Malaria exacerbates experimental mycobacterial infection in vitro and in vivo

2010 ◽  
Vol 12 (11) ◽  
pp. 864-874 ◽  
Author(s):  
Michael Hawkes ◽  
Xiaoming Li ◽  
Maryanne Crockett ◽  
Angelina Diassiti ◽  
W. Conrad Liles ◽  
...  
Keyword(s):  
Mycobacterial Infection

IMB-BZ as an Inhibitor Targeting ESX-1 Secretion System to Control Mycobacterial Infection

2021 ◽  
Author(s):  
Pingping Jia ◽  
Yi Zhang ◽  
Jian Xu ◽  
Mei Zhu ◽  
Shize Peng ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mycobacterial Infection ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
New Drugs ◽  
Dependent Manner ◽  
High Potency ◽  
Resistance Development

Abstract Background Resistance to anti-tuberculosis (TB) drug is a major issue in TB control, and demands the discovery of new drugs targeting virulence factor ESX-1. Methods We first established a high-throughput screen (HTS) assay for the discovery of ESX-1 secretion inhibitors. The positive hits were then evaluated for the potency of diminishing the survival of virulent mycobacterium and reducing bacterial virulence. We further investigated the probability of inducing drug-resistance and the underlying mechanism using M-PFC. Results A robust HTS assay was developed to identify small molecules that inhibit ESX-1 secretion without impairing bacterial growth in vitro. A hit named IMB-BZ specifically inhibits the secretion of CFP-10 and reduces virulence in an ESX-1-dependent manner, therefore resulting in significant reduction in intracellular and in vivo survival of mycobacteria. Blocking the CFP-10-EccCb1 interaction directly or indirectly underlies the inhibitory effect of IMB-BZ on the secretion of CFP-10. Importantly, our finding shows that the ESX-1 inhibitors pose low risk of drug resistance development by mycobacteria in vitro as compared with traditional anti-TB drug, and exhibit high potency against chronic mycobacterial infection. Conclusion Targeting ESX-1 may lead to the development of novel therapeutics for tuberculosis. IMB-BZ holds the potential for future development into a new anti-TB drug.

scholarly journals Long-Term Control of Mycobacterium bovis BCG Infection in the Absence of Toll-Like Receptors (TLRs): Investigation of TLR2-, TLR6-, or TLR2-TLR4-Deficient Mice

2004 ◽  
Vol 72 (12) ◽  
pp. 6994-7004 ◽  
Author(s):  
Delphine Nicolle ◽  
Cécile Fremond ◽  
Xavier Pichon ◽  
André Bouchot ◽  
Isabelle Maillet ◽  
...  
Keyword(s):  
Mycobacterium Bovis ◽  
Chronic Phase ◽  
Mycobacterial Infection ◽  
Infection Period ◽  
Essentially Normal ◽  
Toll Like Receptor 2 ◽  
Deficient Mice

ABSTRACT Live mycobacteria have been reported to signal through both Toll-like receptor 2 (TLR2) and TLR4 in vitro. Here, we investigated the role of TLR2 in the long-term control of the infection by the attenuated Mycobacterium, Mycobacterium bovis BCG, in vivo. We sought to determine whether the reported initial defect of bacterial control (K. A. Heldwein et al., J. Leukoc. Biol. 74:277-286, 2003) resolved in the chronic phase of BCG infection. Here we show that TLR2-deficient mice survived a 6-month infection period with M. bovis BCG and were able to control bacterial growth. Granuloma formation, T-cell and macrophage recruitment, and activation were normal. Furthermore, the TLR2 coreceptor, TLR6, is also not required since TLR6-deficient mice were able to control chronic BCG infection. Finally, TLR2-TLR4-deficient mice infected with BCG survived the 8-month observation period. Interestingly, the adaptive response of TLR2- and/or TLR4-deficient mice seemed essentially normal on day 14 or 56 after infection, since T cells responded normally to soluble BCG antigens. In conclusion, our data demonstrate that TLR2, TLR4, or TLR6 are redundant for the control of M. bovis BCG mycobacterial infection.

scholarly journals Mycobacterium aviumComplex Infection in a Patient with Sickle Cell Disease and Severe Iron Overload

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Kamal Shemisa ◽  
Nasima Jafferjee ◽  
David Thomas ◽  
Gretta Jacobs ◽  
Howard J. Meyerson
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Unknown Origin ◽  
Mycobacterial Infection ◽  
In Vivo Studies ◽  
Recurrent Pain ◽  
Cell Disease

A 34-year-old female with sickle cell anemia (hemoglobin SS disease) and severe iron overload presented to our institution with the subacute presentation of recurrent pain crisis, fever of unknown origin, pancytopenia, and weight loss. A CT scan demonstrated both lung and liver nodules concerning for granulomatous disease. Subsequent biopsies of the liver and bone marrow confirmed the presence of noncaseating granulomas and blood cultures isolatedMycobacterium aviumcomplex MAC. Disseminated MAC is considered an opportunistic infection typically diagnosed in the immunocompromised and rarely in immunocompetent patients. An appreciable number of mycobacterial infection cases have been reported in sickle cell disease patients without immune dysfunction. It has been reported that iron overload is known to increase the risk for mycobacterial infection in vitro and in vivo studies. While iron overload is primarily known to cause end organ dysfunction, the clinical relationship with sickle cell disease and disseminated MAC infection has not been reported. Clinical iron overload is a common condition diagnosed in the sub-Saharan African population. High dietary iron, genetic defects in iron trafficking, as well as hemoglobinopathy are believed to be the etiologies for iron overload in this region. Patients with iron overload in this region were 17-fold more likely to die fromMycobacterium tuberculosis. Both experimental and clinical evidence suggest a possible link to iron overload and mycobacterial infections; however larger observational studies are necessary to determine true causality.

scholarly journals A vitamin B 12 transporter in Mycobacterium tuberculosis

Open Biology ◽  
2013 ◽  
Vol 3 (2) ◽  
pp. 120175 ◽  
Author(s):  
Krishnamoorthy Gopinath ◽  
Česlovas Venclovas ◽  
Thomas R. Ioerger ◽  
James C. Sacchettini ◽  
John D. McKinney ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Type System ◽  
Mycobacterial Infection ◽  
Vitamin B ◽  
Abc Protein ◽  
Genome Wide ◽  
Host Infection ◽  
Obligate Pathogen

Vitamin B 12 -dependent enzymes function in core biochemical pathways in Mycobacterium tuberculosis , an obligate pathogen whose metabolism in vivo is poorly understood. Although M. tuberculosis can access vitamin B 12 in vitro , it is uncertain whether the organism is able to scavenge B 12 during host infection. This question is crucial to predictions of metabolic function, but its resolution is complicated by the absence in the M. tuberculosis genome of a direct homologue of BtuFCD, the only bacterial B 12 transport system described to date. We applied genome-wide transposon mutagenesis to identify M. tuberculosis mutants defective in their ability to use exogenous B 12 . A small proportion of these mapped to Rv1314c , identifying the putative PduO-type ATP : co(I)rrinoid adenosyltransferase as essential for B 12 assimilation. Most notably, however, insertions in Rv1819c dominated the mutant pool, revealing an unexpected function in B 12 acquisition for an ATP-binding cassette (ABC)-type protein previously investigated as the mycobacterial BacA homologue. Moreover, targeted deletion of Rv1819c eliminated the ability of M. tuberculosis to transport B 12 and related corrinoids in vitro . Our results establish an alternative to the canonical BtuCD-type system for B 12 uptake in M. tuberculosis , and elucidate a role in B 12 metabolism for an ABC protein implicated in chronic mycobacterial infection.

scholarly journals Surfactant Protein A Modulates the Inflammatory Response in Macrophages during Tuberculosis

2004 ◽  
Vol 72 (2) ◽  
pp. 645-650 ◽  
Author(s):  
Jeffrey A. Gold ◽  
Yoshihiko Hoshino ◽  
Naohiko Tanaka ◽  
William N. Rom ◽  
Bindu Raju ◽  
...  
Keyword(s):  
Protein A ◽  
Mycobacterial Infection ◽  
Surfactant Protein ◽  
In Vitro Models ◽  
Dominant Negative ◽  
Surfactant Protein A ◽  
Low Concentrations ◽  
Hiv 1

ABSTRACT Tuberculosis leads to immune activation and increased human immunodeficiency virus type 1 (HIV-1) replication in the lung. However, in vitro models of mycobacterial infection of human macrophages do not fully reproduce these in vivo observations, suggesting that there are additional host factors. Surfactant protein A (SP-A) is an important mediator of innate immunity in the lung. SP-A levels were assayed in the human lung by using bronchoalveolar lavage (BAL). There was a threefold reduction in SP-A levels during tuberculosis only in the radiographically involved lung segments, and the levels returned to normal after 1 month of treatment. The SP-A levels were inversely correlated with the percentage of neutrophils in BAL fluid, suggesting that low SP-A levels were associated with increased inflammation in the lung. Differentiated THP-1 macrophages were used to test the effect of decreasing SP-A levels on immune function. In the absence of infection with Mycobacterium tuberculosis, SP-A at doses ranging from 5 to 0.01 μg/ml inhibited both interleukin-6 (IL-6) production and HIV-1 long terminal repeat (LTR) activity. In macrophages infected with M. tuberculosis, SP-A augmented both IL-6 production and HIV-1 LTR activity. To better understand the effect of SP-A, we measured expression of CAAT/enhancer binding protein beta (C/EBPβ), a transcription factor central to the regulation of IL-6 and the HIV-1 LTR. In macrophages infected with M. tuberculosis, SP-A reduced expression of a dominant negative isoform of C/EBPβ. These data suggest that SP-A has pleiotropic effects even at the low concentrations found in tuberculosis patients. This protein augments inflammation in the presence of infection and inhibits inflammation in uninfected macrophages, protecting uninvolved lung segments from the deleterious effects of inflammation.

scholarly journals microRNA-146a promotes mycobacterial survival in macrophages through suppressing nitric oxide production

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Miao Li ◽  
Jinli Wang ◽  
Yimin Fang ◽  
Sitang Gong ◽  
Meiyu Li ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mycobacterial Infection ◽  
Nuclear Factor Κb ◽  
Inos Expression ◽  
Transcriptional Level ◽  
No Production ◽  
Promising Therapeutic Target ◽  
Mitogen Activated Protein

Abstract Macrophages play a crucial role in host innate anti-mycobacterial defense, which is tightly regulated by multiple factors, including microRNAs. Our previous study showed that a panel of microRNAs was markedly up-regulated in macrophages upon mycobacterial infection. Here, we investigated the biological function of miR-146a during mycobacterial infection. miR-146a expression was induced both in vitro and in vivo after Mycobacterium bovis BCG infection. The inducible miR-146a could suppress the inducible nitric oxide (NO) synthase (iNOS) expression and NO generation, thus promoting mycobacterial survival in macrophages. Inhibition of endogenous miR-146a increased NO production and mycobacterial clearance. Moreover, miR-146a attenuated the activation of nuclear factor κB and mitogen-activated protein kinases signaling pathways during BCG infection, which in turn repressed iNOS expression. Mechanistically, miR-146a directly targeted tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) at post-transcriptional level. Silencing TRAF6 decreased iNOS expression and NO production in BCG-infected macrophages, while overexpression of TRAF6 reversed miR-146a-mediated inhibition of NO production and clearance of mycobacteria. Therefore, we demonstrated a novel role of miR-146a in the modulation of host defense against mycobacterial infection by repressing NO production via targeting TRAF6, which may provide a promising therapeutic target for tuberculosis.

scholarly journals Differential Regulation of DAP12 and Molecules Associated with DAP12 during Host Responses to Mycobacterial Infection

2004 ◽  
Vol 72 (5) ◽  
pp. 2477-2483 ◽  
Author(s):  
Naoko Aoki ◽  
Anna Zganiacz ◽  
Peter Margetts ◽  
Zhou Xing
Keyword(s):  
Mycobacterial Infection ◽  
Host Responses ◽  
Necrosis Factor Alpha ◽  
Lung Macrophage ◽  
Tnf Α ◽  
Kinetic Expression ◽  
Ifn Γ

ABSTRACT DAP12 and its associating molecules MDL-1, TREM-1, and TREM-2 are the recently identified immune regulatory molecules, expressed primarily on myeloid cells including monocytes/macrophages, dendritic cells, NK cells, and neutrophils. However, little is known about the regulation of their expression during host antimicrobial responses. We have investigated the effect of pulmonary mycobacterial infection and type 1 cytokines on the expression of these molecules both in vivo and in vitro. While DAP12 was constitutively expressed at high levels in the lungs, the MDL-1, TREM-1, and TREM-2 molecules were inducible during mycobacterial infection. Their kinetic expression was correlated with that of the type 1 cytokines tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ). In primary lung macrophage cultures, high constitutive levels of DAP12 and TREM-2 were not modulated by mycobacterial or type 1 cytokine exposure. In contrast, expression of both MDL-1 and TREM-1 was markedly induced by mycobacterial infection and such induction was inhibited by concurrent exposure to IFN-γ. On mycobacterial infection of TNF-α−/− and IFN-γ−/− mice in vivo or their lung macrophages in vitro, TNF-α was found to be critical for mycobacterially induced MDL-1, but not TREM-1, expression whereas IFN-γ negatively regulated mycobacterially induced MDL-1 and TREM-1 expression. Our findings thus suggest that DAP12 and its associating molecules are differentially regulated by mycobacterial infection and type 1 cytokines and that MDL-1- and TREM-1-triggered DAP12 signaling may play an important role in antimicrobial type 1 immunity.

scholarly journals CTLA-4 Blockade Enhances the Immune Response Induced by Mycobacterial Infection but Does Not Lead to Increased Protection

1999 ◽  
Vol 67 (8) ◽  
pp. 3786-3792 ◽  
Author(s):  
Joanna Kirman ◽  
Kathy McCoy ◽  
Sarah Hook ◽  
Melanie Prout ◽  
Brett Delahunt ◽  
...  
Keyword(s):  
Immune Response ◽  
Lymph Node ◽  
Cytokine Production ◽  
Mediastinal Lymph Node ◽  
Mycobacterial Infection ◽  
Primary Site ◽  
Draining Lymph Node ◽  
Cell Cytokine Production

ABSTRACT The murine immune response to a pulmonary mycobacterial infection is slow to develop, allowing bacterial numbers to increase in the lung for several weeks after infection. We sought to enhance the protective immune response induced during Mycobacterium bovis BCG infection by administering an antibody that blocks the interaction of CTLA-4 with its ligands, CD80 and CD86. We found that injection of anti-CTLA-4 monoclonal antibody (MAb) greatly enhanced and accelerated the immune response, as measured by increased cellularity of the draining mediastinal lymph nodes, and enhanced antigen-inducible proliferation and gamma interferon production by mediastinal lymphocytes in vitro. However, despite the apparently enhanced immune response in the mediastinal lymph node following treatment with anti-CTLA-4 MAb, there was no improvement in clearance of mycobacteria in the lungs, liver, or spleen. Examination of the primary site of infection, the lung, revealed that CTLA-4 blockade had no effect on the number or function of lymphocytes infiltrating the infected lung tissue. Taken together, these data suggest that in vivo CTLA-4 blockade enhances mycobacterial-infection-induced lymphocyte expansion and effector cell cytokine production in the draining lymph node but does not alter the number or function of lymphocytes at the primary site of infection and therefore does not lead to enhanced clearance of the infection.

scholarly journals Mycobacterial Infection is Promoted by Neutral Sphingomyelinase 2 Regulating a Signaling Cascade Leading to Activation of β1-Integrin

2018 ◽  
Vol 51 (4) ◽  
pp. 1815-1829 ◽  
Author(s):  
Yuqing Wu ◽  
Cao Li ◽  
Andrea Riehle ◽  
Barbara Pollmeier ◽  
Erich Gulbins ◽  
...  
Keyword(s):  
Systemic Infection ◽  
Mycobacterial Infection ◽  
Granuloma Formation ◽  
In Vitro Assays ◽  
Signaling Cascade ◽  
Β1 Integrin ◽  
Neutral Sphingomyelinase

Background/Aims: Mycobacteria-induced diseases, especially tuberculosis, cause more than 1 million deaths each year, which is higher than any other single bacterial pathogen. Neutral sphingomyelinase 2 (Nsm2) has been implied in many physiological processes and diseases, but the role of Nsm2 in pathogen-host interactions and mycobacterial infections has barely been studied. Methods: We investigated the role of the Nsm2/ceramide system in systemic infection of mice and murine macrophages with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) as a model for mycobacterial infection. For in vitro assays we isolated bone marrow-derived macrophages from Wildtype mice or Nsm2-heterozygous and investigated the role of Nsm2 for macrophage migration/clustering as well as the involvement of p38 mitogen-activated protein kinases (p38K), c-Jun N-terminal kinase (JNK), β1-integrin and Rac1 activity by Western blot and microscopic studies. For in vivo assays we injected mice intravenously with BCG and analyzed infected tissues for the role of Nsm2-mediated activation of β1-integrin in granuloma formation and bacterial burden. Results: Our results reveal that BCG infection of macrophages results in rapid stimulation of Nsm2. Genetic and pharmacological studies demonstrate that Nsm2 stimulates a signaling cascade via p38K and JNK to an activation of surface β1-integrin and Rac1 that leads to the formation of granuloma-like macrophages clusters in vitro and granuloma in vivo. Heterozygosity of Nsm2 in macrophages or antibody-mediated neutralization of active b1-integrin reduced macrophage clusters in vitro and granuloma formation in vivo. Most importantly, Nsm2 heterozygosity or treatment with neutralizing antibodies against β1-integrin protected mice from systemic BCG infections and chronic infections of the liver and spleen. Conclusion: The findings indicate that the Nsm2/ ceramide system plays an important role in systemic infection of mice with mycobacteria by regulating a signaling cascade via p38K, JNK, b1-integrin and Rac1.

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