Abstract
Understanding the distribution patterns of antibiotics at the site of infection is paramount to selecting adequate drug regimens and developing new antibiotics. Tuberculosis (TB) lung lesions are made of various immune cell types, some of which harbor persistent forms of the pathogen, Mycobacterium tuberculosis. By combining high resolution MALDI MSI with histology staining and quantitative image analysis in rabbits with active TB, we have mapped the distribution of a fluoroquinolone at high resolution, and identified the immune-pathological factors driving its heterogeneous penetration within TB lesions, in relation to where bacteria reside. We find that macrophage content, distance from lesion border and extent of necrosis drive the uneven fluoroquinolone penetration. Preferential uptake in macrophages and foamy macrophages, where persistent bacilli reside, compared to other immune cells present in TB granulomas, was recapitulated in vitro using primary human cells. A nonlinear modeling approach was developed to help predict the observed drug behavior in TB lesions. This work constitutes a methodological advance for the co-localization of drugs and infectious agents at high spatial resolution in diseased tissues, which can be applied to other diseases with complex immunopathology.
Highlights
In human tuberculosis (TB), necrotic granulomas and cavities are the most prominent and treatment recalcitrant lesion types (Canetti, 1955)
Using nonlinear mixed effect modeling with the full dataset, we found that accounting for histiocyte fraction reduced the between-regions of interest (ROI) MXF variability from 44.0% to 28.3%, which further decreased to 20.0% when relative distance of ROI to lesion edge was integrated in the model
MALDI mass spectrometry imaging (MSI) and traditional mass spectrometry analysis of human lesions revealed a correlation between diffusion into caseum and caseum cellularity (Prideaux et al, 2015a)
Summary
In human tuberculosis (TB), necrotic granulomas and cavities are the most prominent and treatment recalcitrant lesion types (Canetti, 1955). The major histopathological features of these lesions are a caseous or necrotic core surrounded by a cuff of immune cells including lymphocytes, epithelioid macrophages, foam cells or lipid-laden macrophages, and interspersed neutrophils and epithelial cells (Leong et al, 2011; Dannenberg, 2006). In these lesions, Mycobacterium tuberculosis (Mtb), the etiologic agent of TB, is found intracellularly in macrophages and foamy macrophages (Peyron et al, 2008), neutrophils (Dallenga and Schaible, 2016; Berry et al, 2010), epithelial cells (Scordo et al, 2016) and dendritic cells (Tailleux et al, 2003).
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