scholarly journals Investigating the Role of Everolimus in mTOR Inhibition and Autophagy Promotion as a Potential Host-Directed Therapeutic Target in Mycobacterium tuberculosis Infection

2019 ◽  
Vol 8 (2) ◽  
pp. 232 ◽  
Author(s):  
Stephen Cerni ◽  
Dylan Shafer ◽  
Kimberly To ◽  
Vishwanath Venketaraman
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mammalian Target Of Rapamycin ◽  
Treatment Protocol ◽  
Current Treatment ◽  
Current Therapy ◽  
Mycobacterium Tuberculosis Infection ◽  
Novel Therapy ◽  
Mtor Inhibition ◽  
Treatment Protocols ◽  
Tb Treatment

Tuberculosis (TB) is a serious infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb). The current therapy consists of a combination of antibiotics over the course of four months. Current treatment protocols run into problems due to the growing antibiotic resistance of Mtb and poor compliance to the multi-drug-resistant TB treatment protocol. New treatments are being investigated that target host intracellular processes that could be effective in fighting Mtb infections. Autophagy is an intracellular process that is involved in eliminating cellular debris, as well as intracellular pathogens. Mammalian target of rapamycin (mTOR) is an enzyme involved in inhibiting this pathway. Modulation of mTOR and the autophagy cellular machinery are being investigated as potential therapeutic targets for novel Mtb treatments. In this review, we discuss the background of Mtb pathogenesis, including its interaction with the innate and adaptive immune systems, the mTOR and autophagy pathways, the interaction of Mtb with these pathways, and finally, the drug everolimus, which targets these pathways and is a potential novel therapy for TB treatment.

Immigration Brings New Pathology with No Standardized Treatment Protocol

2018 ◽  
Vol 108 (6) ◽  
pp. 517-522
Author(s):  
Tara L. Harrington ◽  
Denten Eldredge ◽  
Erica K. Benson
Keyword(s):  
Opportunistic Infections ◽  
Treatment Options ◽  
Treatment Protocol ◽  
Current Treatment ◽  
Foot And Ankle ◽  
Treatment Protocols ◽  
Clinical Presentations ◽  
Standardized Treatment ◽  
Madura Foot ◽  
Antimicrobial Interventions

Madura foot is an uncommon invasive soft-tissue infection that foot and ankle specialists encounter. We present two rare cases of Phialemonium and Phaeoacremonium fungi infections of the foot diagnosed in northern California to inform physicians on the presentation and current treatment options for this unique pathology. The two cases presented outline the clinical presentations, diagnostic data, and surgical and antimicrobial interventions. There is a concentration on the antimicrobial options depending on which of the over 20 species is encountered. The pertinent literature and supporting data are reviewed to create an outline for discussion of treatment protocols when faced with these emerging opportunistic infections.

scholarly journals Screening for Mycobacterium tuberculosis Infection Using Beijing/K Strain-Specific Peptides in a School Outbreak Cohort

2021 ◽  
Vol 11 ◽  
Author(s):  
Ji Young Hong ◽  
Ahreum Kim ◽  
So Yeong Park ◽  
Sang-Nae Cho ◽  
Hazel M. Dockrell ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mycobacterium Tuberculosis Infection ◽  
Tb Treatment ◽  
Diagnostic Potential ◽  
Tnf Α ◽  
Latent Tb ◽  
Ifn Γ ◽  
Latent Tb Infection ◽  
Tb Diagnostics ◽  
Active Disease

BackgroundThe Beijing strain of Mycobacterium tuberculosis (M. tb) has been most frequently isolated from TB patients in South Korea, and the hyper-virulent Beijing/K genotype is associated with TB outbreaks. To examine the diagnostic potential of Beijing/K-specific peptides, we performed IFN-γ release assays (IGRA) using a MTBK antigen tube containing Beijing/K MTBK_24800, ESAT-6, and CFP-10 peptides in a cohort studied during a school TB outbreak.MethodsA total of 758 contacts were investigated for M. tb infection, and 43 contacts with latent TB infection (LTBI) and 25 active TB patients were enrolled based on serial screening with QuantiFERON-TB Gold In-Tube tests followed by clinical examinations. Blood collected in MTBK antigen tubes was utilized for IGRA and multiplex cytokine bead arrays. Immune responses were retested in 24 patients after TB treatment, and disease progression was investigated in subjects with LTBI.ResultsTotal proportions of active disease and LTBI during the outbreak were 3.7% (28/758) and 9.2% (70/758), respectively. All clinical isolates had a Beijing/K M. tb genotype. IFN-γ responses to the MTBK antigen identified M. tb infection and distinguished between active disease and LTBI. After anti-TB treatment, IFN-γ responses to the MTBK antigen were significantly reduced, and strong TNF-α responses at diagnosis were dramatically decreased.ConclusionsMTBK antigen-specific IFN-γ has diagnostic potential for differentiating M. tb infection from healthy controls, and between active TB and LTBI as well. In addition, TNF-α is a promising marker for monitoring therapeutic responses. These data provide informative readouts for TB diagnostics and vaccine studies in regions where the Beijing/K strain is endemic.

Comparison of Screening Procedures for Mycobacterium tuberculosis Infection Among Patients with Inflammatory Diseases

2009 ◽  
Vol 36 (9) ◽  
pp. 1876-1884 ◽  
Author(s):  
BOLETTE SOBORG ◽  
MORTEN RUHWALD ◽  
MERETE LUND HETLAND ◽  
SØREN JACOBSEN ◽  
AASE BENGAARD ANDERSEN ◽  
...  
Keyword(s):  
Risk Factors ◽  
Mycobacterium Tuberculosis ◽  
Inflammatory Diseases ◽  
Interferon Γ ◽  
Mycobacterium Tuberculosis Infection ◽  
Tb Treatment ◽  
Latent Tb ◽  
Latent Tb Infection ◽  
High Degree

Objective.To test if Mycobacterium tuberculosis screening results differ among patients with inflammatory disease depending on whether the QuantiFeron TB-Gold test (QFT) or tuberculin skin test (TST) is used; and to evaluate if a possible difference is influenced by the presence of risk factors or immunosuppression.Methods.The interferon-γ response to in vitro stimulation of M. tuberculosis-specific antigens was measured with QFT and results were compared with TST. Associations to bacillus Calmette-Guerin (BCG) vaccination, risk factors, and immunosuppression were analyzed for both tests.Results.QFT and TST results were available for 294/302 and 241/302 patients, respectively; 234 had results from both tests. Twenty-one (7%) tested positive with QFT and 45 (19%) with TST. A positive QFT was associated with risk factors for M. tuberculosis infection: i.e., birth or upbringing in a TB-endemic area [risk ratio (RR) = 7.8, 95% CI 1.5–18.2, p < 0.001], previous TB treatment (RR 4.7, 95% CI 1.6–13.5, p = 0.005), and any latent TB infection risk factor (RR 4.7, 95% CI 2.1–11.0, p = 0.0002). Treatment with corticosteroids increased the risk for an inconclusive QFT result (RR 4.2, 95% CI 1.6–10.7, p = 0.04) and decreased the risk for a positive TST result (RR 0.4, 95% CI 0.1–1.0, p = 0.04). Agreement between the tests was low (kappa 0.2, 95% CI 0.02–0.3, p = 0.002).Conclusion.The study documented a high degree of discordant positive QFT and TST results. A positive QFT was more closely associated with risk factors for M. tuberculosis infection than the TST. The use of corticosteroids affected test outcome by increasing the risk for an inconclusive QFT result and decreasing the risk for a positive TST result.

scholarly journals Autophagy Induction as a Host-Directed Therapeutic Strategy against Mycobacterium tuberculosis Infection

Medicina ◽  
2021 ◽  
Vol 57 (6) ◽  
pp. 522
Author(s):  
Harresh Adikesavalu ◽  
Radha Gopalaswamy ◽  
Ashok Kumar ◽  
Uma Devi Ranganathan ◽  
Sivakumar Shanmugam
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Treatment Regimen ◽  
Mammalian Cells ◽  
Therapeutic Strategy ◽  
Clinical Investigation ◽  
Mycobacterial Infection ◽  
Current Treatment ◽  
Autophagic Flux ◽  
Mycobacterium Tuberculosis Infection ◽  
Chemical Screening

Tuberculosis (TB), a bacterialinfectious disease caused by Mycobacterium tuberculosis (M.tb), which causes significant mortality in humans worldwide. Current treatment regimen involve the administration of multiple antibiotics over the course of several months that contributes to patient non-compliance leading to relapse and the development of drug-resistant M.tb (MDR and XDR) strains. Together, these facts highlight the need for the development of shorter TB treatment regimens. Host-directed therapy (HDT) is a new and emerging concept that aims to augment host immune response using drugs/compounds with or without adjunct antibiotics against M.tb infection. Autophagy is a natural catabolic mechanism of the cell that involves delivering the cytosolic constituents to the lysosomes for degradation and recycling the components; thereby maintaining the cellular and energy homoeostasis of a cell. However, over the past decade, an improved understanding of the role of autophagy in immunity has led to autophagy activation by using drugs or agents. This autophagy manipulation may represent a promising host-directed therapeutic strategy for human TB. However, current clinical knowledge on implementing autophagy activation by drugs or agents, as a stand-alone HDT or as an adjunct with antibiotics to treat human TB is insufficient. In recent years, many reports on high-throughput drug screening and measurement of autophagic flux by fluorescence, high-content microscopy, flow cytometry, microplate reader and immunoblotting have been published for the discovery of drugs that modulate autophagy. In this review, we discuss the commonly used chemical screening approaches in mammalian cells for the discovery of autophagy activating drugs against M.tbinfection. We also summarize the various autophagy-activating agents, both pre-clinical candidates and compounds approved for advanced clinical investigation during mycobacterial infection. Finally, we discuss the opportunities and challenges in using autophagy activation as HDT strategy to improve TB outcome and shorten treatment regimen.

scholarly journals Rapamycin modulates pulmonary pathology in a Murine model of Mycobacterium tuberculosis infection

2021 ◽  
Author(s):  
Kamlesh Bhatt ◽  
Madhuri Bhagavathula ◽  
Sheetal Verma ◽  
Graham S. Timmins ◽  
Vojo P. Deretic ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Potential Role ◽  
Mtor Inhibitor ◽  
Tuberculosis Infection ◽  
Clinical Tool ◽  
Mycobacterium Tuberculosis Infection ◽  
Tb Treatment ◽  
Pulmonary Pathology ◽  
Potential Use

In this study we employed C3HeB/FeJ mice as an experimental model to investigate the potential role of rapamycin, an mTOR inhibitor, as an adjunctive therapy candidate during the treatment of Mycobacterium tuberculosis infection with moxifloxacin. We report that administration of rapamycin with or without moxifloxacin reduced infection-induced lung inflammation, and the number and size of caseating necrotic granulomas. Results from this study strengthen the potential use of rapamycin and its analogs as adjunct TB therapy and importantly underscore the utility of the C3HeB/FeJ mouse model as a pre-clinical tool to evaluate HDT candidates in TB treatment.

scholarly journals Mycobacterium tuberculosis infection and diabetes mellitus-mycobacterium tuberculosis dual burden in subjects attending infectious diseases hospital Calabar, Nigeria

2019 ◽  
Vol 7 (8) ◽  
pp. 3155
Author(s):  
Raymond E. Eworo ◽  
Zibril A. Okhormhe ◽  
Ntamu A. Ntamu ◽  
Kaiso-Umo S. Esiere
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Treatment Outcome ◽  
Mycobacterium Tuberculosis Infection ◽  
Double Burden ◽  
Continuation Phase ◽  
Tb Treatment ◽  
Dual Burden ◽  
The Mean ◽  
Student’S T ◽  
And Control

Background: The rising global DM epidemic is driving the problem of TB control. This research determined glycemic control in TB only infected and DM-TB comorbidity and the consequence of the double burden on treatment outcome.Methods: fifty M. TB infected subjects and fifty control subjects were enrolled into the study, all the participants gave consents. FPG and HbA1c were determined by Colorimetry. Data were analyzed using SPSS version 20.0 statistical package, differences between groups and variation among groups were determined by Student’s t-test and ANOVA respectively while the association between variables by Pearson’s correlation. Differences were considered statistically significant at p<0.05.Results: The mean FPG and HbA1c levels of TB subjects were significantly (P<0.05) higher than those of the control. The mean BMI of the TB infected subjects was significantly lower (p=0.001) than that of the controls. The mean age, FPG and HbA1c of TB subjects at the beginning phase of treatment were significantly lower (p<0.05) than those of subjects at the continuation phase of treatment. The mean age, FPG and HbA1c of subjects with DM-M.TB coexistence were significantly (p<0.05) higher than those of the M.TB only infected subjects. BMI of the DM-M.TB comorbidity subjects was lower than that of the M.TB only infected subjects (p=0.109). A significant positive correlation was obtained between HbA1C and FPG in M.tb infected subjects. (r=0.910, p=0.001). A negative correlation obtained between HbA1C and BMI in M.tb infected subjects. (r=0.267, p=0.061).Conclusion: Infection with mycobacterium tuberculosis poses a risk to DM and vice versa, which may adversely affect treatment outcome and control of both diseases. Firm efforts to control DM may likely have a significant valuable effect on TB treatment outcome.

Effects of Relative Humidity on Impregnated Filters Used in Measurement of Airborne Sulfur Dioxide

2019 ◽  
Vol 63 (7) ◽  
pp. 806-813
Author(s):  
Chih-Hsiang Chien ◽  
Chufan Zhou ◽  
Simon Yang Sing ◽  
Benjamin Lopez ◽  
Alexandros Theodore ◽  
...  
Keyword(s):  
Sulfur Dioxide ◽  
Relative Humidity ◽  
Occupational Safety ◽  
Treatment Protocol ◽  
Current Treatment ◽  
Breakthrough Time ◽  
Treatment Protocols ◽  
Safety And Health ◽  
Significant Underestimation

Abstract Impregnated filters treated with alkali and humectant were first used as collection media to assess occupational exposure to sulfur dioxide (SO2), as outlined in the National Institute for Occupational Safety and Health Method 6004 in 1979. Since then, updated treatment protocols have been proposed with decreased amounts of alkali and glycerol, which claim the same filtering capacity. However, there has been no report on how the collection of SO2 on such impregnated media is influenced by relative humidity (RH). This study investigated the role of glycerol (G) amount on impregnated filters (G2 and G10, referring to 2 and 10% glycerol, respectively) in the collection of SO2 (100 l of 10 ppm at 1 l per minute) under low, medium, and high RHs. The testing results show that RH significantly impacted G2 filters with respect to breakthrough time, capacity, and recovery. At low RH, the 5% breakthrough time was less than 10 min and its recovery was merely 42%; at medium and high RHs, although the recovery was satisfactory, the 5% breakthrough time was still less than 100 min. By contrast, G10 filters illustrated nearly 100% recovery and evaluation by analysis of variance showed no significant effect of RH on recovery. In summary, the current treatment protocol of 2% glycerol leads to a significant underestimation of the exposure to SO2 in a low-RH environment; increasing the glycerol content can be an effective alternative to compensating for the effect of RH.

scholarly journals Treatment difficulties in salivary gland cancer

2019 ◽  
Vol 9 (34) ◽  
pp. 83-89
Author(s):  
Elena Patrascu ◽  
Violeta Melinte ◽  
Carmen Paraschiv-Ferariu ◽  
Codrut Sarafoleanu
Keyword(s):  
Salivary Gland ◽  
Salivary Glands ◽  
Treatment Protocol ◽  
Current Therapy ◽  
Salivary Gland Cancer ◽  
Local Health ◽  
Treatment Protocols ◽  
Heterogeneous Distribution ◽  
Pre Treatment ◽  
Few Data

Abstract Salivary gland cancers are represented by a heterogeneous histologic group of tumors, with low incidence, which may appear both in major and minor salivary glands. This article presents a review of the difficulties which may be encountered in this pathology during the treatment. The diagnosis of salivary gland cancers is often delayed, due to the histopathologic and immunohistochemistry results given in different period of times. There can be several difficulties in following the oncologic pre-treatment protocols, in terms of imaging technique, as MRI, useful for disease staging. The treatment of salivary gland cancers is complex, due to the local anatomy and their aggressive potential. Because of their decreased incidence, there are few data that investigate the treatment in the case of these diseases. The current therapy available for the patients with salivary gland cancers is represented by complete surgical resection. Several treatment difficulties in cancers of the salivary glands may come from the surgical limitations and the insufficient data for adjuvant and palliative treatment. Due to the limitations of the local health system, there is a heterogeneous distribution of the oncologic centers, lack of equipment, prolonged time to follow general protocols, despite the aspect of case-individualized therapy according to the guidelines. We must not forget the tumor behaviour and individual reactivity of different patients to the same treatment protocol.

scholarly journals Dual mTORC1/mTORC2 inhibition as a Host-Directed Therapeutic Target in Pathologically Distinct Mouse Models of Tuberculosis

2021 ◽  
Author(s):  
Rokeya Tasneen ◽  
Deborah S. Mortensen ◽  
Paul J. Converse ◽  
Michael E. Urbanowski ◽  
Anna Upton ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Kinase Domain ◽  
Lung Damage ◽  
Mtor Inhibition ◽  
Mtor Kinase ◽  
Tb Treatment ◽  
Mtor Complex 1

Efforts to develop more effective and shorter-course therapies for tuberculosis have included a focus on host-directed therapy (HDT). The goal of HDT is to modulate the host response to infection, thereby improving immune defenses to reduce the duration of antibacterial therapy and/or the amount of lung damage. As a mediator of innate and adaptive immune responses involved in eliminating intracellular pathogens, autophagy is a potential target for HDT in tuberculosis. Because Mycobacterium tuberculosis modulates mammalian target of rapamycin (mTOR) signaling to impede autophagy, pharmacologic mTOR inhibition could provide effective HDT. mTOR exists within two distinct multiprotein complexes, mTOR complex-1 (mTORC1) and mTOR complex-2 (mTORC2). Rapamycin and its analogs only partially inhibit mTORC1. We hypothesized that novel mTOR kinase inhibitors blocking both complexes would have expanded therapeutic potential. We compared the effects of two mTOR inhibitors: rapamycin and the orally available mTOR kinase domain inhibitor CC214-2, which blocks both mTORC1 and mTORC2, as adjunctive therapies against murine TB, when added to the first-line regimen (RHZE) or the novel bedaquiline-pretomanid-linezolid (BPaL) regimen. Neither mTOR inhibitor affected lung CFU counts after 4-8 weeks of treatment when combined with BPaL or RHZE. However, addition of CC214-2 to BPaL and RHZE was associated with significantly fewer relapses in C3HeB/FeJ compared to addition of rapamycin and, in RHZE-treated mice, resulted in fewer relapses compared to RHZE alone. Therefore, CC214-2 and related mTOR kinase inhibitors may be more effective candidates for HDT than rapamycin analogs and may have the potential to shorten the duration of TB treatment.

Sign in / Sign up

Export Citation Format

Share Document