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Experimental ocular tuberculosis in guinea pigs.

ABSTRACT: To develop an animal model of intraocular tuberculosis (TB) with features of pulmonary TB and extrapulmonary dissemination to the eye.Hartley strain guinea pigs were infected via an aerosol route with virulent Mycobacterium tuberculosis. One group of guinea pigs was infected with a relatively low bacterial inoculum and received no treatment. A second group of guinea pigs received high-dose infection and were treated with the first-line anti-TB drugs isoniazid, rifampin, and pyrazinamide. Development of ocular TB lesions was documented by histological analysis, acid-fast staining, and real-time polymerase chain reaction for M tuberculosis DNA.Untreated guinea pigs developed pulmonary and extrapulmonary TB. Ocular TB, primarily involving the uvea, developed in 5 of 12 eyes (42%). Uveal granulomatous lesions showed the presence of acid-fast organisms and M tuberculosis DNA. In treated animals, none of the 8 eyes examined revealed the presence of acid-fast organisms; however, there was mild nongranulomatous uveitis in 4 eyes.Mycobacterium tuberculosis delivered via aerosol to guinea pigs results in extrapulmonary dissemination to the eye. Of significance, intraocular changes in this model include granulomatous inflammation and the presence of acid-fast organisms, as seen in human cases of ocular TB. Clinical Relevance The guinea pig model may provide greater insight into the pathogenesis of intraocular TB and assist in the development of novel modalities to treat this global infectious disease.

SUBMITTER: Rao NA

PROVIDER: S-EPMC3062475 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Experimental ocular tuberculosis in guinea pigs.

Rao Narsing A NA Albini Thomas A TA Kumaradas Mirnalini M Pinn Michael L ML Fraig Mostafa M MM Karakousis Petros C PC

Archives of ophthalmology (Chicago, Ill. : 1960) 20090901 9

<h4>Objective</h4>To develop an animal model of intraocular tuberculosis (TB) with features of pulmonary TB and extrapulmonary dissemination to the eye.<h4>Methods</h4>Hartley strain guinea pigs were infected via an aerosol route with virulent Mycobacterium tuberculosis. One group of guinea pigs was infected with a relatively low bacterial inoculum and received no treatment. A second group of guinea pigs received high-dose infection and were treated with the first-line anti-TB drugs isoniazid, r ...[more]

PMID: 19752425

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Project description:Hyperglycemia, the diagnostic feature of diabetes also occurs in non-diabetics associated with chronic inflammation and systemic insulin resistance. Since the increased risk of active TB in diabetics has been linked to the severity and duration of hyperglycemia, we investigated what effect diet-induced hyperglycemia had on the severity of Mycobacterium tuberculosis (Mtb) infection in non-diabetic guinea pigs. Post-prandial hyperglycemia was induced in guinea pigs on normal chow by feeding a 40% sucrose solution daily or water as a carrier control. Sucrose feeding was initiated on the day of aerosol exposure to the H37Rv strain of Mtb and continued for 30 or 60 days of infection. Despite more severe hyperglycemia in sucrose-fed animals on day 30, there was no significant difference in lung bacterial or lesion burden until day 60. However the higher spleen and lymph node bacterial and lesion burden at day 30 indicated earlier and more severe extrapulmonary TB in sucrose-fed animals. In both sucrose- and water-fed animals, serum free fatty acids, important mediators of insulin resistance, were increased by day 30 and remained elevated until day 60 of infection. Hyperglycemia mediated by Mtb infection resulted in accumulation of advanced glycation end products (AGEs) in lung granulomas, which was exacerbated by sucrose feeding. However, tissue and serum AGEs were elevated in both sucrose and water-fed guinea pigs by day 60. These data indicate that Mtb infection alone induces insulin resistance and chronic hyperglycemia, which is exacerbated by sucrose feeding. Moreover, Mtb infection alone resulted in the accumulation tissue and serum AGEs, which are also central to the pathogenesis of diabetes and diabetic complications. The exacerbation of insulin resistance and hyperglycemia by Mtb infection alone may explain why TB is more severe in diabetics with poorly controlled hyperglycemia compared to non-diabetics and patients with properly controlled blood glucose levels.

Project description:PurposeThe objective of this study was to explore the ocular and systemic outcomes of herpes simplex virus type 1 (HSV-1) infection in guinea pigs, to monitor the spontaneous reactivation of the virus, and to assess the effectiveness of various treatments, drawing comparisons to conventional rabbit models.MethodsGuinea pigs and rabbits were infected in the right corneas with differing doses and strains of HSV-1. Observations were made over a 71-day period, focusing on comparing ocular lesions, viral shedding patterns, and weight loss between the two animal models. Postinfection, the effectiveness of trifluridine ophthalmic drops, oral acyclovir, and valacyclovir was evaluated. The confirmation of viral infection was done through virus titer assay, fluorescein staining, and corneal imaging.ResultsGuinea pigs and rabbits manifested symptoms akin to human herpes stromal keratitis (HSK) when exposed to varying titers of viral suspension. Regardless of the initial viral load, all guinea pig groups demonstrated comparable ocular pathology, witnessing conditions like blepharitis and conjunctivitis within 3 days, progressing to severe conditions, including total corneal opacification and necrotizing keratitis. Tear film collection revealed nonsignificant differences in viral plaques between all groups. Notably, guinea pigs in the low-infection group experienced the most weight loss, although without significant differences. The replication of the same experiment on rabbits yielded consistent results in disease pathology across different groups, with occurrences of blepharitis and conjunctivitis. Interestingly, after initial resolution, guinea pigs presented a more frequent and broadly observed increase in disease score and corneal opacity, a phenomenon rarely seen in rabbits within the same timeframe. The effectiveness of 1% trifluridine was observed in mitigating ocular HSV-1 disease in both species, whereas oral acyclovir and valacyclovir were found to be detrimental and ineffective in guinea pigs but not in rabbits.ConclusionsThis study demonstrates the potential suitability of guinea pigs as new models for ocular HSV-1 investigations, filling a critical preclinical void of models capable of showcasing spontaneous HSV reactivation in the eye. The observed similarities and differences in the reactions of guinea pigs and rabbits to HSV-1 infection and treatments provide crucial insights, laying the foundation for future studies on ocular HSV pathogenesis, latency, and improved treatment options.

Project description:The development of granulomatous inflammation with caseous necrosis is an important but poorly understood manifestation of tuberculosis in humans and some animal models. In this study we measured the byproducts of oxidative stress in granulomatous lesions as well as the systemic antioxidant capacity of BCG vaccinated and non-vaccinated guinea pigs experimentally infected with Mycobacterium tuberculosis. In non-vaccinated guinea pigs, oxidative stress was evident within 2 weeks of infection as measured by a decrease in the serum total antioxidant capacity and blood glutathione levels accompanied by an increase in malondialdehyde, a byproduct of lipid peroxidation, within lesions. Despite a decrease in total and reduced blood glutathione concentrations, there was an increase in lesion glutathione by immunohistochemistry in response to localized oxidative stress. In addition there was an increase in the expression of the host transcription factor nuclear erythroid 2 p45-related factor 2 (Nrf2), which regulates several protein and non-proteins antioxidants, including glutathione. Despite the increase in cytoplasmic expression of Nrf2, immunohistochemical staining revealed a defect in Nrf2 nuclear translocation within granulomatous lesions as well as a decrease in the expression of the Nrf2-regulated antioxidant protein NQO1. Treating M. tuberculosis-infected guinea pigs with the antioxidant drug N-acetyl cysteine (NAC) partially restored blood glutathione concentrations and the serum total antioxidant capacity. Treatment with NAC also decreased spleen bacterial counts, as well as decreased the lung and spleen lesion burden and the severity of lesion necrosis. These data suggest that the progressive oxidative stress during experimental tuberculosis in guinea pigs is due in part to a defect in host antioxidant defenses, which, we show here, can be partially restored with antioxidant treatment. These data suggest that the therapeutic strategies that reduce oxidant-mediated tissue damage may be beneficial as an adjunct therapy in the treatment and prevention of tuberculosis in humans.

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Experimental ocular tuberculosis in guinea pigs.

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Experimental ocular tuberculosis in guinea pigs.

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