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Prophylactic efficacy of orally administered Bacillus poly-?-glutamic acid, a non-LPS TLR4 ligand, against norovirus infection in mice.

ABSTRACT: Poly-gamma-glutamic acid (?-PGA), an extracellular biopolymer produced by Bacillus sp., is a non-canonical toll-like receptor 4 (TLR4) agonist. Here we show its antiviral efficacy against noroviruses. ?-PGA with a molecular mass of 2,000-kDa limited murine norovirus (MNV) replication in the macrophage cell line RAW264.7 by inducing interferon (IFN)-? and conferred resistance to viral infection-induced cell death. Additionally, ?-PGA interfered with viral entry into cells. The potent antiviral state mounted by ?-PGA was not attributed to the upregulation of TLR4 or TLR3, a sensor known to recognize norovirus RNA. ?-PGA sensing by TLR4 required the two TLR4-associated accessory factors MD2 and CD14. In ex vivo cultures of mouse ileum, ?-PGA selectively increased the expression of IFN-? in villi. In contrast, IFN-? induction was negligible in the ileal Peyer's patches (PPs) where its expression was primarily induced by the replication of MNV. Oral administration of ?-PGA, which increased serum IFN-? levels without inducing proinflammatory cytokines, reduced MNV loads in the ileum with PPs and mesenteric lymph nodes in mice. Our results disclose a ?-PGA-mediated non-conventional TLR4 signaling in the ileum, highlighting the potential use of ?-PGA as a prophylactic antiviral agent against noroviruses.

SUBMITTER: Lee W

PROVIDER: S-EPMC5989232 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Prophylactic efficacy of orally administered Bacillus poly-γ-glutamic acid, a non-LPS TLR4 ligand, against norovirus infection in mice.

Lee Wooseong W Kim Minwoo M Lee Seung-Hoon SH Jung Hae-Gwang HG Oh Jong-Won JW

Scientific reports 20180606 1

Poly-gamma-glutamic acid (γ-PGA), an extracellular biopolymer produced by Bacillus sp., is a non-canonical toll-like receptor 4 (TLR4) agonist. Here we show its antiviral efficacy against noroviruses. γ-PGA with a molecular mass of 2,000-kDa limited murine norovirus (MNV) replication in the macrophage cell line RAW264.7 by inducing interferon (IFN)-β and conferred resistance to viral infection-induced cell death. Additionally, γ-PGA interfered with viral entry into cells. The potent antiviral st ...[more]

PMID: 29875467

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Project description:BackgroundPoly-γ-glutamic acid (γ-PGA) is a valuable polymer with glutamate as its sole precursor. Enhancement of the intracellular glutamate synthesis is a very important strategy for the improvement of γ-PGA production, especially for those glutamate-independent γ-PGA producing strains. Corynebacterium glutamicum has long been used for industrial glutamate production and it exhibits some unique features for glutamate synthesis; therefore introduction of these metabolic characters into the γ-PGA producing strain might lead to increased intracellular glutamate availability, and thus ultimate γ-PGA production.ResultsIn this study, the unique glutamate synthesis features from C. glutamicum was introduced into the glutamate-independent γ-PGA producing Bacillus amyloliquefaciens NK-1 strain. After introducing the energy-saving NADPH-dependent glutamate dehydrogenase (NADPH-GDH) pathway, the NK-1 (pHT315-gdh) strain showed slightly increase (by 9.1%) in γ-PGA production. Moreover, an optimized metabolic toggle switch for controlling the expression of ɑ-oxoglutarate dehydrogenase complex (ODHC) was introduced into the NK-1 strain, because it was previously shown that the ODHC in C. glutamicum was completely inhibited when glutamate was actively produced. The obtained NK-PO1 (pHT01-xylR) strain showed 66.2% higher γ-PGA production than the NK-1 strain. However, the further combination of these two strategies (introducing both NADPH-GDH pathway and the metabolic toggle switch) did not lead to further increase of γ-PGA production but rather the resultant γ-PGA production was even lower than that in the NK-1 strain.ConclusionsWe proposed new metabolic engineering strategies to improve the γ-PGA production in B. amyloliquefaciens. The NK-1 (pHT315-gdh) strain with the introduction of NADPH-GDH pathway showed 9.1% improvement in γ-PGA production. The NK-PO1 (pHT01-xylR) strain with the introduction of a metabolic toggle switch for controlling the expression of ODHC showed 66.2% higher γ-PGA production than the NK-1 strain. This work proposed a new strategy for improving the target product in microbial cell factories.

Dataset Information

Prophylactic efficacy of orally administered Bacillus poly-?-glutamic acid, a non-LPS TLR4 ligand, against norovirus infection in mice.

Publications

Prophylactic efficacy of orally administered Bacillus poly-γ-glutamic acid, a non-LPS TLR4 ligand, against norovirus infection in mice.

Similar Datasets

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