Expanding the antiviral potential of the mosquito lipid‐transfer protein <scp>AEG12</scp> against <scp>SARS‐CoV</scp>‐2 using hydrophobic antiviral ligands

Foo, Alexander C. Y.; Lafont, Bernard A. P.; Mueller, Geoffrey A.

doi:10.1002/1873-3468.14456

Cited by 3 publications

(12 citation statements)

References 57 publications

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“…Similar cytotoxicity profiles were observed in these cells, mirroring the nonspecific nature of Bla g 1 and other MA proteins reported previously (Figure 2). 4,5 Pulmonary injury and allergen exposure have been shown to induce the production and release of specialized proinflammatory cytokines such as IL-1β. 8,19 Using CALU-3 cells as a model system for the pulmonary environment, we observed elevated levels of IL-1β upon exposure to 40 μM Bla g 1: a concentration at which extensive cell lysis was observed (Figure 2c).…”

Section: ■ Resultsmentioning

confidence: 99%

“…This response is dose-dependent, with significant IL-1β release occurring over the CC 50 cytotoxicity ranges reported this work and others (Figure 2d). 4,5 It should be noted that the release of IL-1β can be stimulated by the presence of bacterial lipids such as LPS. Such lipids can be retained by Bla g 1 when purified from its recombinant expression source.…”

Section: ■ Resultsmentioning

confidence: 99%

“…Insect major allergen (MA) proteins such as the cockroach allergen Bla g 1 form a unique structural fold consisting of 6 amphipathic α-helices, which encompass a large hydrophobic cavity. This cavity can bind up to 6 phospholipid or 12 fatty acids, with a mixture of saturated and unsaturated fatty acids (nMix) representing the natural ligands when purified from its allergen source. − This large lipid binding capacity (∼14% w/w when fully loaded) makes Bla g 1 an ideal system to study the immunological effect of allergen-associated lipids. Previous works demonstrated that MA proteins such as Bla g 1 can deliver their nMix ligands into phospholipid bilayers.…”

Section: Introductionmentioning

confidence: 99%

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Production and Release of Proinflammatory Mediators by the Cockroach Allergen Bla g 1 via a Shared Membrane-Destabilization Mechanism

Foo,

Edin,

Lin

et al. 2024

Biochemistry

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The cockroach allergen Bla g 1 encloses an exceptionally large hydrophobic cavity, which allows it to bind and deliver unsaturated fatty acid ligands. Bla g 1-mediated delivery of naturally occurring (nMix) ligands has been shown to destabilize lipid membranes, contributing to its digestive/antiviral functions within the source organism. However, the consequences of this activity on Bla g 1 allergenicity following human exposure remain unknown. In this work, we show that Bla g 1-mediated membrane disruption can induce a proinflammatory immune response in mammalian cells via two complementary pathways. At high concentrations, the cytotoxic activity of Bla g 1 induces the release of proinflammatory cytosolic contents including damageassociated molecular patterns (DAMPs) such as heat-shock Protein-70 (HSP70) and the cytokine interleukin-1 (IL-1β). Sublytic concentrations of Bla g 1 enhanced the ability of phospholipase A2 (PLA 2 ) to extract and hydrolyze phospholipid substrates from cellular membranes, stimulating the production of free polyunsaturated fatty acids (PUFAs) and various downstream inflammatory lipid mediators. Both of these effects are dependent on the presence of Bla g 1's natural fatty-acid (nMix) ligands with CC 50 values corresponding to the concentrations required for membrane destabilization reported in previous studies. Taken together, these results suggest that mechanisms through which Bla g 1mediated lipid delivery and membrane destabilization could directly contribute to cockroach allergic sensitization.

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Section: ■ Resultsmentioning

confidence: 99%

Section: ■ Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Production and Release of Proinflammatory Mediators by the Cockroach Allergen Bla g 1 via a Shared Membrane-Destabilization Mechanism

Foo,

Edin,

Lin

et al. 2024

Biochemistry

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“…In the context of the human exposome, this model would ensure that PFAS remain sequestered within its protein scaffold and thus insulated from loss or degradation by the outside environment until it is exposed to a pulmonary surfactant or epithelial cell membrane, further increasing the efficacy of BSA and other lipid-binding proteins as a delivery vehicle for PFAS contaminants. Previous studies have attempted to leverage these same properties to design novel drug-delivery systems based on serum albumins and other lipid-binding protein scaffolds. − Likewise, the use of albumins as a bioremediation tool to bind and sequester PFAS from the environment has also been explored . However, the ability of proteins to facilitate the delivery of PFAS into lipid membranes represents a novel pathway through which these compounds can interact with other elements of the human exposome to negatively impact human health.…”

Section: Resultsmentioning

confidence: 99%

Albumin Proteins as Delivery Vehicles for PFAS Contaminants into Respiratory Membranes

Pye,

Wallace,

Marangoni

et al. 2023

ACS Omega

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Poly- and perfluoroalkyl substances (PFAS) are a family of chemicals that have been used in a wide range of commercial products. While their use is declining, the prevalence of PFAS, combined with their chemical longevity, ensures that detectable levels will remain in the environment for years to come. As such, there is a pressing need to understand how PFAS contaminants interact with other elements of the human exposome and the consequences of these interactions for human health. Using serum albumin as a model system, we show that proteins can bind PFAS contaminants and facilitate their incorporation into model pulmonary surfactant systems and lipid bilayers. Protein-mediated PFAS delivery significantly altered the structure and function of both model membrane systems, potentially contributing to respiratory dysfunction and airway diseases in vivo. These results provide valuable insights into the synergistic interaction between PFAS contaminants and other elements of the human exposome and their potential consequences for human health.

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“…The exchange or delivery of various lipids may affect the stability of these membrane structures. For example, the MA domains AEG12 and Bla g 1 lyse mammalian cells and AEG12 disrupts replication of enveloped viruses ( 44 , 45 ). The nsLTP Ole e 7 has a similar high affinity to MA domains for charged phospholipids and it was shown to absorb to air-liquid interfaces.…”

Section: Discussionmentioning

confidence: 99%

Structural and ligand binding analysis of the pet allergens Can f 1 and Fel d 7

et al. 2023

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IntroductionPet lipocalins are respiratory allergens with a central hydrophobic ligand-binding cavity called a calyx. Molecules carried in the calyx by allergens are suggested to influence allergenicity, but little is known about the native ligands.MethodsTo provide more information on prospective ligands, we report crystal structures, NMR, molecular dynamics, and florescence studies of a dog lipocalin allergen Can f 1 and its closely related (and cross-reactive) cat allergen Fel d 7.ResultsStructural comparisons with reported lipocalins revealed that Can f 1 and Fel d 7 calyxes are open and positively charged while other dog lipocalin allergens are closed and negatively charged. We screened fatty acids as surrogate ligands, and found that Can f 1 and Fel d 7 bind multiple ligands with preferences for palmitic acid (16:0) among saturated fatty acids and oleic acid (18:1 cis-9) among unsaturated ones. NMR analysis of methyl probes reveals that conformational changes occur upon binding of pinolenic acid inside the calyx. Molecular dynamics simulation shows that the carboxylic group of fatty acids shuttles between two positively charged amino acids inside the Can f 1 and Fel d 7 calyx. Consistent with simulations, the stoichiometry of oleic acid-binding is 2:1 (fatty acid: protein) for Can f 1 and Fel d 7.DiscussionThe results provide valuable insights into the determinants of selectivity and candidate ligands for pet lipocalin allergens Can f 1 and Fel d 7.

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Expanding the antiviral potential of the mosquito lipid‐transfer protein AEG12 against SARS‐CoV‐2 using hydrophobic antiviral ligands

Cited by 3 publications

References 57 publications

Production and Release of Proinflammatory Mediators by the Cockroach Allergen Bla g 1 via a Shared Membrane-Destabilization Mechanism

Production and Release of Proinflammatory Mediators by the Cockroach Allergen Bla g 1 via a Shared Membrane-Destabilization Mechanism

Albumin Proteins as Delivery Vehicles for PFAS Contaminants into Respiratory Membranes

Structural and ligand binding analysis of the pet allergens Can f 1 and Fel d 7

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