GM-CSF knockout mice for preclinical testing of agents with antimicrobial activity against Mycobacterium abscessus.
OBJECTIVE
Of the non-tuberculous mycobacteria, Mycobacterium abscessus is particularly refractory to antimicrobial therapy and new agents with activity against these pathogens are urgently needed. The screening of candidate antimicrobial agents against M. abscessus requires a relevant and reproducible animal model of chronic infection. Granulocyte-macrophage colony-stimulating factor knockout (GM-CSF KO) mice were used to develop a new animal model of chronic pulmonary M. abscessus infection that can be used for preclinical efficacy testing of antimicrobial drugs.


METHODS
GM-CSF KO mice were infected with a clinical isolate of M. abscessus via intrapulmonary aerosol delivery using a microsprayer device. The clinical condition, histology and cfu of M. abscessus-infected GM-CSF KO mice were evaluated over a period of 4 months. Mice were treated with azithromycin (100 mg/kg) by oral gavage and the clinical condition, histology and bacterial burden was determined after 2 weeks of treatment.


RESULTS
We show that pulmonary infection of GM-CSF KO mice with M. abscessus results in a chronic pulmonary infection that lends itself to preclinical testing of new antimicrobial drugs against this bacterium. Azithromycin treatment of M. abscessus-infected GM-CSF KO mice resulted in a lower bacterial burden in the lungs and spleen, weight gain and significant improvement in lung pathology.


CONCLUSIONS
Intrapulmonary aerosol infection of GM-CSF KO mice with M. abscessus is a useful animal model for studying pathogenesis as well as pre-clinical testing of new compounds against M. abscessus in acute or chronic phases of infection.
Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA.
Mary Ann
MA
De Groote
Laura
L
Johnson
Brendan
B
Podell
Elizabeth
E
Brooks
Randall
R
Basaraba
Mercedes
M
Gonzalez-Juarrero
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D017963:Azithromycin / Q000627:therapeutic use*; D058491:Bacterial Load; D002908:Chronic Disease; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency*; D006651:Histocytochemistry; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009161:Mycobacterium / Q000187:drug effects*; D009164:Mycobacterium Infections / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D013154:Spleen / Q000382:microbiology
D000900:Anti-Bacterial Agents; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017963:Azithromycin
M. abscessus; drug treatment; macrolides; mouse model