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Identification of novel salivary candidate protein biomarkers for tuberculosis diagnosis: a preliminary biomarker discovery study.

ABSTRACT: Abstract Background There is an urgent need for new, accurate, rapid, and affordable tuberculosis (TB) diagnostic tests. The aim of the present study was to use mass spectrometry to identify new preliminary candidate TB diagnostic protein biomarkers in saliva obtained from individuals with TB, and patients with other respiratory diseases (ORD). Methods Saliva samples were collected from 22 individuals who self-presented with symptoms suggestive of TB as part of a larger TB biomarker project. Purified salivary proteins were subjected to tryptic digestion peptides were analysed using a QExactive Orbitrap Mass Spectrometer. Identified proteins were subjected to gene ontology and ingenuity pathway analysis for functional enrichment analysis. Results 26 of the 652 identified proteins significantly discriminated individuals with TB from those with ORD after Benjamini Hochberg correction (5% FDR), with five of these proteins diagnosing TB with an AUC ≥ 0.80. A 5-protein biosignature comprising of P01011, Q8NCW5, P28072, A0A2Q2TTZ9, and Q99574 diagnosed TB with an AUC of 1.00 (95% CI, 1.00-1.00), sensitivity of 100% (95% CI, 76.2-100%) and specificity of 90.9% (95% CI, 58.7-99.8%) after leave-one-out cross validation. Conclusions We identified novel candidate salivary protein biomarkers and biosignatures with strong potential as TB diagnostic candidates. Our results are preliminary and require validation in larger studies.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Saliva

SUBMITTER: Hygon Mutavhatsindi

LAB HEAD: Professor Jonathan Blackburn

PROVIDER: PXD027294 | Pride | 2021-08-05

REPOSITORIES: Pride

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Project description:Mycobacteria of the Mycobacterium tuberculosis complex (MTBC) greatly impact on human and animal health worldwide. Mycobacterial life cycle is complex and the mechanisms resulting in pathogen infection and survival in host cells are not fully understood. Eurasian wild boar (Sus scrofa) are natural reservoir hosts for MTBC and a model for mycobacterial infection and tuberculosis (TB). In the wild boar TB model, mycobacterial infection affects the expression of innate and adaptive immune response genes in mandibular lymph nodes and oropharyngeal tonsils and biomarkers have been proposed as correlates with resistance to natural infection. However, the mechanisms used by mycobacteria to manipulate host immune response are not fully characterized. Our hypothesis is that the immune system proteins under-represented in infected animals when compared to uninfected controls are used by mycobacteria to guarantee pathogen infection and transmission. To address this hypothesis, a comparative proteomics approach was used to compare host response between uninfected (TB-) and M. bovis-infected young (TB+) and adult animals with different infection status [TB lesions localized in the head (TB+) or affecting multiple organs (TB++)]. The results identified host immune system proteins that play an important role in host response to mycobacteria. Calcium binding protein A9, Heme peroxidase, Lactotransferrin, Cathelicidin and Peptidoglycan-recognition protein were under-represented in TB+ animals when compared to uninfected TB- controls but protein levels increased as infection progressed in TB++ animals when compared to TB- and/or TB+ adult wild boar. MHCI was the only protein over-represented in TB+ adult wild boar when compared to uninfected TB- controls. The results reported here suggested that M. bovis manipulates host immune response by reducing the production of immune system proteins. However, as infection progresses, wild boar immune response recover to limit pathogen multiplication and promote survival that also facilitates pathogen transmission.

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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Identification of novel salivary candidate protein biomarkers for tuberculosis diagnosis: a preliminary biomarker discovery study.

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