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Cell-autonomous targeting of arabinogalactan by host immune factors inhibits mycobacterial growth

ABSTRACT: Deeper understanding of the crosstalk between host cells and Mycobacterium tuberculosis (Mtb) provides crucial guidelines for the rational design of novel intervention strategies against tuberculosis (TB). Mycobacteria possess a unique complex cell wall with arabinogalactan (AG) as critical component. AG has been identified as a virulence factor of Mtb which is recognized by host galectin-9. Here we demonstrate that galectin-9 directly inhibited mycobacterial growth through AG-binding property of carbohydrate-recognition domain 2. Furthermore, IgG antibodies with AG specificity were detected in serum of TB patients. Based on the interaction between galectin-9 and AG, we developed monoclonal antibody (mAb) screening assay and identified AG-specific mAbs which profoundly inhibit Mtb growth. Mechanistically, proteomic profiling and morphological characterizations revealed that AG-specific mAbs regulate AG biosynthesis, thereby inducing cell wall swelling. Thus, direct AG-binding by galectin-9 or antibodies contributes to protection against TB. Our findings pave the way for the rational design of novel immunotherapeutic strategies for TB control.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Mycobacterium Tuberculosis Na-a0009

TISSUE(S): Cell Culture

SUBMITTER: Jianxia Chen

LAB HEAD: Haipeng Liu

PROVIDER: PXD056927 | Pride | 2024-10-18

REPOSITORIES: Pride

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Project description:The venom apparatus is a conserved organ in parasitoid wasps that shows adaptations correlated with life-style diversification. Recent venom analyses from selected species reveal considerable complexity and high diversity in venom composition existing not only between closely related species but even between strains and individuals, which may partly determine the potential for parasitoid adaptation. However, the investigations have paid little attention to secondary venom components that also have significant functions in parasitism, and the data in regard to full and accurate quantity of venom compositions at the protein level is not available. Using a combination of transcriptomic and label-free quantitative proteomic, we here explored the venom components of the endoparasitoid Tetrastichus brontispae (Eulophidae), a species devoid of polydnavirus, and provided an in-depth comparison of the venom proteomes between its two closely related strains, Tb-On and Tb-Bl. Results showed that approximately 1505 venom proteins were identified in the venom apparatus of T. brontispae, consistent with the classical venom protein characteristics, including enzymes, protease inhibitors, binding proteins and some immune related proteins. The venom extracts also contained novel venom proteins, such as kynurenine-oxoglutarate transaminase, 4-coumarate CoA ligase and venom protein r-like protein. Comparative venom proteomes revealed that significant quantitative and qualitative changes in venom composition occurred when Tb-Bl strain, with an invasive beetle Brontispae longissima pupa as its habitual host, was exposed to another invasive beetle Octodonta nipae pupa as host consecutively for two years; although the most abundant venom proteins were shared between them. These significantly differentially expressed proteins were mainly enriched in fatty acid biosynthesis and melanotic encapsulation response by enrichment analyses. Furthermore, most of the significantly enriched proteins presented strikingly increased levels or were exclusively identified in the Tb-On strain. These combined results indicated that virulence factors in Tb-On strain might be linked to lipid metabolism or more venom is required to inhibit O. nipae pupa’s melanotic encapsulation upon its parasitism. Altogether, our data reveal that venom composition can quickly evolve and respond to host selection, mainly through rapid changes in regulation of protein abundance and/or the emergence of multigenic families by gene duplication. Our data additionally provide invaluable data for further functional analysis of parasitoid venoms.

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	Y126_1_Slot2-29_1_2164.d.zip	Other
	Y126_2_Slot2-30_1_2166.d.zip	Other
	Y126_Slot2-28_1_2162.d.zip	Other
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Cell-autonomous targeting of arabinogalactan by host immune factors inhibits mycobacterial growth

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