Animal Models of Tuberculosis: Guinea Pigs

Clark, Simon; Hall, Yper; Williams, Ann

doi:10.1101/cshperspect.a018572

Cited by 85 publications

(74 citation statements)

References 44 publications

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“…*p # 0.05, **p # 0.01, ***p # 0.001, ****p # 0.0001. post infection with M. tuberculosis or whether they are also induced by BCG vaccination. The guinea pig is a well-accepted small animal model for TB because it is naturally susceptible to virulent mycobacteria and, upon infection, reproduces similar pathological changes to those seen in TB patients (32). Using outbred Dunkin-Hartley guinea pigs, we could demonstrate that BCG-vaccinated animals mount strong and robust Th cell responses to hydrophobic peptide Ags present in mycobacterial CMEs.…”

Section: Discussionmentioning

confidence: 88%

BCG Vaccination Induces Robust CD4+ T Cell Responses to Mycobacterium tuberculosis Complex–Specific Lipopeptides in Guinea Pigs

Kaufmann

Spohr

Battenfeld

et al. 2016

The Journal of Immunology

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A new class of highly antigenic, MHC-II–restricted mycobacterial lipopeptides that are recognized by CD4-positive T lymphocytes of Mycobacterium tuberculosis–infected humans has recently been described. To investigate the relevance of this novel class of mycobacterial Ags in the context of experimental bacille Calmette-Guérin (BCG) vaccination, Ag-specific T cell responses to mycobacterial lipid and lipopeptide-enriched Ag preparations were analyzed in immunized guinea pigs. Lipid and lipopeptide preparations as well as complex Ag mixtures, such as tuberculin, mycobacterial lysates, and culture supernatants, all induced a similar level of T cell proliferation. The hypothesis that lipopeptide-specific T cells dominate the early BCG-induced T cell response was corroborated in restimulation assays by the observation that Ag-expanded T cells specifically responded to the lipopeptide preparation. A comparative analysis of the responses to Ag preparations from different mycobacterial species revealed that the antigenic lipopeptides are specific for strains of the M. tuberculosis complex. Their intriguing conservation in pathogenic tuberculous bacteria and the fact that these highly immunogenic Ags seem to be actively released during in vitro culture and intracellular infection prompt the urgent question about their role in the fine-tuned interplay between the pathogen and its mammalian host, in particular with regard to BCG vaccination strategies.

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Section: Discussionmentioning

confidence: 88%

BCG Vaccination Induces Robust CD4+ T Cell Responses to Mycobacterium tuberculosis Complex–Specific Lipopeptides in Guinea Pigs

Kaufmann

Spohr

Battenfeld

et al. 2016

The Journal of Immunology

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“…Accordingly, dissemination of the bacilli from the respiratory parenchyma to other tissue sites, albeit essential for induction of adaptive immunity, also promotes immunopathology and disease transmission. TB progression promotes formation of perivascular and peribronchiolar cuffs of lymphocytes and in certain animal models, e.g., guinea pigs, massive infiltration of lymphatics [102]. In line with the lymphocentric model, such species show heightened susceptibility to TB.…”

Section: Early Lesions and Immune Events In Pulmonary Tbmentioning

confidence: 97%

Pathology and immune reactivity: understanding multidimensionality in pulmonary tuberculosis

2015

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Heightened morbidity and mortality in pulmonary tuberculosis (TB) are consequences of complex disease processes triggered by the causative agent, Mycobacterium tuberculosis (Mtb). Mtb modulates inflammation at distinct stages of its intracellular life. Recognition and phagocytosis, replication in phagosomes and cytosol escape induce tightly regulated release of cytokines [including interleukin (IL)-1, tumor necrosis factor (TNF), IL-10], chemokines, lipid mediators, and type I interferons (IFN-I). Mtb occupies various lung lesions at sites of pathology. Bacteria are barely detectable at foci of lipid pneumonia or in perivascular/bronchiolar cuffs. However, abundant organisms are evident in caseating granulomas and at the cavity wall. Such lesions follow polar trajectories towards fibrosis, encapsulation and mineralization or liquefaction, extensive matrix destruction, and tissue injury. The outcome is determined by immune factors acting in concert. Gradients of cytokines and chemokines (CCR2, CXCR2, CXCR3/CXCR5 agonists; TNF/IL-10, IL-1/IFN-I), expression of activation/death markers on immune cells (TNF receptor 1, PD-1, IL-27 receptor) or abundance of enzymes [arginase-1, matrix metalloprotease (MMP)-1, MMP-8, MMP-9] drive genesis and progression of lesions. Distinct lesions coexist such that inflammation in TB encompasses a spectrum of tissue changes. A better understanding of the multidimensionality of immunopathology in TB will inform novel therapies against this pulmonary disease.

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“…CRISPR-Cas editing will also be a boon to infectious disease research. Many human pathogens are best modelled in hosts other than mouse, such as influenza (ferrets) 107 , leptospirosis (hamsters) 107 and tuberculosis (Guinea pigs) 108 , and we expect zygote editing to be proven feasible in these organisms in the near future. Optimizing conditions for ESC work was one of the biggest challenges in the genetic manipulation of new mammalian model organisms.…”

Section: Crispr-cas As a Tool For Drug Discoverymentioning

confidence: 99%

Cornerstones of CRISPR–Cas in drug discovery and therapy

Fellmann

Gowen

Lin

et al. 2016

Nat Rev Drug Discov

391

310

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The recent development of CRISPR-Cas systems as easily accessible and programmable tools for genome editing and regulation is spurring a revolution in biology. Paired with the rapid expansion of personalized and reference genomic sequence information, technologies based on CRISPR-Cas are enabling nearly unlimited genetic manipulation even in previously difficult contexts, including human cells. Although much attention has focused on the potential of CRISPR-Cas to cure Mendelian diseases, the technology also holds promise to transform the development of therapies to treat complex heritable and somatic disorders. Here we discuss how CRISPR-Cas can impact the next generation of drugs through accelerating the identification and validation of high-value targets, uncovering high confidence biomarkers and developing differentiated breakthrough therapies. We focus on the promises, pitfalls and hurdles of this revolutionary gene editing technology, and also discuss key aspects of different CRISPR-Cas screening platforms and offer our perspectives on the best practices in genome engineering.

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Animal Models of Tuberculosis: Guinea Pigs

Cited by 85 publications

References 44 publications

BCG Vaccination Induces Robust CD4+ T Cell Responses to Mycobacterium tuberculosis Complex–Specific Lipopeptides in Guinea Pigs

BCG Vaccination Induces Robust CD4+ T Cell Responses to Mycobacterium tuberculosis Complex–Specific Lipopeptides in Guinea Pigs

Pathology and immune reactivity: understanding multidimensionality in pulmonary tuberculosis

Cornerstones of CRISPR–Cas in drug discovery and therapy

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