scholarly journals High-dose Mycobacterium tuberculosis aerosol challenge cannot overcome BCG-induced protection in Chinese origin cynomolgus macaques; implications of natural resistance for vaccine evaluation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Laura Sibley ◽  
Andrew D. White ◽  
Karen E. Gooch ◽  
Lisa M. Stevens ◽  
Rachel Tanner ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Evaluation ◽  
Evaluation Studies ◽  
Early Response ◽  
Natural Resistance ◽  
Effector Memory ◽  
High Dose ◽  
Host Immune System ◽  
Chinese Origin ◽  
Cynomolgus Macaques

AbstractThis study describes the use of cynomolgus macaques of Chinese origin (CCM) to evaluate the efficacy and immunogenicity of the BCG vaccine against high dose aerosol Mycobacterium tuberculosis challenge. Progressive disease developed in three of the unvaccinated animals within 10 weeks of challenge, whereas all six vaccinated animals controlled disease for 26 weeks. Three unvaccinated animals limited disease progression, highlighting the intrinsic ability of this macaque species to control disease in comparison to macaques of other species and genotypes. Low levels of IFNγ were induced by BCG vaccination in CCM suggesting that IFNγ alone does not provide a sufficiently sensitive biomarker of vaccination in this model. An early response after challenge, together with the natural bias towards terminal effector memory T-cell populations and the contribution of monocytes appears to enhance the ability of CCM to naturally control infection. The high dose aerosol challenge model of CCM has value for examination of the host immune system to characterise control of infection which would influence future vaccine design. Although it may not be the preferred platform for the assessment of prophylactic vaccine candidates, the model could be well suited for testing post-exposure vaccination strategies and drug evaluation studies.

scholarly journals High dose aerosol challenge with Mycobacterium tuberculosis fails to overcome BCG vaccination-induced protection in cynomolgus macaques of Chinese origin: implications of natural resistance for TB vaccine evaluation.

2021 ◽  
Author(s):  
Laura Sibley ◽  
Andrew D White ◽  
Karen E Gooch ◽  
Lisa M Stevens ◽  
Rachel Tanner ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Evaluation ◽  
Evaluation Studies ◽  
Natural Resistance ◽  
Effector Memory ◽  
High Dose ◽  
Host Immune System ◽  
Bcg Vaccination ◽  
Chinese Origin ◽  
Cynomolgus Macaques

Abstract This study describes the use of cynomolgus macaques of Chinese origin (CCM) to evaluate the efficacy and immunogenicity of the BCG vaccine against high dose aerosol Mycobacterium tuberculosis challenge. Progressive disease developed in three of the unvaccinated animals within ten weeks of challenge, whereas all six vaccinated animals controlled disease for 26 weeks. Three unvaccinated animals limited disease progression, highlighting the intrinsic ability of this macaque species to control disease in comparison to macaques of other species and genotypes. Low levels of IFNγ were induced by BCG vaccination in CCM suggesting that IFNγ alone does not provide a sufficiently sensitive biomarker of vaccination in this model. An early response after challenge, together with the natural bias towards terminal effector memory T-cell populations and the contribution of monocytes appears to enhance the ability of CCM to naturally control infection. The high dose aerosol challenge model of CCM has value for examination of the host immune system to characterise control of infection which would influence future vaccine design. Although it may not be the preferred platform for the assessment of prophylactic vaccine candidates, the model could be well suited for testing post-exposure vaccination strategies and drug evaluation studies.

scholarly journals Mycobacterium tuberculosis Erdman infection of cynomolgus macaques of Chinese origin

2018 ◽  
Vol 10 (6) ◽  
pp. 3609-3621 ◽  
Author(s):  
Jing Zhang ◽  
Ming Guo ◽  
Yan Rao ◽  
Yong Wang ◽  
Qiaoyang Xian ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Chinese Origin ◽  
Cynomolgus Macaques

Exploration of Ion Channels in Mycobacterium tuberculosis: Implication on Drug Discovery and Potent Drug Targets Against Tuberculosis

2020 ◽  
Vol 14 (1) ◽  
pp. 14-29
Author(s):  
Manish Dwivedi
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Targets ◽  
Cell Envelope ◽  
Intracellular Pathogen ◽  
Host Immune System ◽  
Transporter Proteins ◽  
Channel Proteins ◽  
Medical Importance ◽  
Potent Drug ◽  
Emergence Of Resistance

Scientific interest in mycobacteria has been sparked by the medical importance of Mycobacterium tuberculosis (Mtb) that is known to cause severe diseases in mammals, i.e. tuberculosis and by properties that distinguish them from other microorganisms which are notoriously difficult to treat. The treatment of their infections is difficult because mycobacteria fortify themselves with a thick impermeable cell envelope. Channel and transporter proteins are among the crucial adaptations of Mycobacterium that facilitate their strength to combat against host immune system and anti-tuberculosis drugs. In previous studies, it was investigated that some of the channel proteins contribute to the overall antibiotic resistance in Mtb. Moreover, in some of the cases, membrane proteins were found responsible for virulence of these pathogens. Given the ability of M. tuberculosis to survive as an intracellular pathogen and its inclination to develop resistance to the prevailing anti-tuberculosis drugs, its treatment requires new approaches and optimization of anti-TB drugs and investigation of new targets are needed for their potential in clinical usage. Therefore, it is imperative to investigate the survival of Mtb. in stressed conditions with different behavior of particular channel/ transporter proteins. Comprehensive understanding of channel proteins and their mechanism will provide us direction to find out preventive measures against the emergence of resistance and reduce the duration of the treatment, eventually leading to plausible eradication of tuberculosis.

scholarly journals Biofilm formation in the lung contributes to virulence and drug tolerance of Mycobacterium tuberculosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Poushali Chakraborty ◽  
Sapna Bajeli ◽  
Deepak Kaushal ◽  
Bishan Dass Radotra ◽  
Ashwani Kumar
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune System ◽  
Biofilm Formation ◽  
Antimycobacterial Activity ◽  
Drug Tolerance ◽  
Host Immune System ◽  
Tissue Sections ◽  
Slow Growing

AbstractTuberculosis is a chronic disease that displays several features commonly associated with biofilm-associated infections: immune system evasion, antibiotic treatment failures, and recurrence of infection. However, although Mycobacterium tuberculosis (Mtb) can form cellulose-containing biofilms in vitro, it remains unclear whether biofilms are formed during infection in vivo. Here, we demonstrate the formation of Mtb biofilms in animal models of infection and in patients, and that biofilm formation can contribute to drug tolerance. First, we show that cellulose is also a structural component of the extracellular matrix of in vitro biofilms of fast and slow-growing nontuberculous mycobacteria. Then, we use cellulose as a biomarker to detect Mtb biofilms in the lungs of experimentally infected mice and non-human primates, as well as in lung tissue sections obtained from patients with tuberculosis. Mtb strains defective in biofilm formation are attenuated for survival in mice, suggesting that biofilms protect bacilli from the host immune system. Furthermore, the administration of nebulized cellulase enhances the antimycobacterial activity of isoniazid and rifampicin in infected mice, supporting a role for biofilms in phenotypic drug tolerance. Our findings thus indicate that Mtb biofilms are relevant to human tuberculosis.

scholarly journals Evolutionary Genetics of Mycobacterium tuberculosis and HIV-1: “The Tortoise and the Hare”

2021 ◽  
Vol 9 (1) ◽  
pp. 147
Author(s):  
Ana Santos-Pereira ◽  
Carlos Magalhães ◽  
Pedro M. M. Araújo ◽  
Nuno S. Osório
Keyword(s):  
Genetic Diversity ◽  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Evolutionary Dynamics ◽  
Evolutionary Genetics ◽  
Host Cells ◽  
Whole Genome Sequencing Data ◽  
Host Immune System ◽  
Viral Mutant ◽  
Hiv 1

The already enormous burden caused by Mycobacterium tuberculosis and Human Immunodeficiency Virus type 1 (HIV-1) alone is aggravated by co-infection. Despite obvious differences in the rate of evolution comparing these two human pathogens, genetic diversity plays an important role in the success of both. The extreme evolutionary dynamics of HIV-1 is in the basis of a robust capacity to evade immune responses, to generate drug-resistance and to diversify the population-level reservoir of M group viral subtypes. Compared to HIV-1 and other retroviruses, M. tuberculosis generates minute levels of genetic diversity within the host. However, emerging whole-genome sequencing data show that the M. tuberculosis complex contains at least nine human-adapted phylogenetic lineages. This level of genetic diversity results in differences in M. tuberculosis interactions with the host immune system, virulence and drug resistance propensity. In co-infected individuals, HIV-1 and M. tuberculosis are likely to co-colonize host cells. However, the evolutionary impact of the interaction between the host, the slowly evolving M. tuberculosis bacteria and the HIV-1 viral “mutant cloud” is poorly understood. These evolutionary dynamics, at the cellular niche of monocytes/macrophages, are also discussed and proposed as a relevant future research topic in the context of single-cell sequencing.

scholarly journals Patients with Primary Central Nervous System Lymphoma Not Eligible for Clinical Trials: Prognostic Factors, Treatment and Outcome

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2934
Author(s):  
Sabine Seidel ◽  
Michelle Margold ◽  
Thomas Kowalski ◽  
Alexander Baraniskin ◽  
Roland Schroers ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Clinical Trials ◽  
Nervous System ◽  
Prognostic Factors ◽  
Central Nervous System Lymphoma ◽  
Initial Response ◽  
Early Response ◽  
Multicenter Trial ◽  
High Dose ◽  
Therapeutic Trials

Patients with primary central nervous system lymphoma (PCNSL) not fulfilling inclusion criteria for clinical trials represent an underreported population. Thirty-four consecutive PCNSL patients seen at our center between 2005 and 2019 with exclusion criteria for therapeutic trials were analyzed (non-study patients) and compared with patients from the G-PCNSL-SG-1 (German PCNSL Study Group 1) study (study patients), the largest prospective multicenter trial on PCNSL, comprising 551 patients. Median follow up was 68 months (range 1–141) in non-study patients and 51 months (1–105) in study patients. Twenty-seven/34 (79.4%) non-study patients received high dose methotrexate (HDMTX), while seven/34 (20.6%) with a glomerular filtration rate (GFR) < 50 mL/min did not. Median overall survival (OS) was six months (95% confidence interval [CI] 0–21 months) in those 34 non-study patients. The 27 non-study patients treated with HDMTX were compared with 526/551 G-PCNSL-SG-1 study patients who had received HDMTX as well. Median OS was 20 months (95% CI 0–45)/21 months (95% CI 18–25) in 27 non-study/526 study patients (p = 0.766). Favorable prognostic factors in non-study patients were young age, application of HDMTX and early response on magnet resonance imaging (MRI). If HDMTX-based chemotherapy can be applied, long-term disease control is possible even in patients not qualifying for clinical trials. Initial response on early MRI might be useful for decision on treatment continuation.

scholarly journals Characterization of T Cells Specific for CFP-10 and ESAT-6 in Mycobacterium tuberculosis-Infected Mauritian Cynomolgus Macaques

2017 ◽  
Vol 85 (4) ◽  
Author(s):  
Amy Ellis ◽  
Alexis Balgeman ◽  
Mark Rodgers ◽  
Cassaundra Updike ◽  
Jaime Tomko ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Mhc Class Ii ◽  
Nonhuman Primates ◽  
Content Type ◽  
Host Immune Responses ◽  
Cell Responses ◽  
Cynomolgus Macaques ◽  
Mhc Haplotype

ABSTRACT Nonhuman primates can be used to study host immune responses to Mycobacterium tuberculosis. Mauritian cynomolgus macaques (MCMs) are a unique group of animals that have limited major histocompatibility complex (MHC) genetic diversity, such that MHC-identical animals can be infected with M. tuberculosis. Two MCMs homozygous for the relatively common M1 MHC haplotype were bronchoscopically infected with 41 CFU of the M. tuberculosis Erdman strain. Four other MCMs, which had at least one copy of the M1 MHC haplotype, were infected with a lower dose of 3 CFU M. tuberculosis. All animals mounted similar T-cell responses to CFP-10 and ESAT-6. Two epitopes in CFP-10 were characterized, and the MHC class II alleles restricting them were determined. A third epitope in CFP-10 was identified but exhibited promiscuous restriction. The CFP-10 and ESAT-6 antigenic regions targeted by T cells in MCMs were comparable to those seen in cases of human M. tuberculosis infection. Our data lay the foundation for generating tetrameric molecules to study epitope-specific CD4 T cells in M. tuberculosis-infected MCMs, which may guide future testing of tuberculosis vaccines in nonhuman primates.

scholarly journals Monkey Models of Tuberculosis: Lessons Learned

2014 ◽  
Vol 83 (3) ◽  
pp. 852-862 ◽  
Author(s):  
Juliet C. Peña ◽  
Wen-Zhe Ho
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Animal Models ◽  
Nonhuman Primates ◽  
Lessons Learned ◽  
Preclinical Testing ◽  
Content Type ◽  
Cynomolgus Macaques ◽  
Drug Regimens

The use of animal models has been invaluable for studying the pathogenesis ofMycobacterium tuberculosisinfection, as well as for testing the efficacy of vaccines and drug regimens for tuberculosis. Among the applied animal models, nonhuman primates, particularly macaques, share the greatest anatomical and physiological similarities with humans. As such, macaque models have been used for investigating tuberculosis pathogenesis and preclinical testing of drugs and vaccines. This review focuses on published major studies which illustrate how the rhesus and cynomolgus macaques have enriched and may continue to advance the field of global tuberculosis research.

scholarly journals Polyfunctional Mycobacterium tuberculosis-specific effector memory CD4+ T cells at sites of pleural TB

Tuberculosis ◽  
2011 ◽  
Vol 91 (3) ◽  
pp. 224-230 ◽  
Author(s):  
L. El Fenniri ◽  
Z. Toossi ◽  
H. Aung ◽  
G. El Iraki ◽  
J. Bourkkadi ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Cd4 T Cells ◽  
Effector Memory ◽  
Specific Effector ◽  
Memory Cd4 T Cells

scholarly journals Magnetic Resonance Imaging during Proton Therapy Irradiation Allows for the Early Response Assessment of Pediatric Chordoma

Diagnostics ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1117
Author(s):  
Sabina Vennarini ◽  
Dante Amelio ◽  
Stefano Lorentini ◽  
Giovanna Stefania Colafati ◽  
Antonella Cacchione ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Proton Therapy ◽  
Treatment Plan ◽  
Surgical Excision ◽  
Response Assessment ◽  
Early Response ◽  
High Dose ◽  
Resonance Imaging ◽  
Early Response Assessment

Chordoma in pediatric patients is very rare. Proton therapy has become a gold standard in the treatment of these neoplasms, as high dose escalation can be achieved regarding the target while maximizing the sparing of the healthy tissues near the tumor. The aim of the work was to assess the evolution of morphological sequences during treatment using T1/T2-weighted magnetic resonance imaging (MRI) for the early response assessment of a classic chordoma of the skull base in a pediatric patient who had undergone surgical excision. Our results demonstrated a significant quantitative reduction in the residual nodule component adhered to the medullary bulb junction, with an almost complete recovery of normal anatomy at the end of the irradiation treatment. This was mainly shown in the T2-weighted MRI. On the other hand, the classic component of the lesion was predominantly present and located around the tooth of the axis. The occipital condyles were morphologically and dimensionally stable for the entire irradiation period. In conclusion, the application of this type of monitoring methodology, which is unusual during the administration of a proton treatment for chordoma, highlighted the unexpected early response of the disease. At the same time, it allowed the continuous assessment of the reliability of the treatment plan.

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