Experimental Reactivation of Pulmonary Mycobacterium avium Complex Infection in a Modified Cornell-Like Murine Model

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.

Mycobacterium avium Infection in a C3HeB/FeJ Mouse Model

“…Finding demonstrate that C3HeB/FeJ mice infected with MAC (∼2,000 organisms per mouse) – as compared to an inoculum dose of 1 × 10 8 –1 × 10 9 organisms per mouse typically utilized with infection of mouse models (Torrelles et al, 2002; van Ingen et al, 2013; Andrejak et al, 2015; Cha et al, 2015)- resulted in a progressive infection, distinct temporal immune responses, and histopathologic changes resulting in small foci of necrosis in the lungs.…”

“…Previous work using immunocompetent mouse strains demonstrated rapid clearance with lower amounts of MAC (Gangadharam, 1995), making such models suboptimal for more chronic human lung infection. In a MAC aerosol model using high doses of bacteria (1 × 10 9 –1 × 10 11 CFU per mouse) in comparing BALB/c, C57BL/6, Nude and Beige mice, the Nude mice were identified as the most sensitive mouse strain to MAC while treatment efficacy was most noticeable in BALB/c mice (Torrelles et al, 2002; van Ingen et al, 2013; Andrejak et al, 2015; Cha et al, 2015). Beige mice are not uncommonly utilized as an in vivo mouse model for MAC infection and display many immune deficiencies similar to those occuring in AIDS patients such as a dominant Th2 response resulting in enhanced susceptibility to infection with NTM following either intravenous or aerosol infection (Caverly et al, 2015).…”

“…C3HeB/FeJ mice showed a delayed dissemination to the spleen, and liver, over the first 30 days of infection, followed by an increase of ∼4.0 log 10 CFU in the spleen and ∼3.0 log 10 CFU in the liver during the chronic phase of disease. An advantage of the C3HeB/FeJ model over the currently utilized MAC mouse models that use 1 × 10 8 –1 × 10 9 CFU (Torrelles et al, 2002; van Ingen et al, 2013; Andrejak et al, 2015; Cha et al, 2015) to infect mice is that much fewer bacteria were used to infect the mice, mimicking the relative paucibacillary load seen in non-HIV infected subjects infected with NTM (Farhi et al, 1986; Hibiya et al, 2013; Kobashi et al, 2013).…”

Effects of hip abduction and adduction accuracy on post-stroke gait

“…By minimizing the active torque demands of the hip oscillation task, we were able to identify deficits in movement accuracy that are not solely due to weakness, and relate these deficits to gait performance. Therefore, functional mobility may be improved by training methods focused on post-stroke movement accuracy, including step accuracy training currently under investigation [Heeren et al 2013; Hollands et al 2015]. In addition, interventions designed to enhance available sensory feedback could contribute to improvements in movement accuracy.…”

The complexities and challenges of preventing and treating nontuberculous mycobacterial diseases

“…Preclinical modeling of these different disease states may help isolate treatment options, including harnessing host immunity. NTM infection reactivation has been studied using a modified Cornell-like murine model (typically used to study reactivation of latent Mtb ) and has successfully been developed for experimental reactivation of pulmonary MAC infection (Table 1), [103]. In this model, C57BL/6 mice are infected by the aerosol route with MAC strains and are treated with CLR and rifampicin for 6 weeks, and then treatment is stopped.…”