptococcus neoformans to the host brain by promoting phosphate uptake and growth at alkaline pH

Sophie Lev, Keren Kaufman-Francis, Desmarini Desmarini, Pierre G. Juillard, Cecilia Li, Sebastian A. Stifter, Carl G. Feng, Tania C. Sorrell, Georges E.R. Grau, Yong Sun Bahn, Julianne T. Djordjevic

Research output: Contribution to journalArticle

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Abstract

Phosphate acquisition by fungi is regulated by the phosphate-sensing and acquisition (PHO) signaling pathway. Cryptococcus neoformans 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 (hlh3Δ/pho4Δ) 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 pho4Δ 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 pho4Δ mutant had a growth defect and compromised phosphate uptake. The pho4Δ 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 pho4Δ 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.

Original languageEnglish
Article numbere00381-16
JournalmSphere
Volume2
Issue number1
DOIs
Publication statusPublished - 2017 Jan 1

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Cryptococcus neoformans
Phosphates
Brain
Growth
Cryptococcus
Fungal Meningitis
Transcription Factors
Fungal Proteins
Meningitis
Inhalation
Monocytes
Fungi
Gene Expression
Lung

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Molecular Biology

Cite this

Lev, S., Kaufman-Francis, K., Desmarini, D., Juillard, P. G., Li, C., Stifter, S. A., ... Djordjevic, J. T. (2017). Pho4 is essential for dissemination of Cryptococcus neoformans to the host brain by promoting phosphate uptake and growth at alkaline pH. mSphere, 2(1), [e00381-16]. https://doi.org/10.1128/mSphere.00381-16
Lev, Sophie ; Kaufman-Francis, Keren ; Desmarini, Desmarini ; Juillard, Pierre G. ; Li, Cecilia ; Stifter, Sebastian A. ; Feng, Carl G. ; Sorrell, Tania C. ; Grau, Georges E.R. ; Bahn, Yong Sun ; Djordjevic, Julianne T. / Pho4 is essential for dissemination of Cryptococcus neoformans to the host brain by promoting phosphate uptake and growth at alkaline pH. In: mSphere. 2017 ; Vol. 2, No. 1.
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title = "Pho4 is essential for dissemination of Cryptococcus neoformans to the host brain by promoting phosphate uptake and growth at alkaline pH",
abstract = "Phosphate acquisition by fungi is regulated by the phosphate-sensing and acquisition (PHO) signaling pathway. Cryptococcus neoformans 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 (hlh3Δ/pho4Δ) 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 pho4Δ 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 pho4Δ mutant had a growth defect and compromised phosphate uptake. The pho4Δ 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 pho4Δ 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.",
author = "Sophie Lev and Keren Kaufman-Francis and Desmarini Desmarini and Juillard, {Pierre G.} and Cecilia Li and Stifter, {Sebastian A.} and Feng, {Carl G.} and Sorrell, {Tania C.} and Grau, {Georges E.R.} and Bahn, {Yong Sun} and Djordjevic, {Julianne T.}",
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Lev, S, Kaufman-Francis, K, Desmarini, D, Juillard, PG, Li, C, Stifter, SA, Feng, CG, Sorrell, TC, Grau, GER, Bahn, YS & Djordjevic, JT 2017, 'Pho4 is essential for dissemination of Cryptococcus neoformans to the host brain by promoting phosphate uptake and growth at alkaline pH', mSphere, vol. 2, no. 1, e00381-16. https://doi.org/10.1128/mSphere.00381-16

Pho4 is essential for dissemination of Cryptococcus neoformans to the host brain by promoting phosphate uptake and growth at alkaline pH. / Lev, Sophie; Kaufman-Francis, Keren; Desmarini, Desmarini; Juillard, Pierre G.; Li, Cecilia; Stifter, Sebastian A.; Feng, Carl G.; Sorrell, Tania C.; Grau, Georges E.R.; Bahn, Yong Sun; Djordjevic, Julianne T.

In: mSphere, Vol. 2, No. 1, e00381-16, 01.01.2017.

Research output: Contribution to journalArticle

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T1 - Pho4 is essential for dissemination of Cryptococcus neoformans to the host brain by promoting phosphate uptake and growth at alkaline pH

AU - Lev, Sophie

AU - Kaufman-Francis, Keren

AU - Desmarini, Desmarini

AU - Juillard, Pierre G.

AU - Li, Cecilia

AU - Stifter, Sebastian A.

AU - Feng, Carl G.

AU - Sorrell, Tania C.

AU - Grau, Georges E.R.

AU - Bahn, Yong Sun

AU - Djordjevic, Julianne T.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Phosphate acquisition by fungi is regulated by the phosphate-sensing and acquisition (PHO) signaling pathway. Cryptococcus neoformans 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 (hlh3Δ/pho4Δ) 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 pho4Δ 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 pho4Δ mutant had a growth defect and compromised phosphate uptake. The pho4Δ 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 pho4Δ 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.

AB - Phosphate acquisition by fungi is regulated by the phosphate-sensing and acquisition (PHO) signaling pathway. Cryptococcus neoformans 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 (hlh3Δ/pho4Δ) 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 pho4Δ 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 pho4Δ mutant had a growth defect and compromised phosphate uptake. The pho4Δ 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 pho4Δ 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.

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