scholarly journals TLR7 Stimulation With Imiquimod Induces Selective Autophagy and Controls Mycobacterium tuberculosis Growth in Mouse Macrophages

2020 ◽  
Vol 11 ◽  
Author(s):  
Hyo-Ji Lee ◽  
Su-Jin Kang ◽  
Yunseo Woo ◽  
Tae-Wook Hahn ◽  
Hyun-Jeong Ko ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Selective Autophagy ◽  
Mouse Macrophages ◽  
Tlr7 Stimulation

scholarly journals Therapeutic Efficacy of SQ641-NE against Mycobacterium tuberculosis

2013 ◽  
Vol 58 (1) ◽  
pp. 587-589 ◽  
Author(s):  
Boris Nikonenko ◽  
Venkata M. Reddy ◽  
Elena Bogatcheva ◽  
Marina Protopopova ◽  
Leo Einck ◽  
...  
Keyword(s):  
Body Weight ◽  
Mycobacterium Tuberculosis ◽  
Therapeutic Efficacy ◽  
Content Type ◽  
Mouse Macrophages

ABSTRACTA phospholipid-based nanoemulsion formulation of SQ641 (SQ641-NE) was active against intracellularMycobacterium tuberculosisin J774A.1 mouse macrophages, although SQ641 by itself was not. Intravenous (i.v.) SQ641-NE was cleared from circulation and reached peak concentrations in lung and spleen in 1 h. In a murine tuberculosis (TB) model, 8 i.v. doses of SQ641-NE at 100 mg/kg of body weight over 4 weeks caused a 1.73 log10CFU reduction ofM. tuberculosisin spleen and were generally bacteriostatic in lungs.

Mycobacterial 3-hydroxyacyl-l-thioester dehydratase Y derived from Mycobacterium tuberculosis induces COX-2 expression in mouse macrophages through MAPK-NF-κB pathway

2014 ◽  
Vol 161 (1) ◽  
pp. 125-132 ◽  
Author(s):  
Jun-Wei Zhao ◽  
Zhan-Qiang Sun ◽  
Xiang-Yan Zhang ◽  
Yue Zhang ◽  
Jun Liu ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mouse Macrophages ◽  
Cox 2

scholarly journals Dihydrolipoamide Acyltransferase Is Critical for Mycobacterium tuberculosis Pathogenesis

2006 ◽  
Vol 74 (1) ◽  
pp. 56-63 ◽  
Author(s):  
Shuangping Shi ◽  
Sabine Ehrt
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Sodium Nitrite ◽  
Pyruvate Dehydrogenase ◽  
Nitrosative Stress ◽  
Oxidative And Nitrosative Stress ◽  
Retarded Growth ◽  
Mouse Macrophages

ABSTRACT Mycobacterium tuberculosis has evolved to persist in host macrophages, where it faces a nutrient-poor environment and is exposed to oxidative and nitrosative stress. To defend itself against oxidative/nitrosative stress, M. tuberculosis expresses an NADH-dependent peroxidase and peroxynitrite reductase that is encoded by ahpC, ahpD, lpd, and dlaT. In addition to its central role in the peroxynitrite reductase complex, dlaT (Rv2215) also encodes the E2 component of pyruvate dehydrogenase. Here we demonstrate that inactivation of dlaT in the chromosome of H37Rv resulted in a mutant (H37RvΔdlaT) that displayed phenotypes associated with DlaT's role in metabolism and in defense against nitrosative stress. The H37RvΔdlaT strain showed retarded growth in vitro and was highly susceptible to killing by acidified sodium nitrite. Mouse macrophages readily killed intracellular H37RvΔdlaT organisms, and in mice dlaT was required for full virulence.

scholarly journals Galectin-8 senses phagosomal damage and recruits selective autophagy adapter TAX1BP1 to control Mycobacterium tuberculosis infection in macrophages

2020 ◽  
Author(s):  
Samantha L. Bell ◽  
Kayla L. Lopez ◽  
Jeffery S. Cox ◽  
Kristin L. Patrick ◽  
Robert O. Watson
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Specific Interaction ◽  
Secretion System ◽  
Autophagosome Formation ◽  
Mycobacterium Tuberculosis Infection ◽  
Selective Autophagy ◽  
Galectin 3 ◽  
Autophagy Pathway ◽  
Sense And Respond ◽  
Phagosomal Membrane

ABSTRACTMycobacterium tuberculosis (Mtb) infects a quarter of the world and causes the deadliest infectious disease worldwide. Upon infection, Mtb is phagocytosed by macrophages and uses its virulence-associated ESX-1 secretion system to modulate the host cell and establish a replicative niche. We have previously shown the ESX-1 secretion system permeabilizes the Mtb-containing phagosome and that a population (~30%) of intracellular Mtb are recognized within the cytosol, tagged with ubiquitin, and targeted to the selective autophagy pathway. Despite the importance of selective autophagy in controlling infection, the mechanisms through which macrophages sense and respond to damaged Mtb-containing phagosomes remains unclear. Here, we demonstrate that several cytosolic glycan-binding proteins, known as galectins, recognize Mtb-containing phagosomes. We found that galectins-3, -8, and -9 are all recruited to the same Mtb population that colocalizes with selective autophagy markers like ubiquitin, p62, and LC3, which indicates Mtb damages its phagosomal membrane such that cytosolic host sensors can recognize danger signals in the lumen. To determine which galectins are required for controlling Mtb replication in macrophages, we generated CRISPR/Cas9 knockout macrophages lacking individual or multiple galectins and found that galectin-8-/- and galectin-3/8/9-/- knockout macrophages were similarly defective in targeting Mtb to selective autophagy and controlling replication, suggesting galectin-8 plays a privileged role in anti-Mtb autophagy. In investigating this specificity, we identified a novel and specific interaction between galectin-8 and TAX1BP1, one of several autophagy adaptors that bridges cargo and LC3 during the course of autophagosome formation, and this galectin-8/TAX1BP1 interaction was necessary to efficiently target Mtb to selective autophagy. Remarkably, overexpressing individual galectins increased targeting of Mtb to antibacterial autophagy and limited Mtb replication. Taken together, these data imply that galectins recognize damaged Mtb-containing phagosomes, recruit downstream autophagy machinery, and may represent promising targets for host-directed therapeutics to treat Mtb.

scholarly journals Type I interferon signaling mediates Mycobacterium tuberculosis–induced macrophage death

2020 ◽  
Vol 218 (2) ◽  
Author(s):  
Li Zhang ◽  
Xiuju Jiang ◽  
Daniel Pfau ◽  
Yan Ling ◽  
Carl F. Nathan
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Critical Role ◽  
Type I ◽  
Type I Ifn ◽  
Paracrine Signaling ◽  
Type I Ifns ◽  
Genome Wide ◽  
Mouse Macrophages ◽  
Definition Of

Macrophages help defend the host against Mycobacterium tuberculosis (Mtb), the major cause of tuberculosis (TB). Once phagocytized, Mtb resists killing by macrophages, replicates inside them, and leads to their death, releasing Mtb that can infect other cells. We found that the death of Mtb-infected mouse macrophages in vitro does not appear to proceed by a currently known pathway. Through genome-wide CRISPR-Cas9 screening, we identified a critical role for autocrine or paracrine signaling by macrophage-derived type I IFNs in the death of Mtb-infected macrophages in vitro, and blockade of type I IFN signaling augmented the effect of rifampin, a first-line TB drug, in Mtb-infected mice. Further definition of the pathway of type I IFN–mediated macrophage death may allow for host-directed therapy of TB that is more selective than systemic blockade of type I IFN signaling.

scholarly journals Galectin-8 Senses Phagosomal Damage and Recruits Selective Autophagy Adapter TAX1BP1 To Control Mycobacterium tuberculosis Infection in Macrophages

mBio ◽  
2021 ◽  
Author(s):  
Samantha L. Bell ◽  
Kayla L. Lopez ◽  
Jeffery S. Cox ◽  
Kristin L. Patrick ◽  
Robert O. Watson
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Infectious Diseases ◽  
Tuberculosis Infection ◽  
Harsh Environment ◽  
Intracellular Pathogens ◽  
First Line ◽  
Mycobacterium Tuberculosis Infection ◽  
Content Type ◽  
Selective Autophagy ◽  
Global Population

Mycobacterium tuberculosis (Mtb) infects one-quarter of the global population and causes one of the deadliest infectious diseases worldwide. Macrophages are the first line of defense against Mtb infection and are typically incredibly efficient at destroying intracellular pathogens, but Mtb has evolved to survive and replicate in this harsh environment.

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