scholarly journals Modulation of Cystatin C in Human Macrophages Improves Anti-Mycobacterial Immune Responses to Mycobacterium tuberculosis Infection and Coinfection With HIV

2021 ◽  
Vol 12 ◽  
Author(s):  
David Pires ◽  
Marta Calado ◽  
Tomás Velez ◽  
Manoj Mandal ◽  
Maria João Catalão ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Cystatin C ◽  
Human Leukocyte ◽  
Multidrug Resistant ◽  
Endocytic Pathway ◽  
Human Macrophage ◽  
Type I ◽  
Mycobacterium Tuberculosis Infection ◽  
Human Macrophages ◽  
T Lymphocyte Proliferation

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-γ 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.

scholarly journals Orchestration of human macrophage NLRP3 inflammasome activation by Staphylococcus aureus extracellular vesicles

2020 ◽  
Vol 117 (6) ◽  
pp. 3174-3184 ◽  
Author(s):  
Xiaogang Wang ◽  
William J. Eagen ◽  
Jean C. Lee
Keyword(s):  
Staphylococcus Aureus ◽  
Extracellular Vesicles ◽  
Biological Effects ◽  
Endocytic Pathway ◽  
Host Cells ◽  
Human Macrophage ◽  
Inflammasome Activation ◽  
Human Macrophages ◽  
Caspase 1 ◽  
Tlr2 Signaling

Release of extracellular vesicles (EVs) is a common feature among eukaryotes, archaea, and bacteria. However, the biogenesis and downstream biological effects of EVs released from gram-positive bacteria remain poorly characterized. Here, we report that EVs purified from a community-associated methicillin-resistant Staphylococcus aureus strain were internalized into human macrophages in vitro and that this process was blocked by inhibition of the dynamin-dependent endocytic pathway. Human macrophages responded to S. aureus EVs by TLR2 signaling and activation of NLRP3 inflammasomes through K+ efflux, leading to the recruitment of ASC and activation of caspase-1. Cleavage of pro–interleukin (IL)-1β, pro-IL-18, and gasdermin-D by activated caspase-1 resulted in the cellular release of the mature cytokines IL-1β and IL-18 and induction of pyroptosis. Consistent with this result, a dose-dependent cytokine response was detected in the extracellular fluids of mice challenged intraperitoneally with S. aureus EVs. Pore-forming toxins associated with S. aureus EVs were critical for NLRP3-dependent caspase-1 activation of human macrophages, but not for TLR2 signaling. In contrast, EV-associated lipoproteins not only mediated TLR2 signaling to initiate the priming step of NLRP3 activation but also modulated EV biogenesis and the toxin content of EVs, resulting in alterations in IL-1β, IL-18, and caspase-1 activity. Collectively, our study describes mechanisms by which S. aureus EVs induce inflammasome activation and reveals an unexpected role of staphylococcal lipoproteins in EV biogenesis. EVs may serve as a novel secretory pathway for S. aureus to transport protected cargo in a concentrated form to host cells during infections to modulate cellular functions.

scholarly journals TRIM14 Is a Key Regulator of the Type I IFN Response during Mycobacterium tuberculosis Infection

2020 ◽  
Vol 205 (1) ◽  
pp. 153-167 ◽  
Author(s):  
Caitlyn T. Hoffpauir ◽  
Samantha L. Bell ◽  
Kelsi O. West ◽  
Tao Jing ◽  
Allison R. Wagner ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Tuberculosis Infection ◽  
Type I ◽  
Type I Ifn ◽  
Mycobacterium Tuberculosis Infection

scholarly journals The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis

2005 ◽  
Vol 202 (7) ◽  
pp. 987-999 ◽  
Author(s):  
Peter B. Kang ◽  
Abul K. Azad ◽  
Jordi B. Torrelles ◽  
Thomas M. Kaufman ◽  
Alison Beharka ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mannose Receptor ◽  
Human Macrophage ◽  
Phagosome Maturation ◽  
Human Macrophages ◽  
Phagocytic Process ◽  
Fusion Inhibition ◽  
Macrophage Mannose Receptor ◽  
Intracellular Adhesion Molecule ◽  
Intact Molecule

Mycobacterium tuberculosis (M.tb) survives in macrophages in part by limiting phagosome–lysosome (P-L) fusion. M.tb mannose-capped lipoarabinomannan (ManLAM) blocks phagosome maturation. The pattern recognition mannose receptor (MR) binds to the ManLAM mannose caps and mediates phagocytosis of bacilli by human macrophages. Using quantitative electron and confocal microscopy, we report that engagement of the MR by ManLAM during the phagocytic process is a key step in limiting P-L fusion. P-L fusion of ManLAM microspheres was significantly reduced in human macrophages and an MR-expressing cell line but not in monocytes that lack the receptor. Moreover, reversal of P-L fusion inhibition occurred with MR blockade. Inhibition of P-L fusion did not occur with entry via Fcγ receptors or dendritic cell–specific intracellular adhesion molecule 3 grabbing nonintegrin, or with phosphatidylinositol-capped lipoarabinomannan. The ManLAM mannose cap structures were necessary in limiting P-L fusion, and the intact molecule was required to maintain this phenotype. Finally, MR blockade during phagocytosis of virulent M.tb led to a reversal of P-L fusion inhibition in human macrophages (84.0 ± 5.1% vs. 38.6 ± 0.6%). Thus, engagement of the MR by ManLAM during the phagocytic process directs M.tb to its initial phagosomal niche, thereby enhancing survival in human macrophages.

scholarly journals Integrative Analysis of Human Macrophage Inflammatory Response Related to Mycobacterium tuberculosis Virulence

2021 ◽  
Vol 12 ◽  
Author(s):  
Pauline Bade ◽  
Fabrizio Simonetti ◽  
Stephanie Sans ◽  
Patricia Laboudie ◽  
Khadija Kissane ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Inflammatory Response ◽  
Genetic Networks ◽  
Host Cells ◽  
Human Macrophage ◽  
Human Macrophages ◽  
Adaptive Immune ◽  
Adaptive Immune Cells ◽  
Main Host ◽  
Host Inflammatory Response

Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, kills 1.5 to 1.7 million people every year. Macrophages are Mtb’s main host cells and their inflammatory response is an essential component of the host defense against Mtb. However, Mtb is able to circumvent the macrophages’ defenses by triggering an inappropriate inflammatory response. The ability of Mtb to hinder phagolysosome maturation and acidification, and to escape the phagosome into the cytosol, is closely linked to its virulence. The modulation of the host inflammatory response relies on Mtb virulence factors, but remains poorly studied. Understanding macrophage interactions with Mtb is crucial to develop strategies to control tuberculosis. The present study aims to determine the inflammatory response transcriptome and miRNome of human macrophages infected with the virulent H37Rv Mtb strain, to identify macrophage genetic networks specifically modulated by Mtb virulence. Using human macrophages infected with two different live strains of mycobacteria (live or heat-inactivated Mtb H37Rv and M. marinum), we quantified and analyzed 184 inflammatory mRNAs and 765 micro(mi)RNAs. Transcripts and miRNAs differently modulated by H37Rv in comparison with the two other conditions were analyzed using in silico approaches. We identified 30 host inflammatory response genes and 37 miRNAs specific for H37Rv virulence, and highlight evidence suggesting that Mtb intracellular-linked virulence depends on the inhibition of IL-1β-dependent pro-inflammatory response, the repression of apoptosis and the delay of the recruitment and activation of adaptive immune cells. Our findings provide new potential targets for the development of macrophage-based therapeutic strategies against TB.

Sign in / Sign up

Export Citation Format

Share Document