Systematic Evaluation of Mycobacterium tuberculosis Proteins for Antigenic Properties Identifies Rv1485 and Rv1705c as Potential Protective Subunit Vaccine Candidates

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Abstract

ABSTRACT

The lack of efficacious vaccines against Mycobacterium tuberculosis (MTB) infection is a limiting factor in the prevention and control of tuberculosis (TB), the leading cause of death from an infectious agent. Improvement or replacement of the BCG vaccine with one that reliably protects all age groups is urgent. Concerns exist that antigens currently being evaluated are too homogeneous. To identify new protective antigens, we screened 1,781 proteins from a high-throughput proteome-wide protein purification study for antigenic activity. Forty-nine antigens (34 previously unreported) induced antigen-specific gamma interferon (IFN-γ) release from peripheral blood mononuclear cells (PBMCs) derived from 4,452 TB and suspected TB patients and 167 healthy donors. Three (Rv1485, Rv1705c, and Rv1802) of the 20 antigens evaluated in a BALB/c mouse challenge model showed protective efficacy, reducing lung CFU counts by 66.2%, 75.8%, and 60%, respectively. Evaluation of IgG2a/IgG1 ratios and cytokine release indicated that Rv1485 and Rv1705c induce a protective Th1 immune response. Epitope analysis of PE/PPE protein Rv1705c, the strongest candidate, identified a dominant epitope in its extreme N-terminal domain accounting for 90% of its immune response. Systematic preclinical assessment of antigens Rv1485 and Rv1705c is warranted.

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Most cited references 66

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Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.

Da Huang, Brad T. Sherman, Richard A. Lempicki (2009)

DAVID bioinformatics resources consists of an integrated biological knowledgebase and analytic tools aimed at systematically extracting biological meaning from large gene/protein lists. This protocol explains how to use DAVID, a high-throughput and integrated data-mining environment, to analyze gene lists derived from high-throughput genomic experiments. The procedure first requires uploading a gene list containing any number of common gene identifiers followed by analysis using one or more text and pathway-mining tools such as gene functional classification, functional annotation chart or clustering and functional annotation table. By following this protocol, investigators are able to gain an in-depth understanding of the biological themes in lists of genes that are enriched in genome-scale studies.

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Final Analysis of a Trial of M72/AS01E Vaccine to Prevent Tuberculosis

Dereck Tait, Mark Hatherill, Olivier Van Der Meeren … (2019)

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Is Open Access

Interferon-γ derived from cytotoxic lymphocytes directly enhances their motility and cytotoxicity

Purnima Bhat, Graham Leggatt, Nigel J. Waterhouse … (2017)

Interferon gamma (IFNγ) is a key moderator of cell-mediated immunity with diverse, mainly pro-inflammatory actions on immunocytes and target tissue. Recent studies have shown it may enhance anti-tumor and antiviral effects of CD8 T cells. Here we investigate the mechanisms by which IFNγ mediates CD8 T-cell cytotoxic function. We show that in vivo, antigen-specific CD8 T cells that produce INFγ are necessary to effect rejection of skin grafts expressing OVA as a transgene in keratinocytes. The ability of CD8 T cells to produce IFNγ enhanced their ability to migrate to the site of antigen-presenting skin cells. By in vivo imaging, we show that CTL motility, particularly speed, during graft rejection was enhanced by locally available IFNγ. We then used a reductionist two-cell model of CTL effectors and keratinocyte targets to investigate the effects of locally available (paracrine) and CTL-producing (autocrine) IFNγ on the motility behavior and killing ability of the CTL. Using live-cell imaging by prolonged time-lapse microscopy of primary effector CD8 T cells and antigen-expressing primary keratinocyte targets, we show that CD8 T-cell cytotoxic function and motility is enhanced by locally available IFNγ. Conversely, deprivation of either autocrine or paracrine IFNγ, or blockade of IFNγ signaling to CTL markedly reduced their cytotoxic function, their kinematics, and effector cell survival. We conclude that in vitro and in vivo, autocrine production of IFNγ by CTL enhances their motility and promotes killing of primary target keratinocytes. The absolute need for local IFNγ to enable cytotoxic CD8 T-cell function is of significance for immunotherapy for chronic viral infection and for cancer.

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Author and article information

Contributors

Sabine Ehrt: Role: Editor

Journal

Journal ID (nlm-ta): Infect Immun

Journal ID (iso-abbrev): Infect Immun

Journal ID (hwp): iai

Journal ID (pmc): iai

Journal ID (publisher-id): IAI

Title: Infection and Immunity

Publisher: American Society for Microbiology (1752 N St., N.W., Washington, DC )

ISSN (Print): 0019-9567

ISSN (Electronic): 1098-5522

Publication date (Electronic preprint): 14 December 2020

Publication date (Electronic): 16 February 2021

Publication date Collection: March 2021

Publication date PMC-release: 16 February 2021

Volume: 89

Issue: 3

Electronic Location Identifier: e00585-20

Affiliations

[a ]Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

[b ]National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

[c ]Beijing Key Laboratory for Drug Resistant Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China

[d ]Hebei Chest Hospital, Shijiazhuang, China

[e ]Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan Province, China

[f ]School of Stomatology and Medicine, Foshan University, Foshan, Guangdong Province, China

[g ]Guangdong Province Key Laboratory of TB Systems Biology and Translational Medicine, Foshan, Guangdong Province, China

[h ]University of Chinese Academy of Sciences, Beijing, China

Weill Cornell Medical College

Author notes

Address correspondence to Hongtai Zhang, hongtaizhang@ 123456aliyun.com , Junmei Yang, yangjunmei7683@ 123456163.com , or Zongde Zhang, zzd417@ 123456ccmu.edu.cn .

Yaguo Wang, Zihui Li, and Shucai Wu contributed equally to this work. Author order was determined based on overall contribution of time to the study.

Citation Wang Y, Li Z, Wu S, Fleming J, Li C, Zhu G, Chen B, Ren B, Wang X, Du B, Li P, Hu P, Yang J, Liu Y, Zhou C, Zhang X-E, Bi L, Zhang H, Yang J, Zhang Z. 2021. Systematic evaluation of Mycobacterium tuberculosis proteins for antigenic properties identifies Rv1485 and Rv1705c as potential protective subunit vaccine candidates. Infect Immun 89:e00585-20. https://doi.org/10.1128/IAI.00585-20.

Author information

Hongtai Zhang https://orcid.org/0000-0001-9308-5872

Article

Publisher ID: 00585-20

DOI: 10.1128/IAI.00585-20

PMC ID: 8097267

PubMed ID: 33318140

SO-VID: 19af9f37-f970-4310-b363-55773bcb1630

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History

Date received : 17 September 2020

Date revision requested : 13 October 2020

Date accepted : 27 November 2020

Page count

Figures: 5, Tables: 0, Equations: 0, References: 67, Pages: 14, Words: 9620

Funding

Funded by: The Strategic Priority Research Program of the Chinese Academy of Sciences;

Award ID: XDB29020000

Award Recipient : Lijun Bi

Funded by: The National Key Research and Development Program of China;

Award ID: 2017YFD0500300

Award Recipient : Lijun Bi

Funded by: The National Science and Technology Major Project;

Award ID: 2018ZX10101004

Award Recipient : Lijun Bi

Funded by: The National Natural Science Foundation of China;

Award ID: 31770148

Award Recipient : Hongtai Zhang

Funded by: The National Natural Science Foundation of China;

Award ID: 31770150

Award Recipient : Lijun Bi

Funded by: The International Partnership Program of the Chinese Academy of Sciences;

Award ID: 153311KYSB20170001

Award Recipient : Lijun Bi

Funded by: The Special Fund for Public Welfare Research and Capacity Building in Guangdong Province;

Award ID: 2014B030301002

Award Recipient : Lijun Bi

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cover-date March 2021

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: mycobacterium tuberculosis,tb vaccine,antigen,protective efficacy,th1 immune response,ifn-γ,elispot assay,bacillus calmette-guérin vaccine,pe/ppe protein

Data availability:

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: mycobacterium tuberculosis, tb vaccine, antigen, protective efficacy, th1 immune response, ifn-γ, elispot assay, bacillus calmette-guérin vaccine, pe/ppe protein

Systematic Evaluation of Mycobacterium tuberculosis Proteins for Antigenic Properties Identifies Rv1485 and Rv1705c as Potential Protective Subunit Vaccine Candidates

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Point-Of-Care Testing for Tuberculosis

Most cited references 66

Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.

Final Analysis of a Trial of M72/AS01E Vaccine to Prevent Tuberculosis

Interferon-γ derived from cytotoxic lymphocytes directly enhances their motility and cytotoxicity

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