Invasion of the central nervous system by Cryptococcus neoformans requires a secreted fungal metalloprotease

Kiem Vu, Rick Tham, John P. Uhrig, George Richard Thompson, Sarisa Na Pombejra, Mantana Jamklang, Jennifer M. Bautos, Angela C Gelli

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Cryptococcus spp. cause life-threatening fungal infection of the central nervous system (CNS), predominantly in patients with a compromised immune system. Why Cryptococcus neoformans has this remarkable tropism for the CNS is not clear. Recent research on cerebral pathogenesis of C. neoformans revealed a predominantly transcellular migration of cryptococci across the brain endothelium; however, the identities of key fungal virulence factors that function specifically to invade the CNS remain unresolved. Here we found that a novel, secreted metalloprotease (Mpr1) that we identified in the extracellular proteome of C. neoformans (CnMpr1) is required for establishing fungal disease in the CNS. Mpr1 belongs to a poorly characterized M36 class of fungalysins that are expressed in only some fungal species. A strain of C. neoformans lacking the gene encoding Mpr1 (mpr1Δ) failed to breach the endothelium in an in vitro model of the human blood-brain barrier (BBB). A mammalian host infected with the mpr1Δ null strain demonstrated significant improvement in survival due to a reduced brain fungal burden and lacked the brain pathology commonly associated with cryptococcal disease. The in vivo studies further indicate that Mpr1 is not required for fungal dissemination and Mpr1 likely targets the brain endothelium specifically. Remarkably, the sole expression of CnMPR1 in Saccharomyces cerevisiae resulted in a robust migration of yeast cells across the brain endothelium, demonstrating Mpr1's specific activity in breaching the BBB and suggesting that Mpr1 may function independently of the hyaluronic acid-CD44 pathway. This distinct role for Mpr1 may develop into innovative treatment options and facilitate a brain-specific drug delivery platform.

Original languageEnglish (US)
JournalmBio
Volume5
Issue number3
DOIs
StatePublished - Jun 3 2014

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Cryptococcus neoformans
Metalloproteases
Central Nervous System
Endothelium
Brain
Cryptococcus
Blood-Brain Barrier
Central Nervous System Fungal Infections
Tropism
Mycoses
Virulence Factors
Hyaluronic Acid
Proteome
Cell Movement
Saccharomyces cerevisiae
Immune System
Yeasts
Pathology
Survival
Research

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Invasion of the central nervous system by Cryptococcus neoformans requires a secreted fungal metalloprotease. / Vu, Kiem; Tham, Rick; Uhrig, John P.; Thompson, George Richard; Pombejra, Sarisa Na; Jamklang, Mantana; Bautos, Jennifer M.; Gelli, Angela C.

In: mBio, Vol. 5, No. 3, 03.06.2014.

Research output: Contribution to journalArticle

Vu, Kiem ; Tham, Rick ; Uhrig, John P. ; Thompson, George Richard ; Pombejra, Sarisa Na ; Jamklang, Mantana ; Bautos, Jennifer M. ; Gelli, Angela C. / Invasion of the central nervous system by Cryptococcus neoformans requires a secreted fungal metalloprotease. In: mBio. 2014 ; Vol. 5, No. 3.
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