TY - JOUR
T1 - Luteolin-mediated kv1.3 k+ channel inhibition augments bcg vaccine efficacy against tuberculosis by promoting central memory t cell responses in mice
AU - Singh, Dhiraj Kumar
AU - Dwivedi, Ved Prakash
AU - Singh, Shashi Prakash
AU - Kumari, Anjna
AU - Sharma, Saurabh Kumar
AU - Ranganathan, Anand
AU - Kaer, Luc Van
AU - Das, Gobardhan
N1 - Funding Information:
GD was funded by Department of Biotechnology (http://dbtindia.gov.in) grant number BT/PR6312/MED/29/605/2012. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We acknowledge the support of the DBT-supported Tuberculosis Aerosol Challenge Facility at the International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India, and their staff in accomplishing this work. We thank Prof. David Sherman (Seattle Institute of Biomedical Research, Seattle, WA) for providing Mycobacterium tuberculosis strain H37Rv (ATCC 27294). DKS is the recipient of a Senior Research Fellowship from the Council of Scientific and Industrial Research (CSIR), Government of India. VPD is the recipient of a DST-INSPIRE Faculty Fellowship, Department of Science and Technology, Government of India and of Early Career Research Award from Science and Engineering Research Board (SERB), Department of Science and Technology, Government of India.
Publisher Copyright:
© 2020 Singh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2020/9
Y1 - 2020/9
N2 - Despite the availability of multiple antibiotics, tuberculosis (TB) remains a major health problem worldwide, with one third of the population latently infected and ~2 million deaths annually. The only available vaccine for TB, Bacillus Calmette Guérin (BCG), is ineffective against adult pulmonary TB. Therefore, alternate strategies that enhance vaccine efficacy are urgently needed. Vaccine efficacy and long-term immune memory are critically dependent on central memory T (TCM) cells, whereas effector memory T (TEM) cells are important for clearing acute infections. Recently, it has been shown that inhibition of the Kv1.3 K+ ion channel, which is predominantly expressed on TEM but not TCM cells, profoundly enhances TCM cell differentiation. We exploited this phenomenon to improve TCM:TEM cell ratios and protective immunity against Mycobacterium tuberculosis infection in response to BCG vaccination of mice. We demonstrate that luteolin, a plant-derived Kv1.3 K+ channel inhibitor, profoundly promotes TCM cells by selectively inhibiting TEM cells, and significantly enhances BCG vaccine efficacy. Thus, addition of luteolin to BCG vaccination may provide a sustainable means to improve vaccine efficacy by boosting host immunity via modulation of memory T cell differentiation.
AB - Despite the availability of multiple antibiotics, tuberculosis (TB) remains a major health problem worldwide, with one third of the population latently infected and ~2 million deaths annually. The only available vaccine for TB, Bacillus Calmette Guérin (BCG), is ineffective against adult pulmonary TB. Therefore, alternate strategies that enhance vaccine efficacy are urgently needed. Vaccine efficacy and long-term immune memory are critically dependent on central memory T (TCM) cells, whereas effector memory T (TEM) cells are important for clearing acute infections. Recently, it has been shown that inhibition of the Kv1.3 K+ ion channel, which is predominantly expressed on TEM but not TCM cells, profoundly enhances TCM cell differentiation. We exploited this phenomenon to improve TCM:TEM cell ratios and protective immunity against Mycobacterium tuberculosis infection in response to BCG vaccination of mice. We demonstrate that luteolin, a plant-derived Kv1.3 K+ channel inhibitor, profoundly promotes TCM cells by selectively inhibiting TEM cells, and significantly enhances BCG vaccine efficacy. Thus, addition of luteolin to BCG vaccination may provide a sustainable means to improve vaccine efficacy by boosting host immunity via modulation of memory T cell differentiation.
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U2 - 10.1371/journal.ppat.1008887
DO - 10.1371/journal.ppat.1008887
M3 - Article
C2 - 32956412
AN - SCOPUS:85092250113
VL - 16
JO - PLoS pathogens
JF - PLoS pathogens
SN - 1553-7366
IS - 9
M1 - e1008887
ER -