Location of <i>M. tuberculosis</i> bacilli in lungs from <i>M. tuberculosis</i> infected guinea pigs, throughout infection and after 6 weeks of INH or TMC207 drug treatment.

<p>(AR) auramine-rhodamine, hematoxylin QS and DAPI; (H&E) hematoxylin and eosin. (A, B) Low (A) and high (B) magnifications of an early primary granuloma in the lungs of <i>M. tuberculosis</i> infected guinea pigs 4 weeks post-aerosol infection. Primary granulomas are distinguished from secondary lesions by the presence of necrosis (N) (H&E staining, 100× and 1000× magnifications). (C) A secondary lesion in the lungs of an <i>M. tuberculosis</i> infected guinea pig 4 weeks post-aerosol infection. Secondary lesions are distinguished from primary granulomas by the lack of central necrosis in the former (H&E staining, 100× magnification). (D, E) Low (D) and high (E) magnifications of a primary granuloma from the lungs of an <i>M. tuberculosis</i> infected guinea pig 4 weeks after aerosol infection. The majority of AR+ bacilli are extracellular within the necrotic core (c) (AR, 100× and 200× magnifications). (F) High magnification of area demarcated in figure 5E (square). Extracellular AR+ bacilli in the necrotic core of primary granulomas exist as single cells or are situated in clusters (AR, 1000× magnification). (G, H) Confocal micrographs of a necrotic granuloma showing an acellular necrotic core (c) with extracellular AR+ bacilli (red) (AR and DAPI, 200× and 630× magnifications). (I) A primary granuloma from the lungs of an <i>M. tuberculosis</i> infected guinea pig 10 weeks after aerosol infection showing advanced calcification and calcification of the necrotic core (c) and the acellular rim (R) surrounding the core (H&E staining, 100× magnification). (J) Fluorescent image of a primary lung granuloma from an <i>M. tuberculosis</i> infected guinea pig 10 weeks after aerosol infection. Extracellular AR+ bacilli are present within the necrotic core (c) and the acellular rim (R) surrounding the necrotic regions (AR, 200× magnification). (K) Cropped image from figure 5I (square) showing extracellular AR+ stained bacilli in the acellular rim. (L) Fluorescent image of a necrotic primary lung granuloma from an <i>M. tuberculosis</i> infected guinea pig treated for 6 weeks with INH. Extra-cellular AR+ bacilli are primarily within the core (c) of the partially calcified lytic necrosis, and to a lesser extent within the acellular, uncalcified rim (R) (AR, 200× and 400× magnifications). (M) A low magnification of the remnant of a primary lung granuloma in an <i>M. tuberculosis</i> infected guinea pig treated for 6 weeks with TMC207. The primary granuloma shows a caseous necrotic core (c) surrounded by inflammatory cells (H&E staining, 100× magnification). (N) Fluorescent image of the caseous necrotic core (c) in the primary lung granuloma shown in figure 5M taken from a serial tissue section. The few extra-cellular AR+ bacilli remaining after TMC207 treatment are primarily located within the central core of caseous necrosis (AR, 400× magnification).