Abstract
In vitro phagocytosis of Mycobacterium tuberculosis (Mtb) aggregates (Mtb-AG), rather than similar numbers of single bacilli (Mtb-SC), induces host macrophage death and favors bacterial growth. Here, we examined whether aggregation contributes to enhanced Mtb pathogenicity in vivo in rabbit lungs. Rabbits were exposed to infectious aerosols containing mainly Mtb-AG or Mtb-SC. The lung bacterial load, systemic immune response, histology, and immune cell composition were investigated over time. Genome-wide transcriptome analysis, cellular and tissue-level assays, and immunofluorescent imaging were performed on lung tissue to define and compare immune activation and pathogenesis between Mtb-AG and Mtb-SC infection. Lung bacillary loads, disease scores, lesion size, and structure were significantly higher in Mtb-AG than Mtb-SC infected animals. Differences in immune cell distribution and activation were noted in the lungs of the two groups of infected animals. Consistently larger lung granulomas with large aggregates of Mtb, extensive necrotic foci, and elevated matrix metalloproteases expression were observed in Mtb-AG infected rabbits. Our findings suggest that bacillary aggregation increases Mtb fitness for improved growth and accelerates lung inflammation and infected host cell death, thereby exacerbating disease pathology in the lungs.
Highlights
In vitro phagocytosis of Mycobacterium tuberculosis (Mtb) aggregates (Mtb-AG), rather than similar numbers of single bacilli (Mtb-SC), induces host macrophage death and favors bacterial growth
We recently reported that exposure of human monocyte-derived macrophages to Mtb-AG, compared with a similar number of single bacilli, interferes with the control of intracellular bacillary growth and results in efficient replication of the bacilli, in association with the death of the phagocyte[10]
We investigated the expression pattern of early infected rabbit lungs showing multiple, small, solid lesions. b Gross pathology of Mtb-AG infected rabbit lungs showing multiple, large, coalescent lesions. c Representative H&E-stained lung section of Mtb-SC infected rabbits showing a large granuloma with immune cell accumulation and small inflammatory foci surrounded by neutrophils, macrophages (m), and lymphocyte cuff. d Representative H&E-stained lung section of Mtb-AG-infected rabbits showing a granuloma with large necrotic foci surrounded by abundant neutrophils and foamy macrophages. e, f Immunofluorescence imaging of Mtb in Mtb-SC (e) and Mtb-AG (f) infected rabbit lung sections
Summary
In vitro phagocytosis of Mycobacterium tuberculosis (Mtb) aggregates (Mtb-AG), rather than similar numbers of single bacilli (Mtb-SC), induces host macrophage death and favors bacterial growth. It is important to note that Mtb-AG are often seen at the cavitary surface of pulmonary lesions and in the infectious aerosols exhaled by patients with active pulmonary TB9,11,12. Based on these observations, we hypothesize that host exposure to Mtb-AG, as opposed to single bacilli (Mtb-SC), may be an effective bacterial strategy for establishing an infection that is more likely to progress to active disease
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