Pharmacologic Exhaustion of Suppressor Cells with Tasquinimod Enhances Bacterial Clearance during Tuberculosis.
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ABSTRACT:
SUBMITTER: Gupta S
PROVIDER: S-EPMC6363972 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tuberculosis results from an interaction between a chronically persistent pathogen counteracted by IFN-g-mediated immune responses. Modulation of IFN-g signaling could therefore constitute a major immune evasion mechanism for M. tuberculosis. SOCS1 plays a major role in the inhibition of IFN-g-mediated responses. We found that M. tuberculosis infection stimulates SOCS1 expression in mouse and human myeloid cells. Significantly higher levels of SOCS1 were induced after in vitro or in vivo infection with virulent M. tuberculosis-than with attenuated M. bovis BCG. Different innate and adaptive immune mechanisms participated in infection-induced SOCS1 expression. SOCS1 hampered M. tuberculosis clearance both in macrophages and during murine infection in vivo. On the other hand, SOCS1 protected the host from an infection-induced inflammation. Despite SOCS1 expression, mycobacteria-infected macrophages were not tolerant to IFN-g. Instead, an impaired IFN-g secretion by macrophages, associated to lower responses to IL-12, accounted for the increased mycobacterial intracellular growth in presence of SOCS1. SOCS1 attenuated the expression of the majority of genes modulated by infection of macrophages (6,1% of the transcriptome), indicating the relevance of the molecule in the outcome of infection with M. tuberculosis. We suggest that SOCS1 is expressed during M. tuberculosis infection to establish a successful chronic infection, and dampen inflammatory damage. Difference in genotype and TB infection comparison Relative gene expressions were determined by normalized intensity values. GeneSpring analysis was performed using the Treg transcriptome data with following comparisons: no GvHD d90 versus no GvHD d150, no GvHD d90 versus acute GvHD, no GvHD d150 versus chronic GvHD, acute GvHD versus chronic GvHD, acute GvHD versus GvHD d90 and chronic GvHD versus GvHD d150 (Figure 2). Cut-off was a transcript fold change of +2 or -2 in at least one comparison. Student´s t-test was used to identify significant expression changes.
2012-01-18 | E-GEOD-23508 | biostudies-arrayexpress
Project description:Tuberculosis results from an interaction between a chronically persistent pathogen counteracted by IFN-g-mediated immune responses. Modulation of IFN-g signaling could therefore constitute a major immune evasion mechanism for M. tuberculosis. SOCS1 plays a major role in the inhibition of IFN-g-mediated responses. We found that M. tuberculosis infection stimulates SOCS1 expression in mouse and human myeloid cells. Significantly higher levels of SOCS1 were induced after in vitro or in vivo infection with virulent M. tuberculosis-than with attenuated M. bovis BCG. Different innate and adaptive immune mechanisms participated in infection-induced SOCS1 expression. SOCS1 hampered M. tuberculosis clearance both in macrophages and during murine infection in vivo. On the other hand, SOCS1 protected the host from an infection-induced inflammation. Despite SOCS1 expression, mycobacteria-infected macrophages were not tolerant to IFN-g. Instead, an impaired IFN-g secretion by macrophages, associated to lower responses to IL-12, accounted for the increased mycobacterial intracellular growth in presence of SOCS1. SOCS1 attenuated the expression of the majority of genes modulated by infection of macrophages (6,1% of the transcriptome), indicating the relevance of the molecule in the outcome of infection with M. tuberculosis. We suggest that SOCS1 is expressed during M. tuberculosis infection to establish a successful chronic infection, and dampen inflammatory damage. Difference in genotype and TB infection comparison
2012-01-18 | GSE23508 | GEO
Project description:Pseudomonas aeruginosa is an opportunistic bacterial pathogen which is the leading cause of morbidity and mortality among cystic fibrosis patients. Although P. aeruginosa is primarily considered an extacellular pathogen, recent reports have demonstrated that throughout the course of infection the bacterium acquires the ability to enter and reside within host cells. Normally intracellular pathogens are cleared through a process called autophagy which sequesters and degrades portions of the cytosol, including invading bacteria. However the role of autophagy in host defense against P. aeruginosa in vivo remains unknown. Understanding the role of autophagy during P. aeruginosa infection is of particular importance as mutations leading to cystic fibrosis have recently been shown to cause a blockade in the autophagy pathway, which could increase susceptibility to infection. Here we demonstrate that P. aeruginosa induces autophagy in mast cells, which have been recognized as sentinels in the host defense against bacterial infection. We further demonstrate that inhibition of autophagy through pharmacological means or protein knockdown inhibits clearance of intracellular P. aeruginosa in vitro, while pharmacologic induction of autophagy significantly increased bacterial clearance. Finally we find that pharmacological manipulation of autophagy in vivo effectively regulates bacterial clearance of P. aeruginosa from the lung. Together our results demonstrate that autophagy is required for an effective immune response against P. aeruginosa infection in vivo, and suggest that pharmacological interventions targeting the autophagy pathway could have considerable therapeutic potential in the treatment of P. aeruginosa lung infection.
| S-EPMC3756076 | biostudies-literature
Project description:OBJECTIVES:The physiology of nearly all mammalian organisms are entrained by light and exhibit circadian rhythm. The data derived from animal studies show that light influences immunity, and these neurophysiologic pathways are maximally entrained by the blue spectrum. Here, we hypothesize that bright blue light reduces acute kidney injury by comparison with either bright red or standard, white fluorescent light in mice subjected to sepsis. To further translational relevance, we performed a pilot clinical trial of blue light therapy in human subjects with appendicitis. DESIGN:Laboratory animal research, pilot human feasibility trial. SETTING:University basic science laboratory and tertiary care hospital. SUBJECTS:Male C57BL/6J mice, adult (> 17 yr) patients with acute appendicitis. INTERVENTIONS:Mice underwent cecal ligation and puncture and were randomly assigned to a 24-hour photoperiod of bright blue, bright red, or ambient white fluorescent light. Subjects with appendicitis were randomized to receive postoperatively standard care or standard care plus high-illuminance blue light. MEASUREMENTS AND MAIN RESULTS:Exposure to bright blue light enhanced bacterial clearance from the peritoneum, reduced bacteremia and systemic inflammation, and attenuated the degree of acute kidney injury. The mechanism involved an elevation in cholinergic tone that augmented tissue expression of the nuclear orphan receptor REV-ERB? and occurred independent of alterations in melatonin or corticosterone concentrations. Clinically, exposure to blue light after appendectomy was feasible and reduced serum interleukin-6 and interleukin-10 concentrations. CONCLUSIONS:Modifying the spectrum of light may offer therapeutic utility in sepsis.
| S-EPMC6045458 | biostudies-literature
Project description:In this study, we evaluated the PK/PD and explored the efficacy of a PDE4 inhibitor, CC-11050 in a murine model of Mtb infection. Infected mouse lungs with or without CC-11050 treatment was also used to interrogate genome-wide transcriptional changes. Standard aerosol infection of mice with MtbCDC1551, followed by enumeration of lung bacterial load, pathology and transcriptional changes were monitored upto 112 days post infection. Mice were infected with Mtb and treatment with CC11050 was started at 14 days post-infection. Uninfected mice were included as control. At 28 days post-infection, mice from all 3 groups (uninfected, Mtb-infected untreated or CC11050 treated) were euthanized and lung tissue was collected to isolate total RNA and used in microarray experiments. (N=4 per group)
2016-06-10 | E-GEOD-83188 | biostudies-arrayexpress
Project description:A major barrier for cancer immunotherapy is the presence of suppressive cell populations in patients with cancer, such as myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), which contribute to the immunosuppressive microenvironment that promotes tumor growth and metastasis. Tasquinimod is a novel antitumor agent that is currently at an advanced stage of clinical development for treatment of castration-resistant prostate cancer. A target of tasquinimod is the inflammatory protein S100A9, which has been demonstrated to affect the accumulation and function of tumor-suppressive myeloid cells. Here, we report that tasquinimod provided a significant enhancement to the antitumor effects of two different immunotherapeutics in mouse models of cancer: a tumor vaccine (SurVaxM) for prostate cancer and a tumor-targeted superantigen (TTS) for melanoma. In the combination strategies, tasquinimod inhibited distinct MDSC populations and TAMs of the M2-polarized phenotype (CD206(+)). CD11b(+) myeloid cells isolated from tumors of treated mice expressed lower levels of arginase-1 and higher levels of inducible nitric oxide synthase (iNOS), and were less immunosuppressive ex vivo, which translated into a significantly reduced tumor-promoting capacity in vivo when these cells were coinjected with tumor cells. Tumor-specific CD8(+) T cells were increased markedly in the circulation and in tumors. Furthermore, T-cell effector functions, including cell-mediated cytotoxicity and IFNγ production, were potentiated. Taken together, these data suggest that pharmacologic targeting of suppressive myeloid cells by tasquinimod induces therapeutic benefit and provide the rationale for clinical testing of tasquinimod in combination with cancer immunotherapies.
| S-EPMC4323929 | biostudies-literature
Project description:The lengthy duration of multidrug therapy needed to cure tuberculosis (TB) poses significant challenges for global control of the disease. Moreover, chronic inflammation associated with TB leads to pulmonary damage that can remain even after successful cure. Thus, there is a great need for the development of effective shorter drug regimens to improve clinical outcome and strengthen TB control. Host-directed therapy (HDT) is emerging as a novel adjunctive strategy to enhance the efficacy and shorten the duration of TB treatment. Previously, we showed that the administration of CC-3052, a phosphodiesterase-4 inhibitor (PDE4i), reduced the host inflammatory response during Mycobacterium tuberculosis (Mtb) infection and improved the antimicrobial efficacy of isoniazid (INH) in both the mouse and rabbit models. In the present study, we evaluated the pharmacokinetics and explored the mechanism underlying the efficacy of a more potent PDE4i, CC-11050, as adjunct to INH treatment in a mouse model of pulmonary Mtb infection. Genome-wide lung transcriptome analysis confirmed the dampening of inflammation and associated network genes that we previously reported with CC-3052. Consistent with the reduction in inflammation, a significant improvement in Mtb control and pathology was observed in the lungs of mice treated with CC-11050 plus INH, compared to INH alone. This important confirmatory study will be used to help design upcoming human clinical trials with CC-11050 as an HDT for TB treatment.
| S-EPMC4911353 | biostudies-literature
Project description:In this study, we evaluated the PK/PD and explored the efficacy of a PDE4 inhibitor, CC-11050 in a murine model of Mtb infection. Infected mouse lungs with or without CC-11050 treatment was also used to interrogate genome-wide transcriptional changes. Standard aerosol infection of mice with MtbCDC1551, followed by enumeration of lung bacterial load, pathology and transcriptional changes were monitored upto 112 days post infection.
2016-06-10 | GSE83188 | GEO
Project description:While T cell immunity initially limits Mycobacterium tuberculosis infection, why T cell immunity fails to sterilize the infection and allows recrudescence is not clear. One hypothesis is that T cell exhaustion impairs immunity and is detrimental to the outcome of M. tuberculosis infection. Here we provide functional evidence for the development T cell exhaustion during chronic TB. Second, we evaluate the role of the inhibitory receptor T cell immunoglobulin and mucin domain-containing-3 (TIM3) during chronic M. tuberculosis infection. We find that TIM3 expressing T cells accumulate during chronic infection, co-express other inhibitory receptors including PD1, produce less IL-2 and TNF but more IL-10, and are functionally exhausted. Finally, we show that TIM3 blockade restores T cell function and improves bacterial control, particularly in chronically infected susceptible mice. These data show that T cell immunity is suboptimal during chronic M. tuberculosis infection due to T cell exhaustion. Moreover, in chronically infected mice, treatment with anti-TIM3 mAb is an effective therapeutic strategy against tuberculosis.
| S-EPMC4788425 | biostudies-literature
Project description:Suppressor of cytokine signaling (SOCS) proteins are key regulators of innate and adaptive immunity. There is no described biological role for SOCS4, despite broad expression in the hematopoietic system. We demonstrate that mice lacking functional SOCS4 protein rapidly succumb to infection with a pathogenic H1N1 influenza virus (PR8) and are hypersusceptible to infection with the less virulent H3N2 (X31) strain. In SOCS4-deficient animals, this led to substantially greater weight loss, dysregulated pro-inflammatory cytokine and chemokine production in the lungs and delayed viral clearance. This was associated with impaired trafficking of influenza-specific CD8 T cells to the site of infection and linked to defects in T cell receptor activation. These results demonstrate that SOCS4 is a critical regulator of anti-viral immunity.
| S-EPMC4014316 | biostudies-literature