scholarly journals IRG1 controls immunometabolic host response and restricts intracellular Mycobacterium tuberculosis infection

2019 ◽  
Author(s):  
Eik Hoffmann ◽  
Arnaud Machelart ◽  
Imène Belhaouane ◽  
Nathalie Deboosere ◽  
Anne-Marie Pauwels ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Host Response ◽  
Immune Cell ◽  
Isocitrate Lyase ◽  
Metabolic Reprogramming ◽  
Host Cells ◽  
Wild Type ◽  
Term Survival ◽  
Major Player ◽  
Deficient Mice

AbstractMycobacterium tuberculosis (Mtb), the pathogen causing human tuberculosis, has evolved multiple strategies to successfully prevent clearance by immune cells and to establish dissemination and long-term survival in the host. The modulation of host immunity to maximize pathogen elimination while minimizing inflammation-mediated tissue damage may provide another tool to fight drug-resistant Mtb strains. Metabolic reprogramming of immune cell populations can dramatically influence the outcome of immune responses and modulate antimicrobial properties of infected host cells, nicely demonstrating that metabolites are tightly linked to immune cell effector functions. One important endogenous metabolite of the Krebs cycle is itaconate, which has potent bactericidal activity by inhibiting isocitrate lyase and the glyoxylate shunt within prokaryotes including mycobacteria. Recent findings show that itaconate and the catalytic enzyme responsible for its generation in mammalian cells, i.e. IRG1 (immune-responsive gene 1), also modify inflammatory signaling of infected cells enhancing host defense pathways.Here, we demonstrate that IRG1 is recruited to Mtb-containing phagosomes and that it influences the host response controlling Mtb infection. While IRG1 deficiency does not affect uptake of Mtb by macrophages and dendritic cells (DCs) in vitro, it increases the intracellular replication of Mtb. Concomitantly, in comparison to wild type cells, IRG1-deficient macrophages and DCs have increased levels of lipid droplets, a correlate of inflammation. These intracellular organelles store triacylglycerol and phospholipids that are hijacked by Mtb as reservoir of host nutrients. Exposure of IRG1-deficient mice to M. bovis BCG via the intranasal route induced neither lethality nor severe lung immunopathology, while IRG1-deficient mice were highly susceptible to Mtb infection resulting in animal death three weeks post-infection linked to exacerbated inflammation and high mycobacterial burden. The lungs of infected IRG1-deficient mice displayed large areas of necrotizing granulomatous inflammation and neutrophil infiltration, accompanied by reduced levels of B and T lymphocytes and increased levels of alveolar and interstitial macrophage populations, compared to their wild type counterparts. Therefore, our findings demonstrate that IRG1 is a major player in controlling the acute phase of Mtb infection with a specific effect on pathogenic mycobacteria.

scholarly journals Role for nsP2 Proteins in the Cessation of Alphavirus Minus-Strand Synthesis by Host Cells

2006 ◽  
Vol 80 (1) ◽  
pp. 360-371 ◽  
Author(s):  
Dorothea L. Sawicki ◽  
Silvia Perri ◽  
John M. Polo ◽  
Stanley G. Sawicki
Keyword(s):  
Host Response ◽  
Rna Synthesis ◽  
Late Phase ◽  
Host Cells ◽  
Minus Strand ◽  
Wild Type ◽  
Persistent Infections ◽  
Infected Cells ◽  
Replicative Intermediates ◽  
Transcription Complexes

ABSTRACT In order to establish nonlytic persistent infections (PI) of BHK cells, replicons derived from Sindbis (SIN) and Semliki Forest (SFV) viruses have mutations in nsP2. Five different nsP2 PI replicons were compared to wild-type (wt) SIN, SFV, and wt nsPs SIN replicons. Replicon PI BHK21 cells had viral RNA synthesis rates that were less than 5% of those of the wt virus and ∼10% or less of those of SIN wt replicon-infected cells, and, in contrast to wt virus and replicons containing wt nsP2, all showed a phenotype of continuous minus-strand synthesis and of unstable, mature replication/transcription complexes (RC+) that are active in plus-strand synthesis. Minus-strand synthesis and incorporation of [3H]uridine into replicative intermediates differed among PI replicons, depending on the location of the mutation in nsP2. Minus-strand synthesis by PI cells appeared normal; it was dependent on continuous P123 and P1234 polyprotein synthesis and ceased when protein synthesis was inhibited. The failure by the PI replicons to shut off minus-strand synthesis was not due to some defect in the PI cells but rather was due to the loss of some function in the mutated nsP2. This was demonstrated by showing that superinfection of PI cells with wt SFV triggered the shutdown of minus-strand synthesis, which we believe is a host response to infection with alphaviruses. Together, the results indicate alphavirus nsP2 functions to engage the host response to infection and activate a switch from the early-to-late phase. The loss of this function leads to continuous viral minus-strand synthesis and the production of unstable RC+.

scholarly journals Pro-tumoral immune cell alterations in wild type and Shb-deficient mice in response to 4T1 breast carcinomas

Oncotarget ◽  
2018 ◽  
Vol 9 (27) ◽  
pp. 18720-18733 ◽  
Author(s):  
Xiujuan Li ◽  
Kailash Singh ◽  
Zhengkang Luo ◽  
Mariela Mejia-Cordova ◽  
Maria Jamalpour ◽  
...  
Keyword(s):  
Immune Cell ◽  
Breast Carcinomas ◽  
Wild Type ◽  
Cell Alterations ◽  
Deficient Mice

scholarly journals Rv0180c contributes to Mycobacterium tuberculosis cell shape and to infectivity in mice and macrophages

2021 ◽  
Vol 17 (11) ◽  
pp. e1010020
Author(s):  
Delphine Payros ◽  
Henar Alonso ◽  
Wladimir Malaga ◽  
Arnaud Volle ◽  
Serge Mazères ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Cell Shape ◽  
Cell Envelope ◽  
Membrane Receptors ◽  
Host Cells ◽  
Wild Type ◽  
Genes Encoding ◽  
The Difference ◽  
Complement Receptor 3 ◽  
New Perspective

Mycobacterium tuberculosis, the main causative agent of human tuberculosis, is transmitted from person to person via small droplets containing very few bacteria. Optimizing the chance to seed in the lungs is therefore a major adaptation to favor survival and dissemination in the human population. Here we used TnSeq to identify genes important for the early events leading to bacterial seeding in the lungs. Beside several genes encoding known virulence factors, we found three new candidates not previously described: rv0180c, rv1779c and rv1592c. We focused on the gene, rv0180c, of unknown function. First, we found that deletion of rv0180c in M. tuberculosis substantially reduced the initiation of infection in the lungs of mice. Next, we established that Rv0180c enhances entry into macrophages through the use of complement-receptor 3 (CR3), a major phagocytic receptor for M. tuberculosis. Silencing CR3 or blocking the CR3 lectin site abolished the difference in entry between the wild-type parental strain and the Δrv0180c::km mutant. However, we detected no difference in the production of both CR3-known carbohydrate ligands (glucan, arabinomannan, mannan), CR3-modulating lipids (phthiocerol dimycocerosate), or proteins in the capsule of the Δrv0180c::km mutant in comparison to the wild-type or complemented strains. By contrast, we established that Rv0180c contributes to the functionality of the bacterial cell envelope regarding resistance to toxic molecule attack and cell shape. This alteration of bacterial shape could impair the engagement of membrane receptors that M. tuberculosis uses to invade host cells, and open a new perspective on the modulation of bacterial infectivity.

Midkine prevents ventricular remodeling and improves long-term survival after myocardial infarction

2009 ◽  
Vol 296 (2) ◽  
pp. H462-H469 ◽  
Author(s):  
Hiroharu Takenaka ◽  
Mitsuru Horiba ◽  
Hisaaki Ishiguro ◽  
Arihiro Sumida ◽  
Mayumi Hojo ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Ventricular Remodeling ◽  
Umbilical Vein ◽  
Left Ventricular ◽  
Wild Type ◽  
Long Term Effects ◽  
Term Survival ◽  
Deficient Mice

Cardiac remodeling is thought to be the major cause of chronic heart dysfunction after myocardial infarction (MI). However, molecules involved in this process have not been thoroughly elucidated. In this study we investigated the long-term effects of the growth factor midkine (MK) in cardiac remodeling after MI. MI was produced by ligation of the left coronary artery. MK expression was progressively increased after MI in wild-type mice, and MK-deficient mice showed a higher mortality. Exogenous MK improved survival and ameliorated left ventricular dysfunction and fibrosis not only of MK-deficient mice but also of wild-type mice. Angiogenesis in the peri-infarct zone was also enhanced. These in vivo changes induced by exogenous MK were associated with the activation of phosphatidylinositol 3-kinase (PI3K)/Akt and MAPKs (ERK, p38) and the expression of syndecans in the left ventricular tissue. In vitro experiments using human umbilical vein endothelial cells confirmed the potent angiogenic action of MK via the PI3K/Akt pathway. These results suggest that MK prevents the cardiac remodeling after MI and improves the survival most likely through an enhancement of angiogenesis. MK application could be a new therapeutic strategy for the treatment of ischemic heart failure.

scholarly journals The Stringent Response of Mycobacterium tuberculosis Is Required for Long-Term Survival

2000 ◽  
Vol 182 (17) ◽  
pp. 4889-4898 ◽  
Author(s):  
Todd P. Primm ◽  
Susan J. Andersen ◽  
Valerie Mizrahi ◽  
David Avarbock ◽  
Harvey Rubin ◽  
...  
Keyword(s):  
Growth Rate ◽  
Mycobacterium Tuberculosis ◽  
Stringent Response ◽  
Wild Type ◽  
Liquid Media ◽  
Term Survival ◽  
Long Term Survival ◽  
Starvation Conditions

ABSTRACT The stringent response utilizes hyperphosphorylated guanine [(p)ppGpp] as a signaling molecule to control bacterial gene expression involved in long-term survival under starvation conditions. In gram-negative bacteria, (p)ppGpp is produced by the activity of the related RelA and SpoT proteins. Mycobacterium tuberculosis contains a single homolog of these proteins (RelMtb) and responds to nutrient starvation by producing (p)ppGpp. A relMtb knockout strain was constructed in a virulent strain of M. tuberculosis, H37Rv, by allelic replacement. The relMtb mutant displayed a significantly slower aerobic growth rate than the wild type in synthetic liquid media, whether rich or minimal. The growth rate of the wild type was equivalent to that of the mutant when citrate or phospholipid was employed as the sole carbon source. These two organisms also showed identical growth rates within a human macrophage-like cell line. These results suggest that the in vivo carbon source does not represent a stressful condition for the bacilli, since it appears to be utilized in a similar RelMtb-independent manner. In vitro growth in liquid media represents a condition that benefits from RelMtb-mediated adaptation. Long-term survival of therelMtb mutant during in vitro starvation or nutrient run out in normal media was significantly impaired compared to that in the wild type. In addition, the mutant was significantly less able to survive extended anerobic incubation than the wild-type virulent organism. Thus, the RelMtb protein is required for long-term survival of pathogenic mycobacteria under starvation conditions.

scholarly journals Fibrinogen Regulates the Cytotoxicity of Mycobacterial Trehalose Dimycolate but Is Not Required for Cell Recruitment, Cytokine Response, or Control of Mycobacterial Infection

2009 ◽  
Vol 78 (3) ◽  
pp. 1004-1011 ◽  
Author(s):  
Kaori Sakamoto ◽  
Rachel E. Geisel ◽  
Mi-Jeong Kim ◽  
Bryce T. Wyatt ◽  
Llewelyn B. Sellers ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Granulation Tissue ◽  
Inflammatory Responses ◽  
Mycobacterial Infection ◽  
Cytokine Response ◽  
Wild Type ◽  
Cell Recruitment ◽  
Trehalose Dimycolate ◽  
Deficient Mice

ABSTRACT During inflammatory responses and wound healing, the conversion of soluble fibrinogen to fibrin, an insoluble extracellular matrix, long has been assumed to create a scaffold for the migration of leukocytes and fibroblasts. Previous studies concluded that fibrinogen is a necessary cofactor for mycobacterial trehalose 6,6′-dimycolate-induced responses, because trehalose dimycolate-coated beads, to which fibrinogen was adsorbed, were more inflammatory than those to which other plasma proteins were adsorbed. Herein, we investigate roles for fibrin(ogen) in an in vivo model of mycobacterial granuloma formation and in infection with Mycobacterium tuberculosis, the causative agent of tuberculosis. In wild-type mice, the subcutaneous injection of trehalose dimycolate-coated polystyrene microspheres, suspended within Matrigel, elicited a pyogranulomatous response during the course of 12 days. In fibrinogen-deficient mice, neutrophils were recruited but a more suppurative lesion developed, with the marked degradation and disintegration of the matrix. Compared to that in wild-type mice, the early formation of granulation tissue in fibrinogen-deficient mice was edematous, hypocellular, and disorganized. These deficiencies were complemented by the addition of exogenous fibrinogen. The absence of fibrinogen had no effect on cell recruitment or cytokine production in response to trehalose dimycolate, nor was there a difference in lung histopathology or overall bacterial burden in mice infected with Mycobacterium tuberculosis. In this model, fibrin(ogen) was not required for cell recruitment, cytokine response, or response to infection, but it promoted granulation tissue formation and suppressed leukocyte necrosis.

scholarly journals Increased disease burden in Interleukin-3 deficient mice after Mycobacterium tuberculosis and herpes simplex virus infections

2021 ◽  
Author(s):  
Shajo Kunnath-Velayudhan ◽  
Tony W. Ng ◽  
Neeraj K. Saini ◽  
Michael F. Goldberg ◽  
Pooja Arora ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Mouse Models ◽  
Lung Pathology ◽  
Wild Type ◽  
Interleukin 3 ◽  
Simplex Virus ◽  
Deficient Mice ◽  
Hsv 1

AbstractInterleukin-3 (IL-3) is produced during infections caused by parasites, bacteria and viruses, but its contribution to immunity in this context remains largely unknown. In mouse models of parasitic infections, in which the effects of IL-3 have been most extensively studied, IL-3 has been variously reported as protective, detrimental or inconsequential. Similarly, mixed results have been reported in viral and bacterial infection models. Here, we investigated the effects of IL-3 in mouse models of Mycobacterium tuberculosis and herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infections by assessing the pathogen burden, disease manifestations and survival following infection. After infection with M. tuberculosis, IL-3 deficient mice showed higher bacillary burden, increased lung pathology and reduced survival compared to wild type mice. After infection with HSV-1 through cutaneous route and HSV-2 through vaginal route, IL-3 deficient mice showed higher viral burden, increased disease manifestations and reduced survival compared to wild type mice. Our results show that IL-3 makes a subtle but significant contribution to protective immunity in these mouse models of bacterial and viral infections.

scholarly journals The cGAS/STING Pathway Is Important for Dendritic Cell Activation but Is Not Essential to Induce Protective Immunity against Mycobacterium tuberculosis Infection

2018 ◽  
Vol 10 (3) ◽  
pp. 239-252 ◽  
Author(s):  
Fabio V. Marinho ◽  
Sulayman Benmerzoug ◽  
Stephanie  Rose ◽  
Priscila C. Campos ◽  
João T. Marques ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Cell Activation ◽  
Body Weight Gain ◽  
Host Cells ◽  
Health Concern ◽  
Wild Type ◽  
Activation Markers ◽  
Sting Pathway

Mycobacterium tuberculosis (Mtb) infection remains a major public health concern. The STING (stimulator of interferon genes) pathway contributes to the cytosolic surveillance of host cells. Most studies on the role of STING activation in Mtb infection have focused on macrophages. Moreover, a detailed investigation of the role of STING during Mtb infection in vivo is required. Here, we deciphered the involvement of STING in the activation of dendritic cells (DCs) and the host response to Mtb infection in vivo. In DCs, this adaptor molecule was important for Ifn-β expression and IL-12 production as well as for the surface expression of the activation markers CD40 and CD86. We also documented that Mtb DNA induces STING activation in murine fibroblasts. In vivo Mtb aerogenic infection induced the upregulation of the STING and cGAS (cyclic GMP-AMP synthase) genes, and Ifn-β pulmonary expression was dependent on both sensors. However, mice deficient for STING or cGAS presented a similar outcome to wild-type controls, with no major alterations in body weight gain, bacterial burden, or survival. Lung inflammation, proinflammatory cytokine production, and inflammatory cell recruitment were similar in STING- and cGAS-deficient mice compared to wild-type controls. In summary, although the STING pathway seems to be crucial for DC activation during Mtb infection, it is dispensable for host protection in vivo.

scholarly journals Survival and Replication of Clinical Mycobacterium tuberculosis Isolates in the Context of Human Innate Immunity

2005 ◽  
Vol 73 (5) ◽  
pp. 2595-2601 ◽  
Author(s):  
Ernestas Janulionis ◽  
Carolina Sofer ◽  
Stephan K. Schwander ◽  
Denarra Nevels ◽  
Barry Kreiswirth ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Mycobacterium Tuberculosis ◽  
Blood Culture ◽  
Whole Blood ◽  
Host Response ◽  
Host Cells ◽  
Clinical Isolates ◽  
The Face ◽  
Mycobacterial Growth ◽  
Reference Strains

ABSTRACT The initial host response to Mycobacterium tuberculosis is driven by innate immunity. For this study, we examined the ability of 18 recent clinical isolates and 5 reference strains to survive and replicate in the context of host innate immunity by using whole blood culture. Six healthy tuberculin-negative volunteers served as subjects. H37Ra showed the least capacity to replicate of any of the strains tested, decreasing in viability 1.3 log CFU during 72 h of whole blood culture, whereas H37Rv increased 0.32 log. Clinical isolates varied greatly in their ability to replicate in blood cells, ranging from −0.4 to +0.8 log (P < 0.001). Four showed significantly more growth than H37Rv, and one showed significantly reduced growth. Host mechanisms for restricting intracellular mycobacterial growth were more effective during the first 24 h of whole blood culture than during the 24- to 72-h period. Certain mycobacterial isolates appeared preferentially able to withstand host defenses during each of these intervals. Although there was relatively more homogeneity among subjects than among strains, one of the six subjects showed a reduced capacity to restrict intracellular mycobacterial growth due to a defect expressed during the first 24 h of culture. Our findings indicate substantial variability in the capacity of clinical tuberculosis isolates to replicate in host cells in the face of innate host immunity.

scholarly journals Potential Plasticity of the Mannoprotein Repertoire Associated to Mycobacterium tuberculosis Virulence Unveiled by Mass Spectrometry-Based Glycoproteomics

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2348
Author(s):  
Laure Tonini ◽  
Bashir Sadet ◽  
Alexandre Stella ◽  
David Bouyssié ◽  
Jérôme Nigou ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Mycobacterium Tuberculosis ◽  
Large Scale ◽  
Therapeutic Targets ◽  
Multidrug Resistant ◽  
Host Cells ◽  
Bacterial Protein ◽  
Wild Type ◽  
In The Wild ◽  
Resistant Strains

To date, Mycobacterium tuberculosis (Mtb) remains the world’s greatest infectious killer. The rise of multidrug-resistant strains stresses the need to identify new therapeutic targets to fight the epidemic. We previously demonstrated that bacterial protein-O-mannosylation is crucial for Mtb infectiousness, renewing the interest of the bacterial-secreted mannoproteins as potential drug-targetable virulence factors. The difficulty of inventorying the mannoprotein repertoire expressed by Mtb led us to design a stringent multi-step workflow for the reliable identification of glycosylated peptides by large-scale mass spectrometry-based proteomics. Applied to the differential analyses of glycoproteins secreted by the wild-type Mtb strain—and by its derived mutant invalidated for the protein-O-mannosylating enzyme PMTub—this approach led to the identification of not only most already known mannoproteins, but also of yet-unknown mannosylated proteins. In addition, analysis of the glycoproteome expressed by the isogenic recombinant Mtb strain overexpressing the PMTub gene revealed an unexpected mannosylation of proteins, with predicted or demonstrated functions in Mtb growth and interaction with the host cell. Since in parallel, a transient increased expression of the PMTub gene has been observed in the wild-type bacilli when infecting macrophages, our results strongly suggest that the Mtb mannoproteome may undergo adaptive regulation during infection of the host cells. Overall, our results provide deeper insights into the complexity of the repertoire of mannosylated proteins expressed by Mtb, and open the way to novel opportunities to search for still-unexploited potential therapeutic targets.

Sign in / Sign up

Export Citation Format

Share Document