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Expression of Cathepsin S in BCG converts it into a pro-apoptotic and highly immunogenic strain.

Abstract：

BACKGROUND:BCG vaccine, introduced almost 100years ago, is the only option to prevent TB disease. It effectively protects newborns from meningeal TB but fails to prevent adult pulmonary TB. TB kills 1.3million people annually in areas where BCG vaccination is widely practiced. Thus, more effective TB vaccines are urgently needed. Others and we have shown that BCG mimics features of virulent M. tuberculosis, in particular attenuation of essential macrophage functions such as phagosome maturation and antigen presentation. One of these studies revealed that defect in antigen presentation is largely due to down-regulation of the cysteine protease Cathepsin S (CatS), which prevents MHC II molecule maturation and proper antigen peptide loading. Recent studies also suggested a potential role for cysteine proteases in the regulation of apoptosis, a key cellular process used by the macrophage to (i) contain and process ingested bacteria and (ii) facilitate cross-talk antigen presentation between the macrophage and dendritic cells. METHOD:To reverse the phenotype of vaccine-mediated macrophage attenuation, we engineered a novel BCG strain that expresses and secretes active CatS (rBCG-CatS) to examine its pro-apoptotic properties in vitro, and subsequently, immunogenicity in mice. RESULTS:Transcriptomic profiling of macrophages infected with rBCG-CatS, but not BCG, revealed upregulation of key pro-apoptotic genes and downregulation of anti-apoptotic genes, which were further confirmed by RT-qPCR analyses of expression of selected genes. Macrophages infected with rBCG-CatS undergo apoptosis as indicated by increased levels of annexin V staining and intracellular caspase-3 cleavage. Consistent with these findings, mice vaccinated with rBCG-CatS showed increased antigen-specific CD4+ T-cell responses, as well as enhanced cytokine production and proliferation in CD4+ upon ex vivo re-stimulation. CONCLUSION:Collectively, this study shows that a pro-apoptotic BCG strain alleviates adverse traits of the wild-type strain, resulting in a highly immunogenic TB vaccine.

journal_name

Vaccine

journal_title

Vaccine

authors

Lau A,Singh V,Soualhine H,Hmama Z

doi

10.1016/j.vaccine.2017.02.065

subject

Has Abstract

pub_date

2017-04-11 00:00:00

pages

2060-2068

issue

eissn

0264-410X

issn

1873-2518

pii

S0264-410X(17)30290-6

journal_volume

pub_type

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Expression of Cathepsin S in BCG converts it into a pro-apoptotic and highly immunogenic strain.