The Cellular Immune Response to <i>Mycobacterium tuberculosis</i> Infection in the Guinea Pig

Ordway, Diane; Palanisamy, Gopinath S.; Henao-Tamayo, Marcela; Smith, Erin E.; Shanley, Crystal A.; Orme, Ian M.; Basaraba, Randall J.

doi:10.4049/jimmunol.179.4.2532

Cited by 103 publications

(116 citation statements)

References 42 publications

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“…Since lactoferrin is a component of secretory granules of both macrophages and granulocytes, it is released into the extra-cellular space following inflammatory cell degranulation at sites of inflammation (55). We have recently shown by flow cytometry and immunohistochemistry that granulocyte necrosis and degranulation are associated with the development of primary lesion necrosis, a pattern that matches that of extra-cellular lactoferrin in the current study (56). By being more resistant to oxidative modification, lactoferrin may maintain its iron binding and sequestering capacity at sites of inflammation, when released with reactive oxygen species and myeloperoxidase from stimulated and degranulating neutrophils (57).…”

Section: Discussionsupporting

confidence: 75%

Increased expression of host iron-binding proteins precedes iron accumulation and calcification of primary lung lesions in experimental tuberculosis in the guinea pig

Basaraba¹,

Bielefeldt‐Ohmann²,

Eschelbach³

et al. 2008

Tuberculosis

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The growth and virulence of Mycobacterium tuberculosis depends on its ability to scavenge host iron, an essential and limited micronutrient in vivo. In this study we show that ferric iron accumulates both intra-and extra-cellularly in the primary lung lesions of guinea pigs aerosol-infected with the H37Rv strain of Mycobacterium tuberculosis. Iron accumulated within macrophages at the periphery of the primary granulomatous lesions while extra-cellular ferric iron was concentrated in areas of lesion necrosis. Accumulation of iron within primary lesions was preceded by an increase in expression of heavy chain (H) ferritin, lactoferrin and receptors for transferrin, primarily by macrophages and granulocytes. The increased expression of intra-cellular H ferritin and extracellular lactoferrin, more so than transferrin receptor, paralleled the development of necrosis within primary lesions. The deposition of extra-cellular ferric iron within necrotic foci coincided with the accumulation of calcium and phosphorus and other cations in the form of dystrophic calcification. Primary lung lesions from guinea pigs vaccinated with Mycobactrium bovis BCG prior to experimental infection, had reduced iron accumulation as well as H ferritin, lactoferrin and transferrin receptor expression. The amelioration of primary lesion necrosis and dystrophic calcification by BCG vaccination was coincident with the lack of extra-cellular ferric iron and lactoferrin accumulation. These data demonstrate that BCG vaccination ameliorates primary lesion necrosis, dystrophic mineralization and iron accumulation, in part by down-regulating the expression of macrophage H ferritin, lactoferrin and transferrin receptors, in vivo.

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Section: Discussionsupporting

confidence: 75%

Increased expression of host iron-binding proteins precedes iron accumulation and calcification of primary lung lesions in experimental tuberculosis in the guinea pig

Basaraba¹,

Bielefeldt‐Ohmann²,

Eschelbach³

et al. 2008

Tuberculosis

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“…189 TB is also a primarily hematogenously disseminated disease in the guinea pig. 189 Pulmonary lesions in the guinea pig also contain a high proportion of granulocytes, particularly eosinophils, 152 which are not common features of the human disease. Furthermore, although inbred strains of guinea pigs are available, they are not well characterized with respect to Mtb infection, and immune responsiveness and reagents, although improving, are limited.…”

Section: Guinea Pigsmentioning

confidence: 99%

The Pathology ofMycobacterium tuberculosisInfection

Sakamoto

2012

Vet Pathol

116

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Mycobacterium tuberculosis is an old enemy of the human race, with evidence of infection observed as early as 5000 years ago. Although more host-restricted than Mycobacterium bovis, which can infect all warm-blooded vertebrates, M. tuberculosis can infect, and cause morbidity and mortality in, several veterinary species as well. As M. tuberculosis is one of the earliest described bacterial pathogens, the literature describing this organism is vast and overwhelming. This review strives to distill what is currently known about this bacterium and the disease it causes for the veterinary pathologist.

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“…We observed that the number of peripheral IFN-␥ SFCs as well as the circulating levels of IFN-␥ in serum was reduced at 1 month postinfection. The recruitment of IFN-␥-positive T cells to the site of infection might be responsible for the apparent reduction of T cell response which we observed in the blood (27,29). However, regulatory T cells which develop during active disease may also prevent the specific IFN-␥ SFC response to RD-1 antigens (7,21).…”

Section: Discussionmentioning

confidence: 42%

T Cell Monitoring of Chemotherapy in Experimental Rat Tuberculosis

Foo

Tay

Siew

et al. 2011

Antimicrob Agents Chemother

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Mycobacterium tuberculosis is the causative agent of a pulmonary epidemic that is estimated to infect one-third of the world's population and that has an increased incidence of multidrug resistance. The evaluation of new chemical entities against M. tuberculosis is hampered by the lack of biological tools to help predict efficacy, from early drug development to clinical trials. As the rat is the animal species of choice in the pharmaceutical industry, we have developed a rat model of acute and chronic phases of M. tuberculosis infection for drug efficacy testing. In this model, we have evaluated the impact of tuberculosis drugs on T cell response using the enzyme-linked immunospot assay methodology. Infected rats treated with isoniazid (INH) or rifampin (RIF) responded to therapy, the potency of which was comparable to that seen in the mouse. Peripheral blood mononuclear cells from infected rats produced gamma interferon (IFN-␥) in response to RD-1 antigens, such as the 6-kDa early secretory antigen target (ESAT-6) and the 10-kDa culture filtrate protein (CFP-10). A decrease in IFN-␥ spot-forming cells (SFCs) was consistently observed in response to drug treatment. In both the acute-and chronic-phase models, the T cell response was more sensitive to ESAT-6 than to CFP-10. The SFC count in response to ESAT-6 appears to be an indicator of bacterial killing in the rat. Collectively, our data suggest that the ESAT-6 response could be used as a potential surrogate of drug efficacy in the rat and that such a readout could help shorten drug testing during preclinical development.Mycobacterium tuberculosis infection is among the world's leading infectious diseases, causing about 2 million deaths annually. The emergence of multidrug-resistant M. tuberculosis strains along with the increase of HIV coinfected cases worsens the situation (42). In countries with a high incidence of tuberculosis (TB), TB control programs rely on a diagnostic methods and drugs that have been developed decades ago and that are inadequate to effectively control the epidemic. The urgent need to develop new diagnostic tools as well as new therapeutic interventions is hampered by long clinical trials, where markers of infection and drug response are lacking (38).For decades, the tuberculin skin test (TST) has been used to diagnose TB (18). The TST measures cell-mediated immunity in the form of a delayed-type hypersensitivity response to the purified protein derivative (PPD), a crude mixture of antigens shared among M. tuberculosis, Mycobacterium bovis BCG, and several nontuberculous mycobacteria (NTM). As a result, the TST has lower specificity in populations with high BCG coverage and NTM exposure and shows poor sensitivity in immunocompromised individuals (30). The gamma interferon (IFN-␥) enzyme-linked immunospot (ELISpot) assay has emerged as an alternative to the TST. The assay consists of in vitro stimulation of peripheral blood mononuclear cells (PBMCs) using RD-1 antigens, the 6-kDa early secretory antigen target (ESAT-6) and the 10-kDa cul...

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The Cellular Immune Response to Mycobacterium tuberculosis Infection in the Guinea Pig

Cited by 103 publications

References 42 publications

Increased expression of host iron-binding proteins precedes iron accumulation and calcification of primary lung lesions in experimental tuberculosis in the guinea pig

Increased expression of host iron-binding proteins precedes iron accumulation and calcification of primary lung lesions in experimental tuberculosis in the guinea pig

The Pathology ofMycobacterium tuberculosisInfection

T Cell Monitoring of Chemotherapy in Experimental Rat Tuberculosis

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