Abstract
The latency and reactivation of Mycobacterium tuberculosis infection has been well studied. However, there have been few studies of the latency and reactivation of Mycobacterium avium complex (MAC), the most common etiological non-tuberculous Mycobacterium species next to M. tuberculosis in humans worldwide. We hypothesized that latent MAC infections can be reactivated following immunosuppression after combination chemotherapy with clarithromycin and rifampicin under experimental conditions. To this end, we employed a modified Cornell-like murine model of tuberculosis and investigated six strains consisting of two type strains and four clinical isolates of M. avium and M. intracellulare. After aerosol infection of each MAC strain, five to six mice per group were euthanized at 2, 4, 10, 18, 28 and 35 weeks post-infection, and lungs were sampled to analyze bacterial burden and histopathology. One strain of each species maintained a culture-negative state for 10 weeks after completion of 6 weeks of chemotherapy, but was reactivated after 5 weeks of immunosuppression in the lungs with dexamethasone (three out of six mice in M. avium infection) or sulfasalazine (four out of six mice in both M. avium and M. intracellulare infection). The four remaining MAC strains exhibited decreased bacterial loads in response to chemotherapy; however, they remained at detectable levels and underwent regrowth after immunosuppression. In addition, the exacerbated lung pathology demonstrated a correlation with bacterial burden after reactivation. In conclusion, our results suggest the possibility of MAC reactivation in an experimental mouse model, and experimentally demonstrate that a compromised immune status can induce reactivation and/or regrowth of MAC infection.
Highlights
Nontuberculous mycobacteria (NTM) are widely spread in environment which may cause pulmonary disease, skin and soft tissue infections, lymphadenitis, and disseminated disease among which, chronic pulmonary disease is the most commonly found in clinical condition [1, 2]
Bacteriological evaluation of Mycobacterium avium complex reactivation Bacterial counts of two clinical strains, M. avium (MAV) SM#1 and M. intracellulare (MI) SM#42, decreased to an undetectable level after 18 weeks, which was after six weeks of antibiotics treatment (Fig 2A and 2B)
The reactivated bacterial count in MI SM#42 infected mice increased at a faster rate and was higher compared with the bacterial count before chemotherapy
Summary
Nontuberculous mycobacteria (NTM) are widely spread in environment which may cause pulmonary disease, skin and soft tissue infections, lymphadenitis, and disseminated disease among which, chronic pulmonary disease is the most commonly found in clinical condition [1, 2]. It is believed that several unknown susceptibility factors might affect the healthy individuals to develop the NTM lung disease [6]. Analogous to tuberculosis (TB) within several ways, the natural pathogenesis of NTM infection is unknown. Likewise, it is still on debate whether NTM lung disease develops soon after infection or, like TB, develops after a period of latency. NTM may cause both symptomatic disease and asymptomatic infection, and previous skin test studies suggested that a substantial proportion have had prior and presumably asymptomatic NTM infection [7, 8]
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