ExperimentalMycobacterium tuberculosisInfection of Cynomolgus Macaques Closely Resembles the Various Manifestations of HumanM. tuberculosisInfection

Abstract

Nonhuman primates were used to develop an animal model that closely mimics human Mycobacterium tuberculosis infection. Cynomolgus macaques were infected with low doses of virulent M. tuberculosis via bronchoscopic instillation into the lung. All monkeys were successfully infected, based on tuberculin skin test conversion and peripheral immune responses to M. tuberculosis antigens. Progression of infection in the 17 monkeys studied was variable. Active-chronic infection, observed in 50 to 60% of monkeys, was characterized by clear signs of infection or disease on serial thoracic radiographs and in other tests and was typified by eventual progression to advanced disease. Approximately 40% of monkeys did not progress to disease in the 15 to 20 months of study, although they were clearly infected initially. These monkeys had clinical characteristics of latent tuberculosis in humans. Low-dose infection of cynomolgus macaques appears to represent the full spectrum of human M. tuberculosis infection and will be an excellent model for the study of pathogenesis and immunology of this infection. In addition, this model will provide an opportunity to study the latent M. tuberculosis infection observed in ϳ90% of all infected humans.

Metronidazole prevents reactivation of latentMycobacterium tuberculosisinfection in macaques

“…The animals were housed and maintained in accordance with standards established in the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals. Cynomolgus macaques were infected via bronchoscope with 25 cfu of M. tuberculosis Erdman strain (18,19,26). Using our published criteria, monkeys were determined to have active or latent TB by 6-8 mo after infection (18,19) and were randomized to treatment or nontreatment groups.…”

“…Cynomolgus macaques infected with a low inoculum (25 cfu) of M. tuberculosis (strain Erdman) develop primary TB and latent infection in approximately equal proportions (18,19). We developed quantitative outcome measures of disease at necropsy, including gross pathology scoring and determination of bacterial numbers (19), enhancing the use of this animal model for drug efficacy studies.…”

“…Active TB in the primate model presents, as in humans, as a spectrum of disease ranging from minimal to fulminant (18,19,23). For this study we used previously published criteria to determine that monkeys had active pulmonary TB before initiation of treatment, including change in appetite, weight loss, X-ray findings, cough, positive M. tuberculosis growth from bronchoalveolar lavage (BAL) or gastric aspirate, or elevated erythrocyte sedimentation rate (19).…”

“…We previously characterized the histopathologic spectrum of granulomas types seen in active and latently infected monkeys (18,19). Like humans, monkeys with active TB have caseous granulomas and nonnecrotizing granulomas (solid cellular granulomas composed of epithelioid macrophages with sparse lymphocytes), occasionally mineralized granulomas, as well as TB pneumonia (25).…”

“…We hypothesized that a drug that worked under hypoxic conditions, such as MTZ, would affect M. tuberculosis bacilli residing in hypoxic areas, both in active and latent TB, and could shorten therapy by eliminating a population that was refractory to standard drugs. To test this hypothesis, we used a well-characterized nonhuman primate model of active and latent TB that recapitulates the spectrum of disease and granuloma types seen in human TB (18,19).…”