Proteome Exploration of
            <i>Legionella pneumophila</i>
            To Identify Novel Therapeutics: a Hierarchical Subtractive Genomics and Reverse Vaccinology Approach

Khan, Md. Tahsin; Mahmud, Araf; Hasan, Mahmudul; Azim, Kazi Faizul; Begum, Musammat Kulsuma; Rolin, Mohimenul Haque; Akter, Arzuba; Mondal, Shakhinur Islam

doi:10.1128/spectrum.00373-22

Cited by 3 publications

References 157 publications

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Immunoinformatic-guided designing of multi-epitope vaccine construct against Brucella Suis 1300

2022

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Brucella suis mediates the transmission of brucellosis in humans and animals and a significant facultative zoonotic pathogen found in livestock. It has the capacity to survive and multiply in a phagocytic environment and to acquire resistance under hostile conditions thus becoming a threat globally. Antibiotic resistance is posing a substantial public health threat, hence there is an unmet and urgent clinical need for immune-based non-antibiotic methods to treat brucellosis. Hence, we aimed to explore the whole proteome of Brucella suis to predict antigenic proteins as a vaccine target and designed a novel chimeric vaccine (multi-epitope vaccine) through subtractive genomics-based reverse vaccinology approaches. The applied subsequent hierarchical shortlisting resulted in the identification of Multidrug efflux Resistance-nodulation-division (RND) transporter outer membrane subunit (gene BepC) that may act as a potential vaccine target. T-cell and B-cell epitopes have been predicted from target proteins using a number of immunoinformatic methods. Six MHC I, ten MHC II, and four B-cell epitopes were used to create a 324-amino-acid MEV construct, which was coupled with appropriate linkers and adjuvant. To boost the immunological response to the vaccine, the vaccine was combined with the TLR4 agonist HBHA protein. The MEV structure predicted was found to be highly antigenic, non-toxic, non-allergenic, flexible, stable, and soluble. To confirm the interactions with the receptors, a molecular docking simulation of the MEV was done using the human TLR4 (toll-like receptor 4) and HLAs. The stability and binding of the MEV-docked complexes with TLR4 were assessed using molecular dynamics (MD) simulation. Finally, MEV was reverse translated, its cDNA structure was evaluated, and then, in silico cloning into an E. coli expression host was conducted to promote maximum vaccine protein production with appropriate post-translational modifications. These comprehensive computer calculations backed up the efficacy of the suggested MEV in protecting against B. suis infections. However, more experimental validations are needed to adequately assess the vaccine candidate's potential. Highlights• Subtractive genomic analysis and reverse vaccinology for the prioritization of novel vaccine target • Examination of chimeric vaccine in terms of allergenicity, antigenicity, MHC I, II binding efficacy, and structural-based studies • Molecular docking simulation method to rank based vaccine candidate and understand their binding modes

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Immunoinformatic-guided designing of multi-epitope vaccine construct against Brucella Suis 1300

2022

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Multi-epitopes vaccine design for surface glycoprotein against SARS-CoV-2 using immunoinformatic approach

Arshad,

Rehana,

Saleem

et al. 2024

Heliyon

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Development of covalent probes to captureLegionella pneumophilaeffector enzymes

Kloet,

Mukhopadhyay,

Mukherjee

et al. 2024

Preprint

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Upon infection of host cells, Legionella pneumophila releases a multitude of effector enzymes into the cells cytoplasm that hijack a plethora of cellular activities, including the hosts ubiquitination pathways. Effectors belonging to the SidE-family are involved in non-canonical serine phosphoribosyl ubiquitination of host substrate proteins contributing to the formation of a Legionella-containing vacuole that is crucial in the onset of Legionnaires disease. This dynamic process is reversed by effectors called Dups that hydrolyse the phosphodiester in the phosphoribosyl ubiquitinated protein. We installed reactive warheads on chemically prepared ribosylated ubiquitin to generate a set of probes targeting these Legionella enzymes. In vitro tests on recombinant DupA revealed that a vinyl sulfonate warhead was most efficient in covalent complex formation. Mutagenesis and x-ray crystallography approaches were used to identify the site of covalent crosslinking to be an allosteric cysteine residue. The subsequent application of this probe highlights the potential to selectively enrich the Dup enzymes from Legionella-infected cell lysates.

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Proteome Exploration of Legionella pneumophila To Identify Novel Therapeutics: a Hierarchical Subtractive Genomics and Reverse Vaccinology Approach

Cited by 3 publications

References 157 publications

Immunoinformatic-guided designing of multi-epitope vaccine construct against Brucella Suis 1300

Immunoinformatic-guided designing of multi-epitope vaccine construct against Brucella Suis 1300

Multi-epitopes vaccine design for surface glycoprotein against SARS-CoV-2 using immunoinformatic approach

Development of covalent probes to captureLegionella pneumophilaeffector enzymes

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