scholarly journals Mucosal Influenza Vector Vaccine Carrying TB10.4 and HspX Antigens Provides Protection against Mycobacterium tuberculosis in Mice and Guinea Pigs

Vaccines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 394
Author(s):  
Mariia Sergeeva ◽  
Ekaterina Romanovskaya-Romanko ◽  
Natalia Zabolotnyh ◽  
Anastasia Pulkina ◽  
Kirill Vasilyev ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Vaccine Candidate ◽  
Cell Immune Response ◽  
Lung Pathology ◽  
Ns1 Protein ◽  
Reading Frame ◽  
Intranasal Immunization ◽  
Vector Vaccine ◽  
Boost Immunization ◽  
New Strategies

New strategies providing protection against tuberculosis (TB) are still pending. The airborne nature of Mycobacterium tuberculosis (M.tb) infection assumes that the mucosal delivery of the TB vaccine could be a more promising strategy than the systemic route of immunization. We developed a mucosal TB vaccine candidate based on recombinant attenuated influenza vector (Flu/THSP) co-expressing truncated NS1 protein NS1(1–124) and a full-length TB10.4 and HspX proteins of M.tb within an NS1 protein open reading frame. The Flu/THSP vector was safe and stimulated a systemic TB-specific CD4+ and CD8+ T-cell immune response after intranasal immunization in mice. Double intranasal immunization with the Flu/THSP vector induced protection against two virulent M.tb strains equal to the effect of BCG subcutaneous injection in mice. In a guinea pig TB model, one intranasal immunization with Flu/THSP improved protection against M.tb when tested as a vaccine candidate for boosting BCG-primed immunity. Importantly, enhanced protection provided by a heterologous BCG-prime → Flu/THSP vector boost immunization scheme was associated with a significantly reduced lung and spleen bacterial burden (mean decrease of 0.77 lg CFU and 0.72 lg CFU, respectively) and improved lung pathology 8.5 weeks post-infection with virulent M.tb strain H37Rv.

scholarly journals Enhancement of the Local CD8+ T-Cellular Immune Response to Mycobacterium tuberculosis in BCG-Primed Mice after Intranasal Administration of Influenza Vector Vaccine Carrying TB10.4 and HspX Antigens

Vaccines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1273
Author(s):  
Kirill Vasilyev ◽  
Anna-Polina Shurygina ◽  
Natalia Zabolotnykh ◽  
Mariia Sergeeva ◽  
Ekaterina Romanovskaya-Romanko ◽  
...  
Keyword(s):  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
Cellular Immune Response ◽  
Vaccine Candidate ◽  
Protective Efficacy ◽  
Adaptive Immune Response ◽  
Reading Frame ◽  
Vector Vaccine ◽  
Specific Effector ◽  
Cellular Immune

BCG is the only licensed vaccine against Mycobacterium tuberculosis (M.tb) infection. Due to its intramuscular administration route, BCG is unable to induce a local protective immune response in the respiratory system. Moreover, BCG has a diminished ability to induce long-lived memory T-cells which are indispensable for antituberculosis protection. Recently we described the protective efficacy of new mucosal TB vaccine candidate based on recombinant attenuated influenza vector (Flu/THSP) co-expressing TB10.4 and HspX proteins of M.tb within an NS1 influenza protein open reading frame. In the present work, the innate and adaptive immune response to immunization with the Flu/THSP and the immunological properties of vaccine candidate in the BCG-prime → Flu/THSP vector boost vaccination scheme are studied in mice. It was shown that the mucosal administration of Flu/THSP induces the incoming of interstitial macrophages in the lung tissue and stimulates the expression of co-stimulatory CD86 and CD83 molecules on antigen-presenting cells. The T-cellular immune response to Flu/THSP vector was mediated predominantly by the IFNγ-producing CD8+ lymphocytes. BCG-prime → Flu/THSP vector boost immunization scheme was shown to protect mice from severe lung injury caused by M.tb infection due to the enhanced T-cellular immune response, mediated by antigen-specific effector and central memory CD4+ and CD8+ T-lymphocytes.

scholarly journals Comparative Protective Efficacies of Novel Avian Paramyxovirus-Vectored Vaccines against Virulent Infectious Bronchitis Virus in Chickens

Viruses ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 697
Author(s):  
Edris Shirvani ◽  
Siba K. Samal
Keyword(s):  
Infectious Bronchitis Virus ◽  
Vaccine Candidate ◽  
Protective Efficacy ◽  
Study Groups ◽  
Avian Paramyxovirus ◽  
S Protein ◽  
Vector Vaccine ◽  
Infectious Bronchitis ◽  
Boost Immunization ◽  
Highly Virulent

Viral vectored vaccines are desirable alternatives for conventional infectious bronchitis virus (IBV) vaccines. We have recently shown that a recombinant Newcastle disease virus (rNDV) strain LaSota expressing the spike (S) protein of IBV strain Mass-41 (rLaSota/IBV-S) was a promising vaccine candidate for IBV. Here we evaluated a novel chimeric rNDV/avian paramyxovirus serotype 2 (rNDV/APMV-2) as a vaccine vector against IBV. The rNDV/APMV-2 vector was chosen because it is much safer than the rNDV strain LaSota vector, particularly for young chicks and chicken embryos. In order to determine the effectiveness of this vector, a recombinant rNDV/APMV-2 expressing the S protein of IBV strain Mass-41 (rNDV/APMV-2/IBV-S) was constructed. The protective efficacy of this vector vaccine was compared to that of the rNDV vector vaccine. In one study, groups of one-day-old specific-pathogenic-free (SPF) chickens were immunized with rLaSota/IBV-S and rNDV/APMV-2/IBV-S and challenged four weeks later with the homologous highly virulent IBV strain Mass-41. In another study, groups of broiler chickens were single (at day one or three weeks of age) or prime-boost (prime at day one and boost at three weeks of age) immunized with rLaSota/IBV-S and/or rNDV-APMV-2/IBV-S. At weeks six of age, chickens were challenged with a highly virulent IBV strain Mass-41. Our challenge study showed that novel rNDV/APMV-2/IBV-S provided similar protection as rLaSota/IBV-S in SPF chickens. However, compared to prime-boost immunization of chickens with chimeric rNDV/APMV-2, rLaSota/IBV-S and/or a live IBV vaccine, single immunization of chickens with rLaSota/IBV-S, or live IBV vaccine provided better protection against IBV. In conclusion, we have developed the novel rNDV/APMV-2 vector expressing S protein of IBV that can be a safer vaccine against IB in chickens. Our results also suggest a single immunization with a LaSota vectored IBV vaccine candidate provides better protection than prime-boost immunization regimens.

scholarly journals Protection and Long-Lived Immunity Induced by the ID93/GLA-SE Vaccine Candidate against a Clinical Mycobacterium tuberculosis Isolate

2015 ◽  
Vol 23 (2) ◽  
pp. 137-147 ◽  
Author(s):  
Susan L. Baldwin ◽  
Valerie A. Reese ◽  
Po-wei D. Huang ◽  
Elyse A. Beebe ◽  
Brendan K. Podell ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Vaccine Candidate ◽  
Small Animal ◽  
Mouse Strains ◽  
Clinical Strain ◽  
Lung Pathology ◽  
Content Type ◽  
Host Immune Responses ◽  
Immunological Factors ◽  
Induced Immunity

ABSTRACTMycobacterium tuberculosisHN878 represents a virulent clinical strain from the W-Beijing family, which has been tested in small animal models in order to study its virulence and its induction of host immune responses following infection. This isolate causes death and extensive lung pathology in infected C57BL/6 mice, whereas lab-adapted strains, such asM. tuberculosisH37Rv, do not. The use of this clinically relevant isolate ofM. tuberculosisincreases the possibilities of assessing the long-lived efficacy of tuberculosis vaccines in a relatively inexpensive small animal model. This model will also allow for the use of knockout mouse strains to critically examine key immunological factors responsible for long-lived, vaccine-induced immunity in addition to vaccine-mediated prevention of pulmonary immunopathology. In this study, we show that the ID93/glucopyranosyl lipid adjuvant (GLA)-stable emulsion (SE) tuberculosis vaccine candidate, currently in human clinical trials, is able to elicit protection againstM. tuberculosisHN878 by reducing the bacterial burden in the lung and spleen and by preventing the extensive lung pathology induced by this pathogen in C57BL/6 mice.

scholarly journals Mycobacterium tuberculosis Infection Up-Regulates Sialyl Lewis X Expression in the Lung Epithelium

2021 ◽  
Vol 9 (1) ◽  
pp. 99
Author(s):  
Rita Matos ◽  
Kaori L. Fonseca ◽  
Stefan Mereiter ◽  
Ana Raquel Maceiras ◽  
Joana Gomes ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Biosynthetic Pathway ◽  
Molecular Mechanisms ◽  
Tuberculosis Infection ◽  
Host Susceptibility ◽  
Sialyl Lewis X ◽  
Lung Pathology ◽  
Lung Epithelium ◽  
Lewis X ◽  
Sialyl Lewis

Glycans display increasingly recognized roles in pathological contexts, however, their impact in the host-pathogen interplay in many infectious diseases remains largely unknown. This is the case for tuberculosis (TB), one of the ten most fatal diseases worldwide, caused by infection of the bacteria Mycobacterium tuberculosis. We have recently reported that perturbing the core-2 O-glycans biosynthetic pathway increases the host susceptibility to M. tuberculosis infection, by disrupting the neutrophil homeostasis and enhancing lung pathology. In the present study, we show an increased expression of the sialylated glycan structure Sialyl-Lewis X (SLeX) in the lung epithelium upon M. tuberculosis infection. This increase in SLeX glycan epitope is accompanied by an altered lung tissue transcriptomic signature, with up-regulation of genes codifying enzymes that are involved in the SLeX core-2 O-glycans biosynthetic pathway. This study provides novel insights into previously unappreciated molecular mechanisms involving glycosylation, which modulate the host response to M. tuberculosis infection, possibly contributing to shape TB disease outcome.

scholarly journals Recombinant Expression and Characterization of the Major β-Lactamase of Mycobacterium tuberculosis

1998 ◽  
Vol 42 (6) ◽  
pp. 1375-1381 ◽  
Author(s):  
Rama Kishan R. Voladri ◽  
David L. Lakey ◽  
Steven H. Hennigan ◽  
Barbara E. Menzies ◽  
Kathryn M. Edwards ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Recombinant Expression ◽  
Gel Filtration ◽  
Multidrug Resistant ◽  
Chromosomal Dna ◽  
Reading Frame ◽  
Major Mechanism ◽  
Dna Library ◽  
Class A ◽  
Resistant Tuberculosis

ABSTRACT New antibiotic regimens are needed for the treatment of multidrug-resistant tuberculosis. Mycobacterium tuberculosis has a thick peptidoglycan layer, and the penicillin-binding proteins involved in its biosynthesis are inhibited by clinically relevant concentrations of β-lactam antibiotics. β-Lactamase production appears to be the major mechanism by whichM. tuberculosis expresses β-lactam resistance. β-Lactamases from the broth supernatant of 3- to 4-week-old cultures of M. tuberculosis H37Ra were partially purified by sequential gel filtration chromatography and chromatofocusing. Three peaks of β-lactamase activity with pI values of 5.1, 4.9, and 4.5, respectively, and which accounted for 10, 78, and 12% of the total postchromatofocusing β-lactamase activity, respectively, were identified. The β-lactamases with pI values of 5.1 and 4.9 were kinetically indistinguishable and exhibited predominant penicillinase activity. In contrast, the β-lactamase with a pI value of 4.5 showed relatively greater cephalosporinase activity. An open reading frame in cosmid Y49 of the DNA library of M. tuberculosis H37Rv with homology to known class A β-lactamases was amplified from chromosomal DNA of M. tuberculosis H37Ra by PCR and was overexpressed in Escherichia coli. The recombinant enzyme was kinetically similar to the pI 5.1 and 4.9 enzymes purified directly from M. tuberculosis. It exhibited predominant penicillinase activity and was especially active against azlocillin. It was inhibited by clavulanic acid andm-aminophenylboronic acid but not by EDTA. We conclude that the major β-lactamase of M. tuberculosis is a class A β-lactamase with predominant penicillinase activity. A second, minor β-lactamase with relatively greater cephalosporinase activity is also present.

scholarly journals Targeting redox heterogeneity to counteract drug tolerance in replicating Mycobacterium tuberculosis

2019 ◽  
Vol 11 (518) ◽  
pp. eaaw6635 ◽  
Author(s):  
Richa Mishra ◽  
Sakshi Kohli ◽  
Nitish Malhotra ◽  
Parijat Bandyopadhyay ◽  
Mansi Mehta ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Tolerance ◽  
Antibiotic Tolerance ◽  
Lung Pathology ◽  
In Vivo Models ◽  
Drug Efflux Pumps ◽  
Major Drug ◽  
Hiv 1 ◽  
Multiple Antibiotics

The capacity of Mycobacterium tuberculosis (Mtb) to tolerate multiple antibiotics represents a major problem in tuberculosis (TB) management. Heterogeneity in Mtb populations is one of the factors that drives antibiotic tolerance during infection. However, the mechanisms underpinning this variation in bacterial population remain poorly understood. Here, we show that phagosomal acidification alters the redox physiology of Mtb to generate a population of replicating bacteria that display drug tolerance during infection. RNA sequencing of this redox-altered population revealed the involvement of iron-sulfur (Fe-S) cluster biogenesis, hydrogen sulfide (H2S) gas, and drug efflux pumps in antibiotic tolerance. The fraction of the pH- and redox-dependent tolerant population increased when Mtb infected macrophages with actively replicating HIV-1, suggesting that redox heterogeneity could contribute to high rates of TB therapy failure during HIV-TB coinfection. Pharmacological inhibition of phagosomal acidification by the antimalarial drug chloroquine (CQ) eradicated drug-tolerant Mtb, ameliorated lung pathology, and reduced postchemotherapeutic relapse in in vivo models. The pharmacological profile of CQ (Cmax and AUClast) exhibited no major drug-drug interaction when coadministered with first line anti-TB drugs in mice. Our data establish a link between phagosomal pH, redox metabolism, and drug tolerance in replicating Mtb and suggest repositioning of CQ to shorten TB therapy and achieve a relapse-free cure.

scholarly journals Mycobacterial Antigens Exacerbate Disease Manifestations in Mycobacterium tuberculosis-Infected Mice

2002 ◽  
Vol 70 (4) ◽  
pp. 2100-2107 ◽  
Author(s):  
Andre L. Moreira ◽  
Liana Tsenova ◽  
Melles Haile Aman ◽  
Linda-Gail Bekker ◽  
Sherry Freeman ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Pulmonary Disease ◽  
Bacterial Load ◽  
Subcutaneous Administration ◽  
Mycobacterial Antigen ◽  
Lung Pathology ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Aerosol Infection ◽  
Mycobacterial Antigens

ABSTRACT To control tuberculosis worldwide, the burden of adult pulmonary disease must be reduced. Although widely used, Mycobacterium bovis BCG vaccination given at birth does not protect against adult pulmonary disease. Therefore, postexposure vaccination of adults with mycobacterial antigens is being considered. We examined the effect of various mycobacterial antigens on mice with prior M. tuberculosis infection. Subcutaneous administration of live or heat-treated BCG with or without lipid adjuvants to infected mice induced increased antigen-specific T-cell proliferation but did not reduce the bacterial load in the lungs and caused larger lung granulomas. Similarly, additional mycobacterial antigen delivered directly to the lungs by aerosol infection with viable M. tuberculosis mixed with heat-killed Mycobacterium tuberculosis (1:1) also did not reduce the bacillary load but caused increased expression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), which was associated with larger granulomas in the lungs. When M. tuberculosis-infected mice were treated with recombinant BCG that secreted cytokines shown to reduce disease in a preinfection vaccine model, the BCG secreting TNF-α, and to a lesser extent, IL-2 and gamma interferon (IFN-γ), caused a significant increase in granuloma size in the lungs. Moreover, treatment of M. tuberculosis-infected mice with recombinant murine TNF-α resulted in increased inflammation in the lungs and accelerated mortality without affecting the bacillary load. Taken together, these studies suggest that administration of mycobacterial antigens to mice with prior M. tuberculosis infection leads to immune activation that may exacerbate lung pathology via TNF-α-induced inflammation without reducing the bacillary load.

Mycobacterium tuberculosis topoisomerases and EthR as the targets for new anti-TB drugs development

2019 ◽  
Vol 11 (16) ◽  
pp. 2193-2203
Author(s):  
Rafal Sawicki ◽  
Grazyna Ginalska
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Short Review ◽  
Drug Resistant ◽  
Dna Topoisomerases ◽  
Antituberculosis Drugs ◽  
Drug Candidates ◽  
Computational Sciences ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
New Strategies

The significant increase in the detection of drug-resistant strains of Mycobacterium tuberculosis caused an urgent need for the discovery new antituberculosis drugs. Development of bioinformatics and computational sciences enabled the progress of new strategies leading to design, discovery and identification of a series of interesting drug candidates. In this short review, we would like to present recently discovered compounds targeting important mycobacterial proteins: DNA topoisomerases and the transcriptional repressor of EthA monooxygenase – EthR.

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