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 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 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 Mycobacterium tuberculosis Lsr2 Is a Global Transcriptional Regulator Required for Adaptation to Changing Oxygen Levels and Virulence

mBio ◽  
2014 ◽  
Vol 5 (3) ◽  
Author(s):  
I. L. Bartek ◽  
L. K. Woolhiser ◽  
A. D. Baughn ◽  
R. J. Basaraba ◽  
W. R. Jacobs ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Mouse Model ◽  
Oxygen Tension ◽  
Reactive Oxygen ◽  
Transcriptional Regulator ◽  
Oxygen Availability ◽  
World Population ◽  
Lung Pathology ◽  
Content Type ◽  
Oxygen Levels

ABSTRACTTo survive a dynamic host environment,Mycobacterium tuberculosismust endure a series of challenges, from reactive oxygen and nitrogen stress to drastic shifts in oxygen availability. The mycobacterial Lsr2 protein has been implicated in reactive oxygen defense via direct protection of DNA. To examine the role of Lsr2 in pathogenesis and physiology ofM. tuberculosis, we generated a strain deleted forlsr2. Analysis of theM. tuberculosisΔlsr2strain demonstrated that Lsr2 is not required for DNA protection, as this strain was equally susceptible as the wild type to DNA-damaging agents. Thelsr2mutant did display severe growth defects under normoxic and hyperoxic conditions, but it was not required for growth under low-oxygen conditions. However, it was also required for adaptation to anaerobiosis. The defect in anaerobic adaptation led to a marked decrease in viability during anaerobiosis, as well as a lag in recovery from it. Gene expression profiling of the Δlsr2mutant under aerobic and anaerobic conditions in conjunction with published DNA binding-site data indicates that Lsr2 is a global transcriptional regulator controlling adaptation to changing oxygen levels. The Δlsr2strain was capable of establishing an early infection in the BALB/c mouse model; however, it was severely defective in persisting in the lungs and caused no discernible lung pathology. These findings demonstrateM. tuberculosisLsr2 is a global transcriptional regulator required for control of genes involved in adaptation to extremes in oxygen availability and is required for persistent infection.IMPORTANCEM. tuberculosiscauses nearly two million deaths per year and infects nearly one-third of the world population. The success of this aerobic pathogen is due in part to its ability to successfully adapt to constantly changing oxygen availability throughout the infectious cycle, from the high oxygen tension during aerosol transmission to anaerobiosis within necrotic lesions. An understanding of howM. tuberculosiscopes with these changes in oxygen tension is critical for its eventual eradication. Using a mutation inlsr2, we demonstrate that the Lsr2 protein present in all mycobacteria is a global transcriptional regulator in control of genes required for adaptation to changes in oxygen levels.M. tuberculosislackinglsr2was unable to adapt to both high and very low levels of oxygen and was defective in long-term anaerobic survival. Lsr2 was also required for disease pathology and for chronic infection in a mouse model of TB.

scholarly journals Differential Virulence and Disease Progression following Mycobacterium tuberculosis Complex Infection of the Common Marmoset (Callithrix jacchus)

2013 ◽  
Vol 81 (8) ◽  
pp. 2909-2919 ◽  
Author(s):  
Laura E. Via ◽  
Danielle M. Weiner ◽  
Daniel Schimel ◽  
Philana Ling Lin ◽  
Emmanuel Dayao ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Human Disease ◽  
Small Animal ◽  
Common Marmoset ◽  
Callithrix Jacchus ◽  
Primate Model ◽  
Content Type ◽  
Positron Emission ◽  
The Common ◽  
Fdg Pet Ct

ABSTRACTExisting small-animal models of tuberculosis (TB) rarely develop cavitary disease, limiting their value for assessing the biology and dynamics of this highly important feature of human disease. To develop a smaller primate model with pathology similar to that seen in humans, we experimentally infected the common marmoset (Callithrix jacchus) with diverse strains ofMycobacterium tuberculosisof various pathogenic potentials. These included recent isolates of the modern Beijing lineage, the Euro-American X lineage, andM. africanum. All three strains produced fulminant disease in this animal with a spectrum of progression rates and clinical sequelae that could be monitored in real time using 2-deoxy-2-[18F]fluoro-d-glucose (FDG) positron emission tomography (PET)/computed tomography (CT). Lesion pathology at sacrifice revealed the entire spectrum of lesions observed in human TB patients. The three strains produced different rates of progression to disease, various extents of extrapulmonary dissemination, and various degrees of cavitation. The majority of live births in this species are twins, and comparison of results from siblings with different infecting strains allowed us to establish that the infection was highly reproducible and that the differential virulence of strains was not simply host variation. Quantitative assessment of disease burden by FDG-PET/CT provided an accurate reflection of the pathology findings at necropsy. These results suggest that the marmoset offers an attractive small-animal model of human disease that recapitulates both the complex pathology and spectrum of disease observed in humans infected with variousM. tuberculosisstrain clades.

scholarly journals GI-19007, a Novel Saccharomyces cerevisiae-Based Therapeutic Vaccine against Tuberculosis

2017 ◽  
Vol 24 (12) ◽  
Author(s):  
Thomas H. King ◽  
Crystal A. Shanley ◽  
Zhimin Guo ◽  
Donald Bellgrau ◽  
Timothy Rodell ◽  
...  
Keyword(s):  
Bacterial Load ◽  
Therapeutic Vaccine ◽  
Lung Damage ◽  
Clinical Strain ◽  
Interleukin 17 ◽  
Lung Pathology ◽  
Content Type ◽  
Secondary Lesion ◽  
Ifn Γ ◽  
Class Ii Antigen

ABSTRACT As yet, very few vaccine candidates with activity in animals against Mycobacterium tuberculosis infection have been tested as therapeutic postexposure vaccines. We recently described two pools of mycobacterial proteins with this activity, and here we describe further studies in which four of these proteins (Rv1738, Rv2032, Rv3130, and Rv3841) were generated as a fusion polypeptide and then delivered in a novel yeast-based platform (Tarmogen) which itself has immunostimulatory properties, including activation of Toll-like receptors. This platform can deliver antigens into both the class I and class II antigen presentation pathways and stimulate strong Th1 and Th17 responses. In mice this fusion vaccine, designated GI-19007, was immunogenic and elicited strong gamma interferon (IFN-γ) and interleukin-17 (IL-17) responses; despite this, they displayed minimal prophylactic activity in mice that were subsequently infected with a virulent clinical strain. In contrast, in a therapeutic model in the guinea pig, GI-19007 significantly reduced the lung bacterial load and reduced lung pathology, particularly in terms of secondary lesion development, while significantly improving survival in one-third of these animals. In further studies in which guinea pigs were vaccinated with BCG before challenge, therapeutic vaccination with GI-19007 initially improved survival versus that of animals given BCG alone, although this protective effect was gradually lost at around 400 days after challenge. Given its apparent ability to substantially limit bacterial dissemination within and from the lungs, GI-19007 potentially can be used to limit lung damage as well as facilitating chemotherapeutic regimens in infected individuals.

scholarly journals Mutations in Genes for the F420Biosynthetic Pathway and a Nitroreductase Enzyme Are the Primary Resistance Determinants in SpontaneousIn Vitro-Selected PA-824-Resistant Mutants of Mycobacterium tuberculosis

2015 ◽  
Vol 59 (9) ◽  
pp. 5316-5323 ◽  
Author(s):  
Hana L. Haver ◽  
Adeline Chua ◽  
Pramila Ghode ◽  
Suresh B. Lakshminarayana ◽  
Amit Singhal ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Catalytic Domain ◽  
Crystal Structure Analysis ◽  
Phase Iii ◽  
Clinical Strain ◽  
Single Mutation ◽  
Primary Resistance ◽  
Prodrug Activation ◽  
Content Type ◽  
Resistant Mutants

ABSTRACTAlleviating the burden of tuberculosis (TB) requires an understanding of the genetic basis that determines the emergence of drug-resistant mutants. PA-824 (pretomanid) is a bicyclic nitroimidazole class compound presently undergoing the phase III STAND clinical trial, despite lacking identifiable genetic markers for drug-specific resistantMycobacterium tuberculosis. In the present study, we aimed to characterize the genetic polymorphisms of spontaneously generated PA-824-resistant mutant strains by surveying drug metabolism genes for potential mutations. Of the 183 independently selected PA-824-resistantM. tuberculosismutants, 83% harbored a single mutation in one of five nonessential genes associated with either PA-824 prodrug activation (ddn, 29%;fgd1, 7%) or the tangential F420biosynthetic pathway (fbiA, 19%;fbiB, 2%;fbiC, 26%). Crystal structure analysis indicated that identified mutations were specifically located within the protein catalytic domain that would hinder the activity of the enzymes required for prodrug activation. This systematic analysis conducted of genotypes resistant to PA-824 may contribute to future efforts in monitoring clinical strain susceptibility with this new drug therapy.

scholarly journals Assessment of the Plasmodium falciparum Preerythrocytic Antigen UIS3 as a Potential Candidate for a Malaria Vaccine

2016 ◽  
Vol 85 (3) ◽  
Author(s):  
Rhea J. Longley ◽  
Benedict R. Halbroth ◽  
Ahmed M. Salman ◽  
Katie J. Ewer ◽  
Susanne H. Hodgson ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Viral Vectors ◽  
Vaccine Candidate ◽  
Mouse Strains ◽  
Potential Candidate ◽  
Wild Type ◽  
Content Type ◽  
Malaria Vaccines ◽  
Modified Vaccinia Virus Ankara ◽  
Controlled Human Malaria Infection

ABSTRACT Efforts are under way to improve the efficacy of subunit malaria vaccines through assessments of new adjuvants, vaccination platforms, and antigens. In this study, we further assessed the Plasmodium falciparum antigen upregulated in infective sporozoites 3 (PfUIS3) as a vaccine candidate. PfUIS3 was expressed in the viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) and used to immunize mice in a prime-boost regimen. We previously demonstrated that this regimen could provide partial protection against challenge with chimeric P. berghei parasites expressing PfUIS3. We now show that ChAd63-MVA PfUIS3 can also provide partial cross-species protection against challenge with wild-type P. berghei parasites. We also show that PfUIS3-specific cellular memory responses could be recalled in human volunteers exposed to P. falciparum parasites in a controlled human malaria infection study. When ChAd63-MVA PfUIS3 was coadministered with the vaccine candidate P. falciparum thrombospondin-related adhesion protein (PfTRAP) expressed in the ChAd63-MVA system, there was no significant change in immunogenicity to either vaccine. However, when mice were challenged with double chimeric P. berghei-P. falciparum parasites expressing both PfUIS3 and PfTRAP, vaccine efficacy was improved to 100% sterile protection. This synergistic effect was evident only when the two vaccines were mixed and administered at the same site. We have therefore demonstrated that vaccination with PfUIS3 can induce a consistent delay in patent parasitemia across mouse strains and against chimeric parasites expressing PfUIS3 as well as wild-type P. berghei; when this vaccine is combined with another partially protective regimen (ChAd63-MVA PfTRAP), complete protection is induced.

scholarly journals An attenuated Mycobacterium tuberculosis clinical strain with a defect in ESX-1 secretion induces minimal host immune responses and pathology

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Helena Strand Clemmensen ◽  
Niels Peter Hell Knudsen ◽  
Erik Michael Rasmussen ◽  
Jessica Winkler ◽  
Ida Rosenkrands ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Clinical Strain ◽  
Host Immune Responses

scholarly journals Differential Influence of Nutrient-Starved Mycobacterium tuberculosis on Adaptive Immunity Results in Progressive Tuberculosis Disease and Pathology

2015 ◽  
Vol 83 (12) ◽  
pp. 4731-4739 ◽  
Author(s):  
Jes Dietrich ◽  
Sugata Roy ◽  
Ida Rosenkrands ◽  
Thomas Lindenstrøm ◽  
Jonathan Filskov ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Immune System ◽  
Nutrient Starvation ◽  
Host Immune System ◽  
Lung Pathology ◽  
Pronounced Increase ◽  
Content Type ◽  
Tnf Α ◽  
Ifn Γ

When infected withMycobacterium tuberculosis, most individuals will remain clinically healthy but latently infected. Latent infection has been proposed to partially involveM. tuberculosisin a nonreplicating stage, which therefore represents anM. tuberculosisphenotype that the immune system most likely will encounter during latency. It is therefore relevant to examine how this particular nonreplicating form ofM. tuberculosisinteracts with the host immune system. To study this, we first induced a state of nonreplication through prolonged nutrient starvation ofM. tuberculosisin vitro. This resulted in nonreplicating persistence even after prolonged culture in phosphate-buffered saline. Infection with either exponentially growingM. tuberculosisor nutrient-starvedM. tuberculosisresulted in similar lung CFU levels in the first phase of the infection. However, between week 3 and 6 postinfection, there was a very pronounced increase in bacterial levels and associated lung pathology in nutrient-starved-M. tuberculosis-infected mice. This was associated with a shift from CD4 T cells that coexpressed gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) or IFN-γ, TNF-α, and interleukin-2 to T cells that only expressed IFN-γ. Thus, nonreplicatingM. tuberculosisinduced through nutrient starvation promotes a bacterial form that is genetically identical to exponentially growingM. tuberculosisyet characterized by a differential impact on the immune system that may be involved in undermining host antimycobacterial immunity and facilitate increased pathology and transmission.

scholarly journals Differential Mycobacterium bovis BCG Vaccine-Derived Efficacy in C3Heb/FeJ and C3H/HeOuJ Mice Exposed to a Clinical Strain of Mycobacterium tuberculosis

2014 ◽  
Vol 22 (1) ◽  
pp. 91-98 ◽  
Author(s):  
Marcela Henao-Tamayo ◽  
Andrés Obregón-Henao ◽  
Elizabeth Creissen ◽  
Crystal Shanley ◽  
Ian Orme ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Mycobacterium Bovis ◽  
Vaccine Efficacy ◽  
Disease Process ◽  
Bcg Vaccine ◽  
Clinical Strain ◽  
Interleukin 17 ◽  
Content Type ◽  
The Impact

ABSTRACTThe global epidemic caused by the bacterial pathogenMycobacterium tuberculosiscontinues unabated. Moreover, the only available vaccine against tuberculosis,Mycobacterium bovisbacillus Calmette-Guérin (BCG), demonstrates variable efficacy. To respond to this global threat, new animal models that mimic the pathological disease process in humans are required for vaccine testing. One new model, susceptible C3Heb/FeJ mice, is similar to human tuberculosis in that these animals are capable of forming necrotic tubercle granulomas, in contrast to resistant C3H/HeOuJ mice. In this study, we evaluated the impact of prior BCG vaccination of C3Heb/FeJ and C3H/HeOuJ mice on exposure to a low-dose aerosol ofMycobacterium tuberculosisW-Beijing strain SA161. Both BCG-vaccinated murine strains demonstrated reduced bacterial loads 25 days after infection compared to controls, indicating vaccine efficacy. However, during chronic infection, vaccine efficacy waned in C3H/HeOuJ but not in C3Heb/FeJ mice. Protection in vaccinated C3Heb/FeJ mice was associated with reduced numbers of CD11b+Gr1+cells, increased numbers of effector and memory T cells, and an absence of necrotic granulomas. BCG vaccine efficacy waned in C3H/HeOuJ mice, as indicated by reduced expression of gamma interferon (IFN-γ) and increased expressions of interleukin-17 (IL-17), IL-10, and Foxp3 by T cells compared to C3Heb/FeJ mice. This is the first murine vaccine model system described to date that can be utilized to dissect differential vaccine-derived immune efficacy.

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