Aspergillus fumigatus CalA binds to integrin α5β1 and mediates host cell invasion

Liu, Hong; Lee, Mark J.; Solis, Norma V.; Phan, Quynh T.; Swidergall, Marc; Ralph, Benjamin; Ibrahim, Ashraf S.; Sheppard, Donald C.; Filler, Scott G.

doi:10.1038/nmicrobiol.2016.211

Cited by 85 publications

(115 citation statements)

References 47 publications

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“…Thus, FleA represents an essential target of the immune system to clear inhaled conidia. A. fumigatus hyphae also invade epithelial and endothelial cells, a property mediated in part by the CalA protein (96) and by galactosaminogalactan (14). Although CalA is dispensable for host cell adherence, CalA stimulates integrin α5β1-dependent hyphal endocytosis and is required for virulence in immunosuppressed mice (96).…”

Section: Introductionmentioning

confidence: 99%

Immunity against fungi

Lionakis¹,

Iliev²,

Hohl³

2017

JCI Insight

109

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Section: Introductionmentioning

confidence: 99%

Immunity against fungi

Lionakis¹,

Iliev²,

Hohl³

2017

JCI Insight

109

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“…This fungus expresses a variety of virulence factors that enable it to adhere to and invade host cells and to survive within the hypoxic, nutrient-limited environment of the lung [1–9]. Furthermore, A. fumigatus produces a variety of secondary metabolites that may alter the function of host cells and contribute to virulence.…”

Section: Introductionmentioning

confidence: 99%

Functional convergence of gliP and aspf1 in Aspergillus fumigatus pathogenicity

Liu

Solis

et al. 2018

Virulence

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Gliotoxin contributes to the virulence of the fungus Aspergillus fumigatus in non-neutropenic mice that are immunosuppressed with corticosteroids. To investigate how the absence of gliotoxin affects both the fungus and the host, we used a nanoString nCounter to analyze their transcriptional responses during pulmonary infection of a non-neutropenic host with a gliotoxin-deficient ΔgliP mutant. We found that the ΔgliP mutation led to increased expression of aspf1, which specifies a secreted ribotoxin. Prior studies have shown that aspf1, like gliP, is not required for virulence in a neutropenic infection model, but its role in a non-neutropenic infection model has not been fully investigated. To investigate the functional significance of this up-regulation of aspf1, a Δaspf1 single mutant and a Δaspf1 ΔgliP double mutant were constructed. Both Δaspf1 and ΔgliP single mutants had reduced lethality in non-neutropenic mice, and a Δaspf1 ΔgliP double mutant had a greater reduction in lethality than either single mutant. Analysis of mice infected with these mutants indicated that the presence of gliP is associated with massive apoptosis of leukocytes at the foci of infection and inhibition of chemokine production. Also, the combination of gliP and aspf1 is associated with suppression of CXCL1 chemokine expression. Thus, aspf1 contributes to A. fumigatus pathogenicity in non-neutropenic mice and its up-regulation in the ΔgliP mutant may partially compensate for the absence of gliotoxin.Abbreviations:PAS: periodic acid-Schiff; PBS: phosphate buffered saline; ROS: reactive oxygen species; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling

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“…The latter conformation is thought to be the most active for cell adhesion. Because of their ubiquitous distribution, b1 integrins are targeted by a large range of microbes that utilise them as receptors to promote adhesion, host-cell invasion or injection of virulence effectors [10][11][12][13]. Several proteins of the cagT4SS were found to interact with integrins (reviewed in [6]).…”

Section: Introductionmentioning

confidence: 99%

Molecular dissection of protein–protein interactions between integrin α5β1 and the Helicobacter pylori Cag type IV secretion system

et al. 2017

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The more severe strains of the bacterial human pathogen Helicobacter pylori produce a type IV secretion system (cagT4SS) to inject the oncoprotein cytotoxin-associated gene A (CagA) into gastric cells. This syringe-like molecular apparatus is prolonged by an external pilus that exploits integrins as receptors to mediate the injection of CagA. The molecular determinants of the interaction of the cagT4SS pilus with the integrin ectodomain are still poorly understood. In this study, we have used surface plasmon resonance (SPR) to generate a comprehensive analysis of the protein-protein interactions between purified CagA, CagL, CagI, CagY repeat domain II (CagY ), CagY C-terminal domain (CagY ) and integrin α5β1 ectodomain (α5β1 ) or headpiece domain (α5β1 ). We found that CagI, CagA, CagL and CagY but not CagY were able to interact with α5β1 with affinities similar to the one observed for α5β1 interaction with its physiological ligand fibronectin. We further showed that integrin activation and its associated conformational change increased CagA, CagL and CagY affinities for the receptor. Furthermore, CagI did not interact with integrin unless the receptor was in open conformation. CagI, CagA but not CagL and CagY interacted with the α5β1 . Our SPR study also revealed novel interactions between CagA and CagL, CagA and CagY , and CagA and CagI. Altogether, our data map the network of interactions between host-cell α5β1 integrin and the cagT4SS proteins and suggest that activation of the receptor promotes interactions with the secretion apparatus and possibly CagA injection.

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Aspergillus fumigatus CalA binds to integrin α5β1 and mediates host cell invasion

Cited by 85 publications

References 47 publications

Immunity against fungi

Immunity against fungi

Functional convergence of gliP and aspf1 in Aspergillus fumigatus pathogenicity

Molecular dissection of protein–protein interactions between integrin α5β1 and the Helicobacter pylori Cag type IV secretion system

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