PMID- 34867965
OWN - NLM
STAT- MEDLINE
DCOM- 20220119
LR  - 20220119
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 12
DP  - 2021
TI  - Modulation of Cystatin C in Human Macrophages Improves Anti-Mycobacterial Immune 
      Responses to Mycobacterium tuberculosis Infection and Coinfection With HIV.
PG  - 742822
LID - 10.3389/fimmu.2021.742822 [doi]
LID - 742822
AB  - Tuberculosis owes its resurgence as a major global health threat mostly to the 
      emergence of drug resistance and coinfection with HIV. The synergy between HIV 
      and Mycobacterium tuberculosis (Mtb) modifies the host immune environment to 
      enhance both viral and bacterial replication and spread. In the lung immune 
      context, both pathogens infect macrophages, establishing favorable intracellular 
      niches. Both manipulate the endocytic pathway in order to avoid destruction. 
      Relevant players of the endocytic pathway to control pathogens include 
      endolysosomal proteases, cathepsins, and their natural inhibitors, cystatins. 
      Here, a mapping of the human macrophage transcriptome for type I and II cystatins 
      during Mtb, HIV, or Mtb-HIV infection displayed different profiles of gene 
      expression, revealing cystatin C as a potential target to control mycobacterial 
      infection as well as HIV coinfection. We found that cystatin C silencing in 
      macrophages significantly improves the intracellular killing of Mtb, which was 
      concomitant with an increased general proteolytic activity of cathepsins. In 
      addition, downmodulation of cystatin C led to an improved expression of the human 
      leukocyte antigen (HLA) class II in macrophages and an increased CD4(+) 
      T-lymphocyte proliferation along with enhanced IFN-gamma secretion. Overall, our 
      results suggest that the targeting of cystatin C in human macrophages represents 
      a promising approach to improve the control of mycobacterial infections including 
      multidrug-resistant (MDR) TB.
CI  - Copyright (c) 2021 Pires, Calado, Velez, Mandal, Catalao, Neyrolles, 
      Lugo-Villarino, Verollet, Azevedo-Pereira and Anes.
FAU - Pires, David
AU  - Pires D
AD  - Host-Pathogen Interactions, Research Institute for Medicines, iMed-ULisboa, 
      Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
FAU - Calado, Marta
AU  - Calado M
AD  - Host-Pathogen Interactions, Research Institute for Medicines, iMed-ULisboa, 
      Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
FAU - Velez, Tomas
AU  - Velez T
AD  - Host-Pathogen Interactions, Research Institute for Medicines, iMed-ULisboa, 
      Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
FAU - Mandal, Manoj
AU  - Mandal M
AD  - Host-Pathogen Interactions, Research Institute for Medicines, iMed-ULisboa, 
      Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
FAU - Catalao, Maria Joao
AU  - Catalao MJ
AD  - Host-Pathogen Interactions, Research Institute for Medicines, iMed-ULisboa, 
      Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
FAU - Neyrolles, Olivier
AU  - Neyrolles O
AD  - Institut de Pharmacologie et Biologie Structurale, IPBS, Universite de Toulouse, 
      Centre National de la Recherche Scientifique (CNRS), Toulouse, France.
FAU - Lugo-Villarino, Geanncarlo
AU  - Lugo-Villarino G
AD  - Institut de Pharmacologie et Biologie Structurale, IPBS, Universite de Toulouse, 
      Centre National de la Recherche Scientifique (CNRS), Toulouse, France.
FAU - Verollet, Christel
AU  - Verollet C
AD  - Institut de Pharmacologie et Biologie Structurale, IPBS, Universite de Toulouse, 
      Centre National de la Recherche Scientifique (CNRS), Toulouse, France.
FAU - Azevedo-Pereira, Jose Miguel
AU  - Azevedo-Pereira JM
AD  - Host-Pathogen Interactions, Research Institute for Medicines, iMed-ULisboa, 
      Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
FAU - Anes, Elsa
AU  - Anes E
AD  - Host-Pathogen Interactions, Research Institute for Medicines, iMed-ULisboa, 
      Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211118
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (CST3 protein, human)
RN  - 0 (Cystatin C)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - CD4-Positive T-Lymphocytes/immunology
MH  - Cells, Cultured
MH  - Coinfection/*immunology
MH  - Cystatin C/genetics/*immunology
MH  - HIV Infections/*immunology
MH  - HIV-1
MH  - Humans
MH  - Interferon-gamma/immunology
MH  - Macrophages/*immunology/microbiology
MH  - Mycobacterium tuberculosis
MH  - Tuberculosis/*immunology
PMC - PMC8637326
OTO - NOTNLM
OT  - HIV/Mtb coinfection
OT  - cathepsins
OT  - cystatins
OT  - host-directed therapies
OT  - tuberculosis
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/12/07 06:00
MHDA- 2022/01/20 06:00
PMCR- 2021/01/01
CRDT- 2021/12/06 09:07
PHST- 2021/07/16 00:00 [received]
PHST- 2021/10/21 00:00 [accepted]
PHST- 2021/12/06 09:07 [entrez]
PHST- 2021/12/07 06:00 [pubmed]
PHST- 2022/01/20 06:00 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2021.742822 [doi]
PST - epublish
SO  - Front Immunol. 2021 Nov 18;12:742822. doi: 10.3389/fimmu.2021.742822. eCollection 
      2021.