PMID- 29345365
OWN - NLM
STAT- MEDLINE
DCOM- 20190318
LR  - 20200225
IS  - 1938-3673 (Electronic)
IS  - 0741-5400 (Print)
IS  - 0741-5400 (Linking)
VI  - 103
IP  - 4
DP  - 2018 Apr
TI  - Deletion of BCG Hip1 protease enhances dendritic cell and CD4 T cell responses.
PG  - 739-748
LID - 10.1002/JLB.4A0917-363RR [doi]
AB  - Dendritic cells (DCs) play a key role in the generation of CD4 T cell responses 
      to pathogens. Mycobacterium tuberculosis (Mtb) harbors immune evasion mechanisms 
      that impair DC responses and prevent optimal CD4 T cell immunity. The vaccine 
      strain Mycobacterium bovis Bacille Calmette-Guerin (BCG) shares many of the 
      immune evasion proteins utilized by Mtb, but the role of these proteins in DC and 
      T cell responses elicited by BCG is poorly understood. We previously reported 
      that the Mtb serine protease, Hip1, promotes sub-optimal DC responses during 
      infection. Here, we tested the hypothesis that BCG Hip1 modulates DC functions 
      and prevents optimal antigen-specific CD4 T cell responses that limit the 
      immunogenicity of BCG. We generated a strain of BCG lacking hip1 (BCGDeltahip1) and 
      show that it has superior capacity to induce DC maturation and cytokine 
      production compared with the parental BCG. Furthermore, BCGDeltahip1-infected DCs 
      were more effective at driving the production of IFN-gamma and IL-17 from 
      antigen-specific CD4 T cells in vitro. Mucosal transfer of BCGDeltahip1-infected DCs 
      into mouse lungs induced robust CD4 T cell activation in vivo and generated 
      antigen-specific polyfunctional CD4 T cell responses in the lungs. Importantly, 
      BCGDeltahip1-infected DCs enhanced control of pulmonary bacterial burden following 
      Mtb aerosol challenge compared with the transfer of BCG-infected DCs. These 
      results reveal that BCG employs Hip1 to impair DC activation, leading to 
      attenuated lung CD4 T cell responses with limited capacity to control Mtb burden 
      after challenge.
CI  - (c)2017 Society for Leukocyte Biology.
FAU - Bizzell, Erica
AU  - Bizzell E
AD  - Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
FAU - Sia, Jonathan Kevin
AU  - Sia JK
AD  - Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
FAU - Quezada, Melanie
AU  - Quezada M
AD  - Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
FAU - Enriquez, Ana
AU  - Enriquez A
AD  - Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
FAU - Georgieva, Maria
AU  - Georgieva M
AD  - Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
AD  - Current affiliation: Maria Georgieva, Department of Epidemiology, Harvard T. H. 
      Chan School of Public Health, Boston, Massachusetts, USA.
FAU - Rengarajan, Jyothi
AU  - Rengarajan J
AD  - Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.
AD  - Division of Infectious Diseases, Department of Medicine, Emory University School 
      of Medicine, Atlanta, Georgia, USA.
LA  - eng
GR  - P51 OD011132/OD/NIH HHS/United States
GR  - R21 AI117162/AI/NIAID NIH HHS/United States
GR  - P51 RR000165/RR/NCRR NIH HHS/United States
GR  - UL1 TR000454/TR/NCATS NIH HHS/United States
GR  - UL1 TR002378/TR/NCATS NIH HHS/United States
GR  - R56 AI083366/AI/NIAID NIH HHS/United States
GR  - R01 AI083366/AI/NIAID NIH HHS/United States
GR  - R01 AI134244/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20171228
PL  - England
TA  - J Leukoc Biol
JT  - Journal of leukocyte biology
JID - 8405628
RN  - 0 (Bacterial Proteins)
RN  - EC 3.4.- (Hip1 protein, Mycobacterium tuberculosis)
RN  - EC 3.4.- (Serine Proteases)
SB  - IM
MH  - Animals
MH  - Bacterial Proteins/genetics/metabolism
MH  - CD4-Positive T-Lymphocytes/*immunology/microbiology
MH  - Cells, Cultured
MH  - Dendritic Cells/*immunology/microbiology
MH  - *Gene Deletion
MH  - Macrophages/*immunology/microbiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mycobacterium bovis/*immunology
MH  - Serine Proteases/*deficiency/genetics/metabolism
MH  - Tuberculosis/*immunology/metabolism/microbiology
PMC - PMC6457460
MID - NIHMS926854
OTO - NOTNLM
OT  - immune evasion
OT  - immunogenicity
OT  - tuberculosis
OT  - vaccine
COIS- CONFLICT OF INTEREST DISCLOSURE The authors have declared no conflicts of 
      interest.
EDAT- 2018/01/19 06:00
MHDA- 2019/03/19 06:00
PMCR- 2019/04/10
CRDT- 2018/01/19 06:00
PHST- 2017/09/06 00:00 [received]
PHST- 2017/11/29 00:00 [revised]
PHST- 2017/12/02 00:00 [accepted]
PHST- 2018/01/19 06:00 [pubmed]
PHST- 2019/03/19 06:00 [medline]
PHST- 2018/01/19 06:00 [entrez]
PHST- 2019/04/10 00:00 [pmc-release]
AID - 10.1002/JLB.4A0917-363RR [doi]
PST - ppublish
SO  - J Leukoc Biol. 2018 Apr;103(4):739-748. doi: 10.1002/JLB.4A0917-363RR. Epub 2017 
      Dec 28.