Are We There Yet? Recent Progress in the Molecular Diagnosis and Novel Antifungal Targeting of Aspergillus fumigatus and Invasive Aspergillosis

Steinbach, William J.

doi:10.1371/journal.ppat.1003642

Cited by 27 publications

(27 citation statements)

References 20 publications

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“…Invasive aspergillosis (IA) is one of the major detrimental fungal infections in immunocompromised patients, and A. fumigatus causes approximately 90% of IA cases (Denning, ). Despite the increasing number of immunocompromised individuals, the current options for IA diagnosis and treatment are limited (Denning, ; Perfect, ; Steinbach, ). To improve patient outcomes, more information on fungal adaptations to host environments is needed.…”

Section: Introductionmentioning

confidence: 99%

The signal peptide peptidase SppA is involved in sterol regulatory element‐binding protein cleavage and hypoxia adaptation in Aspergillus nidulans

Bat-Ochir

Kwak

Koh

et al. 2016

Molecular Microbiology

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Using forward genetics, we revealed that the signal peptide peptidase (SPP) SppA, an aspartyl protease involved in regulated intramembrane proteolysis (RIP), is essential for hypoxia adaptation in Aspergillus nidulans, as well as hypoxia-sensitive mutant alleles of a sterol regulatory element-binding protein (SREBP) srbA and the Dsc ubiquitin E3 ligase complex dscA-E. Both null and dead activity [D337A] mutants of sppA failed to grow in hypoxia, and the growth defect of ΔsppA was complemented by nuclear SrbA-N381 expression. Additionally, SppA interacted with SrbA in the endoplasmic reticulum, where SppA localized in normoxia and hypoxia. Expression of the truncated SrbA-N414 covering the SrbA sequence prior to the second transmembrane region rescued the growth of ΔdscA but not of ΔsppA in hypoxia. Unlike ΔdscA and ΔdscA;ΔsppA double mutants, in which SrbA cleavage was blocked, the molecular weight of cleaved SrbA increased in ΔsppA compared to the control strain in immunoblot analyses. Overall, our data demonstrate the sequential cleavage of SrbA by Dsc-linked proteolysis followed by SppA, proposing a new model of RIP for SREBP cleavage in fungal hypoxia adaptation. Furthermore, the function of SppA in hypoxia adaptation was consistent in Aspergillus fumigatus, suggesting the potential roles of SppA in fungal pathogenesis.

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Section: Introductionmentioning

confidence: 99%

The signal peptide peptidase SppA is involved in sterol regulatory element‐binding protein cleavage and hypoxia adaptation in Aspergillus nidulans

Bat-Ochir

Kwak

Koh

et al. 2016

Molecular Microbiology

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“…To prevent severe disease caused by Aspergillus spp., early diagnosis and suitable antifungal treatments are required. However, timely and accurate diagnosis remains a challenge and clinical use of antifungal drugs is difficult due to host toxicity and emerging antifungal drug resistance (Steinbach, 2013).…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum localized PerA is required for cell wall integrity, azole drug resistance, and virulence in Aspergillus fumigatus

Chung

Thammahong

Shepardson

et al. 2014

Molecular Microbiology

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Summary GPI-anchoring is a universal and critical post-translational protein modification in eukaryotes. In fungi, many cell wall proteins are GPI-anchored, and disruption of GPI-anchored proteins impairs cell wall integrity. After being synthesized and attached to target proteins, GPI anchors undergo modification on lipid moieties. In spite of its importance for GPI-anchored protein functions, our current knowledge of GPI lipid remodeling in pathogenic fungi is limited. In this study, we characterized the role of a putative GPI lipid remodeling protein, designated PerA, in the human pathogenic fungus Aspergillus fumigatus. PerA localizes to the endoplasmic reticulum and loss of PerA leads to striking defects in cell wall integrity. A perA null mutant has decreased conidia production, increased susceptibility to triazole antifungal drugs, and is avirulent in a murine model of invasive pulmonary aspergillosis. Interestingly, loss of PerA increases exposure of β-glucan and chitin content on the hyphal cell surface, but diminished TNF production by bone marrow derived macrophages relative to wild type. Given the structural specificity of fungal GPI-anchors, which is different from humans, understanding GPI lipid remodeling and PerA function in A. fumigatus is a promising research direction to uncover a new fungal specific antifungal drug target.

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“…4 While therapeutic strides have been made against Aspergillus in the last decade, advances in medical treatment of many cancers and autoimmune diseases continue to increase the patient population at risk for life threatening Aspergillus infections. 5 While epidemiological data on A. fumigatus infections remains enigmatic, recent estimates and clinical experience strongly suggest the incidence of disease is far greater than previously appreciated. [6][7][8] Perhaps most importantly, regardless of disease incidence, the recalcitrant nature of Aspergillus infections to medical intervention too often leads to poor treatment outcomes.…”

mentioning

confidence: 99%

“…[6][7][8] Perhaps most importantly, regardless of disease incidence, the recalcitrant nature of Aspergillus infections to medical intervention too often leads to poor treatment outcomes. 5,9 Many reasons explain the unacceptably high treatment failures with Aspergillus infection. For one, as a fellow eukaryote, survival and proliferation of A. fumigatus relies on fundamental pathways of nutrient acquisition and utilization similar to those used by humans.…”

mentioning

confidence: 99%

“…Consequently, the antifungal drug arsenal used to treat A. fumigatus infections remains limited compared to other pathogenic microbes. 5,[22][23][24] In the context of improving therapeutics, targeting virulence of the fungus is an important ongoing research endeavor. Much has been written, researched, and debated on the nature of virulence in A. fumigatus and related environmental fungi.…”

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confidence: 99%

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In vivo veritas: Aspergillus fumigatusproliferation and pathogenesis – conditionally speaking

Cramer

2015

Virulence

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Are We There Yet? Recent Progress in the Molecular Diagnosis and Novel Antifungal Targeting of Aspergillus fumigatus and Invasive Aspergillosis

Cited by 27 publications

References 20 publications

The signal peptide peptidase SppA is involved in sterol regulatory element‐binding protein cleavage and hypoxia adaptation in Aspergillus nidulans

The signal peptide peptidase SppA is involved in sterol regulatory element‐binding protein cleavage and hypoxia adaptation in Aspergillus nidulans

Endoplasmic reticulum localized PerA is required for cell wall integrity, azole drug resistance, and virulence in Aspergillus fumigatus

In vivo veritas: Aspergillus fumigatusproliferation and pathogenesis – conditionally speaking

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