Effects of Dexamethasone and Transient Malnutrition on Rabbits Infected with AerosolizedMycobacterium tuberculosisCDC1551

Abstract

Malnutrition is common in the developing world, where tuberculosis is often endemic. Rabbits infected with aerosolized Mycobacterium tuberculosis that subsequently became inadvertently and transiently malnourished had compromised cell-mediated immunity comparable to that of the rabbits immunosuppressed with dexamethasone. They had significant leukopenia and reduced delayed-type hypersensitivity responses. Malnutrition dampened cell-mediated immunity and would interfere with diagnostic tests that rely on intact CD4 T-cell responses.Tuberculosis is a major global infectious disease accounting for more than 2 million deaths annually. The majority of cases occur in the developing world where calorie malnutrition is common. Cegielski and McMurray recently reviewed the effect of micronutrient and protein calorie malnutrition on the risk of developing active tuberculosis (2). Although the evidence in human populations is mostly indirect and observational, these data, when combined with results from animal models, suggest that malnutrition increases the risk of developing active tuberculosis (6,11,12,27,30).Animal models have shown that protein and calorie malnutrition can impair macrophage activation (28), alter T-cell function and cytokine production, and decrease the number of circulating lymphocytes (13, 21). In both mice and guinea pigs, malnutrition increases the organ burden of disease, resulting in poor outcomes (3,23), and compromises the ability of the BCG vaccine to protect animals against pulmonary infection with virulent Mycobacterium tuberculosis (1,5,25,26).Here, we report the effects of transient, inadvertent malnutrition in rabbits. Rabbits were housed according to established and approved protocols at the George Washington University Medical Center, Johns Hopkins University, and the United States Army Research Institute of Infectious Diseases. Rabbits were infected with aerosolized M. tuberculosis CDC1551 at the United States Army Research Institute of Infectious Diseases by previously published methods (22). Animals were then transported back to George Washington University Medical Center in HEPA-filtered containers and then housed under biosafety level 3 conditions. Four animals were necropsied on the first day after exposure to aerosolized M. tuberculosis. Lungs were homogenized in phosphate-buffered saline. CFU were enumerated by serial dilution on Middlebrook 7H10 agar, supplemented with oleic acid-dextrose-catalase (Becton Dickenson, Inc., Sparks, MD) and four antibiotics (trimethoprim, 20 g/ml; carbenicillin, 50 g/ml; cycloheximide, 50 g/ml; and polymyxin, 200 U/ml). The right upper lobe was homogenized and plated to enumerate the number of viable bacilli. The average number of bacilli in the right upper lobe of the lung Ϯ standard deviation was 406 Ϯ 102 CFU, and the number was 3,741 Ϯ 921 CFU when extrapolated to the total lung. Impinger samples were taken at the time of infection with aerosolized M. tuberculosis and plated. Impinger concentrations of the organism, combined with each rabbit's ...

Penitentiary or penthouse condo: the tuberculous granuloma from the microbe's point of view

“…Following M. tuberculosis infection, rabbits display a 4‐ to 6‐week period of bacillary replication followed by a bactericidal phase with containment, but incomplete sterilization of viable bacilli. In order to evaluate reactivation of tuberculosis disease, dexamethasone‐induced immunosuppression of infected rabbits has been shown to produce worsening of disease akin to reactivation (Kesavan et al. , 2005; Manabe et al.…”

The aerosol rabbit model of TB latency, reactivation and immune reconstitution inflammatory syndrome

“…Impinger concentrations of organism during aerosol infection and each rabbit's minute ventilation measured with plethysmography were used to calculate the number of bacilli inhaled, as previously described 9 . Twelve rabbits (higher-dose experiment) and 21 rabbits (lower-dose experiment) were treated with intramuscular dexamethasone from week 10 to week 15 as previously published 10 . Four weeks after aerosol infection, all animals were skin tested with Old Tuberculin (Wyeth Lederle, Pearl River, NY).…”

“…Rabbits are the most resistant animal model to Mtb infection and occupy an important niche, because humans are also relatively resistant; the majority of exposed infected individuals contain infection with only a minority of infected people who progress to active tuberculosis infection (~10%). We have previously shown the rabbit's ability to differentiate Mtb on a virulence spectrum 9 as well as to model the effects of malnutrition on the course of tuberculosis 10 . We present, herein, the results of 2 long-term aerosol infections with Mtb H37RV with confirmation of initial replication of bacilli, clearance of visible granulomas over time with approximately one-third of rabbits with persistent caseous granulomas that are culture-positive.…”

Protective Effect of Onion Extract Against Experimental Immunesuppression in Wistar Rats: Biological and Molecular Study

“…Dexamethasone (DEXA) is one of the frequent GCs used as experimental immuno-suppressive drug. The therapeutic dose of dexamethasone is 1-2 mg/kg (Harcourt-Brown, 2002), but under experimental conditions doses up to 10 mg/kg were able to induce immune suppression (Kesavan et al, 2005).…”

“…Onion is a member of the genus Allium, belonging to the family Alliaceae (Kesavan et al, 2005). Onion contains about 25 active compounds with similar therapeutic properties (Augusti, 1996).…”