A mouse model of pulmonary Mycobacteroides abscessus infection

Abstract

there is no preclinical mouse model to investigate pulmonary Mycobacteroides abscessus (formerly Mycobacterium abscessus) infection in an immunocompetent mouse strain, especially in the context of antibiotic testing and regimen development. We developed a mouse model of pulmonary M. abscessus infection using the aerosolized route of infection that leads to an increase in bacterial burden postimplantation and develops pathology as a result. in this mouse model, treatment with corticosteroid allows for initial proliferation and sustained M. abscessus pulmonary infection and permits evaluation of efficacies of antibiotics. Administration of corticosteroids that permitted higher levels of bacterial burden in the lungs were more likely to have pathology. treatment of mice with antibiotics administered intranasally or subcutaneously significantly reduced lung M. abscessus burden. in addition to the reference strain, independent clinical isolates of M. abscessus also readily establish infection and proliferate in the lungs of mice in this model. In the setting of structural lung conditions such as cystic fibrosis, bronchiectasis, and COPD, Mycobacteroides abscessus (formerly Mycobacterium abscessus) can cause chronic pulmonary infection 1,2 that is often incurable and associated with rapid lung function decline 3-5. There is a current interest in developing new drugs and regimens to treat M. abscessus infection, as the cure rate with existing antibiotics is only 30-50% 6. While there have been many exciting demonstrations of in vitro potencies of antibiotics against M. abscessus 7-13 , it has also been established that potency observed in vitro for M. abscessus often does not translate to an equivalent clinical efficacy in the case of pulmonary infections 3. This highlights the need for a preclinical animal model to evaluate experimental antibiotics. A mammalian model that recapitulates aerosol infection leading to progressive M. abscessus burden and development of lung pathology as observed in human disease would facilitate preclinical studies of antibiotic efficacy and M. abscessus genetic determinants for virulence. In investigations of Mycobacterium tuberculosis (M. tuberculosis), several studies have demonstrated that aerosol infected C3HeB/FeJ mice closely mimic human pulmonary pathology 14-17. However, when infected with M. abscessus, these mice are able to clear the infection 18. Other immunocompetent mouse strains also clear the infection over time, although certain genetically manipulated immunocompromised strains were able to maintain bacterial burden 19-22. This is a compromise in favor of perpetuating the infection, but at a loss of immune cells and inflammatory markers normally observed in response to infection. Therefore, as mice are unable to mount an immune response, this precludes evaluation of critical aspects of host-pathogen interactions and pathology development that may impact efficacy of antibiotic treatments. We hypothesized that transient pharmacologically-induced immune suppression of immunoco...

Ex vivo infection of murine precision-cut lung tissue slices with Mycobacterium abscessus: a model to study antimycobacterial agents

“…Foamy macrophages are a distinctive characteristic of granulomas associated with virulent mycobacteria; these cells have been observed in different inflammatory conditions, including infectious and noninfectious diseases, such as natural and experimental TB in particular [ 58 ]. The formation of foamy macrophages has been described in models of infection with M. abscessus both, in vitro [ 59 , 60 ], and in vivo [ 61 , 62 ]. It has been suggested that the induction of foamy macrophages results in an intracellular microenvironment that allows the persistence of mycobacteria, and that the fatty acids that accumulated in their cytoplasmic vacuoles represent a source of nutrients for the bacilli [ 63 ].…”

A new model of chronicMycobacterium abscessuslung infection in immunocompetent mice

“…GM-CSF -/, GKO or SCID mice) [11][12][13]. Moreover, corticosteroids were recently administered to immunocompetent mice to increase their susceptibility to the aereosolized pulmonary MA infection [25]. In our murine model, despite an initial protective high release of TNF-α and IFN-γ, granulomatous lung lesions (characterized by histiocytes, aggregates of foamy cells, neutrophils and lymphocytes) were present in the parenchyma around bronchi for about two months after MA infection, mimicking the damage observed in humans [23].…”

Differentialin vitroactivity of individual drugs and bedaquiline-rifabutin combinations against actively multiplying and nutrient-starvedMycobacterium abscessus

“…In TB drug and regimen development, mouse models have been pivotal for bridging the gap from in vitro to clinical studies (74). Ongoing efforts to develop and improve mouse models of M. abscessus lung infection have already shown promise (20, 21, 51, 75, 76), but nearly all are complicated by the lack of natural bacterial multiplication in the lungs. Thus, while this present series of in vitro studies indicates that a bedaquiline-rifabutin combination has promising activity against M. abscessus , further studies are needed to provide both the tools and the knowledge to translate the clinical relevance of these findings.…”