Mouse model of necrotic tuberculosis granulomas develops hypoxic lesions

Autor: Eric L. Nuermberger, Sanjay K. Jain, Stephanie L. Davis, Mariah Weir, Rokeya Tasneen, William R. Bishai, Jamie Harper, Igor Kramnik, Ciaran Skerry, Martin G. Pomper
Rok vydání: 2011
Předmět:
Zdroj: The Journal of infectious diseases. 205(4)
ISSN: 1537-6613
Popis: With few exceptions, current preclinical evaluation of new tuberculosis drug candidates in animals is limited to mice. Mice are relatively inexpensive and permit investigation of disease mechanisms given the wide availability of reagents. However, the major disadvantage of conventional mouse strains is the lack of necrotic (caseous) granuloma formation in response to infection by Mycobacterium tuberculosis. Caseous granulomas are the hallmark of human tuberculosis and may provide a unique bacterial microenvironment. Furthermore, unlike caseous tuberculosis granulomas in guinea pigs, rabbits, and nonhuman primates, tuberculosis granulomas in the conventional mouse strains are not hypoxic [1]. If caseation or an associated host microenvironment, such as hypoxia, is a determinant of bacterial persistence in human tuberculosis, it may be essential to perform tuberculosis studies and evaluate tools targeting mycobacterial persisters in animals that undergo caseation and develop hypoxic tuberculosis lesions [2]. Pan et al have reported that C3HeB/FeJ mice display lung pathology with central caseous necrosis [3, 4]. In this study, we used noninvasive positron emission tomography (PET) imaging in live animals and postmortem pimonidazole immunohistochemistry [1, 5, 6] and demonstrated that necrotic pulmonary tuberculosis lesions in chronically infected C3HeB/FeJ mice are hypoxic. Using quantitative reverse-transcription polymerase chain reaction (RT-PCR), we also demonstrated significant up-regulation of hypoxia-associated genes in bacteria obtained from these necrotic lesions. Finally, we evaluated the efficacy of combination tuberculosis drug therapies in this novel mouse model, including one regimen containing PA-824, a new tuberculosis drug candidate reported to be active against nonreplicating bacteria under hypoxic conditions [7, 8, 9].
Databáze: OpenAIRE