An autophagy-inducing and TLR-2 activating BCG vaccine induces a robust protection against tuberculosis in mice

Autor: Jin Wang, Subramanian Dhandayuthapani, Dekai Zhang, Chandrashekhar Pasare, Kishore Das, Chinnaswamy Jagannath, Jianjun Sun, Arshad Khan, Robert L. Hunter, Jaymie L. Estrella, Emily Soudani, Sankaralingam Saikolappan, Pearl Bakhru, Christopher R. Singh, N. Tony Eissa, Yue Ma
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: npj Vaccines, Vol 4, Iss 1, Pp 1-19 (2019)
NPJ Vaccines
ISSN: 2059-0105
DOI: 10.1038/s41541-019-0122-8
Popis: Mycobacterium bovis BCG is widely used as a vaccine against tuberculosis due to M. tuberculosis (Mtb), which kills millions of people each year. BCG variably protects children, but not adults against tuberculosis. BCG evades phagosome maturation, autophagy, and reduces MHC-II expression of antigen-presenting cells (APCs) affecting T-cell activation. To bypass these defects, an autophagy-inducing, TLR-2 activating C5 peptide from Mtb-derived CFP-10 protein was overexpressed in BCG in combination with Ag85B. Recombinant BCG85C5 induced a robust MHC-II-dependent antigen presentation to CD4 T cells in vitro, and elicited stronger TH1 cytokines (IL-12, IL-1β, and TNFα) from APCs of C57Bl/6 mice increasing phosphorylation of p38MAPK and ERK. BCG85C5 also enhanced MHC-II surface expression of MΦs by inhibiting MARCH1 ubiquitin ligase that degrades MHC-II. BCG85C5 infected APCs from MyD88 or TLR-2 knockout mice showed decreased antigen presentation. Furthermore, BCG85C5 induced LC3-dependent autophagy in macrophages increasing antigen presentation. Consistent with in vitro effects, BCG85C5 markedly expanded both effector and central memory T cells in C57Bl/6 mice protecting them against both primary aerosol infection with Mtb and reinfection, but was less effective among TLR-2 knockout mice. Thus, BCG85C5 induces stronger and longer lasting immunity, and is better than BCG against tuberculosis of mice.
Tuberculosis: Recombinant BCG vaccine shows enhanced protection via more efficient presentation The BCG vaccine is widely used but has highly variable efficacy due at least in part to its inefficient processing by antigen-presenting cells (APC). Chinnaswamy Jagannath and colleagues at the University of Texas Health Sciences Center identify a peptide (C5) derived from the Mycobacterium tuberculosis (Mtb) virulence factor component CFP10 which can efficiently enhance BCG’s ability to activate APC function. C5’s activity in APCs is dependent on both Toll-like receptor 2 signaling and activation of autophagy which together enhances presentation of the Mtb protein Ag85B. A recombinant BCG vaccine over-expressing both Ag85B and C5 (BCG85C5) more strongly activates TH1-like responses which are known to be protective against Mtb infection. Mouse vaccination with BCG85C5 induces a qualitatively and quantitatively superior response to BCG—including greater expansion of Ag85B-specific T cells, more robust memory T cell formation and better control of Mtb in both lung and spleen.
Databáze: OpenAIRE
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