Murine model of human-like pulmonary necrosis using a TB-resistant mouse strain
Elena Lasunskaia1, Fabricio M. Almeida1, Thatiana L. B. Ventura Simão1, Vinicius Mussi1, Philip Suffys2, Eduardo P. Amaral3.
1 Laboratory of Biology of Recognition, Universidade Estadual do Norte Fluminense, Campos, Rio de Janeiro, Brazil; 2 Laboratory of Molecular Biology Applied to Mycobacteria, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil; 3Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD.
Necrotic pulmonary pathology is a hallmark of tuberculosis (TB) caused by bacteria of the M. tuberculosis complex (Mtb). Additionally, some of the pathogenic non-tuberculous bacteria, such as M. kansasii, can cause lung disease similar to TB. Animal models reproducing human TB pathology are urgently needed for studies of the disease pathogenesis and new therapeutic approaches aimed on lung necrosis reduction. C57BL/6 inbred mice do not develop necrotic pulmonary lesions when infected with standard laboratory virulent Mtb strain H37Rv at a low dose of aerosol infection. These mice are able to develop TH1 polarized immunity in response to Mtb determining relative resistance to TB. In previous studies, we demonstrated that following intratracheal infection at low dose (100 CFU/mouse) of hypervirulent Mtb or M. bovis bacilli, C57BL/6 mice reliably reproduced some types of human TB pathology, such as rapidly progressive TB pneumonia with invasive necrotizing alveolitis driven by enhanced neutrophil influx, leading to caseous necrosis of the lung tissue. These data confirm the Rich's formula proposed in the 1950s, determining important role of bacterial virulence, inoculum, bacillus number and host hypersensitivity in counterbalancing the natural and acquired resistance of the host in the TB pathology progression. In this study, we investigated whether the C57BL/6 model of pulmonary mycobacterial infection may reproduce the human TB-like pathology following infection with M. kansasii. Since M. kansasii is less virulent than Mtb, C57BL/6 were infected intratracheally at high dose (50.000 bacilli/mouse). Four clinical isolates from patients displaying lung disease and the reference ATCC strain 12478 were used in this study to evaluate lung pathology up to 150 days p.i. The results demonstrated that M. kansasii strains exhibiting rough morphotype were able to induce chronic slowly progressive pulmonary infection characterized by granulomatous inflammation, as well as formation of the well-circumscribed encapsulated caseous granulomas in the later stages of infection (120-150 d pi), similar to those found in the lungs of M. kansasii-infected patients. These data demonstrate that the resistant C57BL/6 mice intratracheally infected with highly virulent Mtb or M. kansasii strains may be used for studying lung necrosis as well as for the development of host-directed therapies.