scholarly journals Induction of autophagy by trehalose limits opportunistic mycobacterial infections in HIV-infected macrophages

2017 ◽  
Author(s):  
Vartika Sharma ◽  
Muzamil Makhdoomi ◽  
Purnima Kumar ◽  
Nabab Khan ◽  
Sarman Singh ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Avium ◽  
Defense Mechanisms ◽  
Bacterial Infections ◽  
Opportunistic Infections ◽  
Mycobacterium Fortuitum ◽  
Mycobacterial Infections ◽  
Innate Defense ◽  
Treatment Naïve ◽  
Immense Potential

AbstractOpportunistic bacterial infections amongst HIV-infected individuals pose serious health challenge. While immediate control of bacterial pathogens is typically attributed to innate defense mechanisms, whether HIV-mediated modulation of innate mechanisms like autophagy promote opportunistic infections, remains obscure. Using U1.1 and U937 macrophages, we show, HIV activation or infection inhibits autophagy and helps survival of pathogenic Mycobacterium tuberculosis and non-pathogenic non-tuberculous mycobacterial strains (NTMs) like Mycobacterium avium complex and Mycobacterium fortuitum. HIV achieves this by blocking xenophagy flux, which could be reversed by the autophagy inducer trehalose that kills intracellular Mtb and NTMs. We found trehalose acts as a PI (3,5) P2 agonist and activates TRPML1 to induce autophagy. Remarkably, trehalose treatment significantly reduced p24 levels in PBMCs infected with clinical HIV strains and in PBMCs derived from treatment-naive HIV patients. Taken together, our study highlights the immense potential of autophagy modulators in the therapeutic intervention of HIV and associated opportunistic infection.

scholarly journals Glycobiology of syndecan-1 in bacterial infections

2018 ◽  
Vol 46 (2) ◽  
pp. 371-377 ◽  
Author(s):  
Rafael S. Aquino ◽  
Yvonne Hui-Fang Teng ◽  
Pyong Woo Park
Keyword(s):  
Cell Surface ◽  
Defense Mechanisms ◽  
Bacterial Infections ◽  
Bacterial Pathogens ◽  
Innate Immune ◽  
Host Cells ◽  
Innate Defense ◽  
Immune Clearance ◽  
Bacterial Adhesins ◽  
A Cell

Syndecan-1 (Sdc1) is a major cell surface heparan sulfate (HS) proteoglycan of epithelial cells, a cell type targeted by many bacterial pathogens early in their pathogenesis. Loss of Sdc1 in mice is a gain-of-function mutation that significantly decreases the susceptibility to several bacterial infections, suggesting that subversion of Sdc1 is an important virulence strategy. HS glycosaminoglycan (GAG) chains of cell surface Sdc1 promote bacterial pathogenesis by facilitating the attachment of bacteria to host cells. Engagement of cell surface Sdc1 HS chains by bacterial adhesins transmits signal through the highly conserved Sdc1 cytoplasmic domain, which can lead to uptake of intracellular bacterial pathogens. On the other hand, several bacteria that do not require Sdc1 for their attachment and invasion stimulate Sdc1 shedding and exploit the capacity of Sdc1 ectodomain HS GAGs to disarm innate defense mechanisms to evade immune clearance. Recent data suggest that select HS sulfate motifs, and not the overall charge of HS, are important in the inhibition of innate immune mechanisms. Here, we discuss several examples of Sdc1 subversion in bacterial infections.

scholarly journals Innate immunity against infectious diseases, particularly in swine

2020 ◽  
Vol 76 (2) ◽  
pp. 67-70
Author(s):  
ZYGMUNT PEJSAK ◽  
MARIAN TRUSZCZYŃSKI ◽  
KAZIMIERZ TARASIUK
Keyword(s):  
Infectious Diseases ◽  
Defense Mechanisms ◽  
Bacterial Infections ◽  
Innate Immune ◽  
Mononuclear Phagocytes ◽  
Phagocytic Cells ◽  
Host Defense Peptides ◽  
Innate Defense ◽  
Etiologic Agents ◽  
Monocytes And Macrophages

The importance of innate defense mechanisms especially refering to swine, was characterized. Physical, chemical and microbial barriers were mentioned. The role of cells was underlined in controlling infection by phagocytosis without earlier immunisation by antigens and only depending on the genome of the born animal. The two main types of phagocytic cells were evaluated in antiinfectious activity: a)granular leucocytes, including neutrophils, basophils, eosynophils and mast cells, b)mononuclear phagocytes. These include blood circulating monocytes and macrophages. It was stated that natural killer cells belonging also to innate immune system can kill bacteria and viruses participating as etiologic agents in infectious diseases. Another group of innate immune factors, not cells but molecules, are creating defensins being host defense peptides. The complement mediates the inflammatory response, controlling bacterial infections. The following antiinfectious activity is exerted by Toll-like receptors. The presented cytokines are protein or glycoprotein molecules secreted by cells. They participate in intercellular and intracellular signalling.

A UK centre's experience of mycobacterial infections in HIV-infected patients

1998 ◽  
Vol 9 (10) ◽  
pp. 613-615 ◽  
Author(s):  
J E Clark ◽  
E L C Ong
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Avium ◽  
Retrospective Review ◽  
Mycobacterium Avium Complex ◽  
Mycobacterial Infection ◽  
Biopsy Material ◽  
Mycobacterial Infections ◽  
Resistance Patterns ◽  
The Uk ◽  
Infecting Organisms

A descriptive retrospective review of 26 patients with mycobacterial infection; 7 Mycobacterium tuberculosis (MTB), 17 Mycobacterium avium complex (MAC), one M. xenopei and one M. kansasii . Diagnosis of non-tuberculous mycobacteria (NTM) was made mainly from blood in 68%, with biopsy material initially useful in 68%. All MTB were fully sensitive. No patients received MAC chemoprophylaxis, yet resistance to rifabutin, ciprofloxacin and ethambutol was noted. It is important to examine the UK experience of mycobacterial infection; individual centres may find it useful to review infecting organisms and resistance patterns.

Combination of the Topliss Approach with the Free-Wilson Analysis in the Study of Antimycobacterial Activityof 4-Alkylthiobenzanilides

1997 ◽  
Vol 62 (9) ◽  
pp. 1503-1510 ◽  
Author(s):  
Jiří Kuneš ◽  
Jiří Jáchym ◽  
Petr Jirásko ◽  
Želmíra Odlerová ◽  
Karel Waisser
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Avium ◽  
Steric Effect ◽  
Antimycobacterial Activity ◽  
Mycobacterium Fortuitum ◽  
Mycobacterium Kansasii ◽  
Isopropyl Group ◽  
Butyl Group ◽  
Preliminary Study ◽  
Cyclohexyl Group

On the basis of a preliminary study of the antimycobacterial activity of thiobenzanilides, a group of 4'-isopropyl- and 4'-butylthiobenzanilides have been synthesized and tested against Mycobacterium tuberculosis, Mycobacterium kansasii, Mycobacterium avium and Mycobacterium fortuitum. The effect of the substituents on minimum inhibitory concentrations was calculated by the Free-Wilson method. The separated values were analyzed by the Topliss approach. The substitution of the thiobenzanilide in position 4' by the isopropyl group or butyl group increased the antimycobacterial activity less than the cyclohexyl group. The substitution in position 4 decreased the activity by the steric effect.

scholarly journals Antimycobacterial Calixarenes Enhance Innate Defense Mechanisms in Murine Macrophages and Induce Control of Mycobacterium tuberculosis Infection in Mice

2004 ◽  
Vol 72 (11) ◽  
pp. 6318-6323 ◽  
Author(s):  
M. Joseph Colston ◽  
Helen C. Hailes ◽  
Evangelos Stavropoulos ◽  
Anne C. Hervé ◽  
Gwenaelle Hervé ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Defense Mechanisms ◽  
Antimycobacterial Activity ◽  
Mycobacterium Tuberculosis Infection ◽  
Innate Defense ◽  
Histocompatibility Complex ◽  
Infected Cells ◽  
Resistant Strains ◽  
Oxide Synthase ◽  
Drug Resistant Strains

ABSTRACT Tuberculosis remains the leading cause of death among infectious diseases, accounting for more than two million deaths annually. The incidence of the disease is increasing globally, partially because of the resurgence of drug-resistant strains of Mycobacterium tuberculosis. Calixarenes are macrocyclic oligomers, some of which are able to modify the growth of M. tuberculosis in infected cells. Most experimental work has been carried out with Macrocyclon, also known as HOC 12.5EO. In this study, we demonstrate that Macrocyclon is effective in controlling M. tuberculosis infections, and we provide evidence that its effect is partially mediated by an l-arginine-dependent mechanism of macrophage activation that involves the activity of the inducible nitric oxide synthase. We also show that Macrocyclon is effective in athymic and major histocompatibility complex class II−/− mice and synthesized a number of structurally related calixarenes expressing significant antimycobacterial activity.

scholarly journals CD137 Signaling Is Critical in Fungal Clearance during Systemic Candida albicans Infection

2021 ◽  
Vol 7 (5) ◽  
pp. 382
Author(s):  
Vuvi G. Tran ◽  
Na N. Z. Nguyen ◽  
Byungsuk Kwon
Keyword(s):  
Candida Albicans ◽  
Defense Mechanisms ◽  
Tumor Necrosis ◽  
Fungal Infections ◽  
Fungal Growth ◽  
Wild Type ◽  
Agonistic Antibody ◽  
Innate Defense ◽  
Surface Receptor ◽  
Candida Albicans Infection

Invasive fungal infections by Candida albicans frequently cause mortality in immunocompromised patients. Neutrophils are particularly important for fungal clearance during systemic C. albican infection, yet little has been known regarding which surface receptor controls neutrophils’ antifungal activities. CD137, which is encoded by Tnfrsf9, belongs to the tumor necrosis receptor superfamily and has been shown to regulate neutrophils in Gram-positive bacterial infection. Here, we used genetic and immunological tools to probe the involvement of neutrophil CD137 signaling in innate defense mechanisms against systemic C. albicans infection. We first found that Tnfrsf9−/− mice were susceptible to C. albicans infection, whereas injection of anti-CD137 agonistic antibody protected the host from infection, suggesting that CD137 signaling is indispensable for innate immunity against C. albicans infection. Priming of isolated neutrophils with anti-CD137 antibody promoted their phagocytic and fungicidal activities through phospholipase C. In addition, injection of anti-CD137 antibody significantly augmented restriction of fungal growth in Tnfrsf9−/− mice that received wild-type (WT) neutrophils. In conclusion, our results demonstrate that CD137 signaling contributes to defense mechanisms against systemic C. albicans infection by promoting rapid fungal clearance.

scholarly journals Original Chemical Series of Pyrimidine Biosynthesis Inhibitors That Boost the Antiviral Interferon Response

2017 ◽  
Vol 61 (10) ◽  
Author(s):  
Marianne Lucas-Hourani ◽  
Daniel Dauzonne ◽  
Hélène Munier-Lehmann ◽  
Samira Khiar ◽  
Sébastien Nisole ◽  
...  
Keyword(s):  
Metabolic Pathway ◽  
Defense Mechanisms ◽  
De Novo ◽  
Pyrimidine Biosynthesis ◽  
Interferon Response ◽  
Type I ◽  
Innate Defense ◽  
New Class ◽  
Biosynthesis Inhibitors ◽  
Tightly Coupled

ABSTRACT De novo pyrimidine biosynthesis is a key metabolic pathway involved in multiple biosynthetic processes. Here, we identified an original series of 3-(1H-indol-3-yl)-2,3-dihydro-4H-furo[3,2-c]chromen-4-one derivatives as a new class of pyrimidine biosynthesis inhibitors formed by two edge-fused polycyclic moieties. We show that identified compounds exhibit broad-spectrum antiviral activity and immunostimulatory properties, in line with recent reports linking de novo pyrimidine biosynthesis with innate defense mechanisms against viruses. Most importantly, we establish that pyrimidine deprivation can amplify the production of both type I and type III interferons by cells stimulated with retinoic acid-inducible gene 1 (RIG-I) ligands. Altogether, our results further expand the current panel of pyrimidine biosynthesis inhibitors and illustrate how the production of antiviral interferons is tightly coupled to this metabolic pathway. Functional and structural similarities between this new chemical series and dicoumarol, which was reported before to inhibit pyrimidine biosynthesis at the dihydroorotate dehydrogenase (DHODH) step, are discussed.

scholarly journals CD137 Signaling is Critical in Fungal Clearance During Systemic Candida albicans Infection

2021 ◽  
Author(s):  
Vu Vi Giang Tran ◽  
Zen Na Nu Nguyen ◽  
Byungsuk Kwon
Keyword(s):  
Innate Immunity ◽  
Candida Albicans ◽  
Defense Mechanisms ◽  
Tumor Necrosis ◽  
Fungal Infections ◽  
Fungal Growth ◽  
Immunocompromised Patients ◽  
Agonistic Antibody ◽  
Innate Defense ◽  
Surface Receptor

Invasive fungal infections by Candida albicans frequently cause mortality in immunocompromised patients. Neutrophils are particularly important for fungal clearance at the early phase of infections, yet little has been known regarding which surface receptor controls neutrophil phagocytic activities during systemic C. albicans infection. CD137, which is encoded by Tnfrsf9, belongs to the tumor necrosis receptor superfamily and has been shown to regulate neutrophils in Gram-positive bacterial infection. Here, we used genetic and immunological tools to probe the involvement of CD137 signaling in innate defense mechanisms against systemic C. albicans infection. We first found that Tnfrsf9-/- mice were susceptible to C. albicans infection, whereas injection of anti-CD137 agonistic antibody protected the host from infection, suggesting that CD137 signaling is indispensable for innate immunity against C. albicans infection. Priming of isolated neutrophils with anti-CD137 antibody promoted their phagocytic and fungicidal activities through phospholipase C. In addition, injection of anti-CD137 antibody significantly augmented restriction of fungal growth in Tnfrsf9-/- mice that received WT neutrophils. In conclusion, our results demonstrate that CD137 signaling contributes to defense mechanisms against systemic C. albicans infection by promoting rapid fungal clearance whereby harmful immunopathology-induced tissue injuries are minimalized.

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