Positron emission tomography-based comparison of methods for exposing macaques to respiratory pathogens

Abstract

Non-human primates (NHPs) are relevant models for studies of human respiratory infections due to their similar anatomy and susceptibility to human pathogens, resulting in comparable disease manifestations following exposure via aerosols or liquid instillation. An understanding of pathogen deposition in the respiratory tract (RT) of NHPs according to the method of exposure is essential for infectious disease modeling. Here, we evaluated and compared three conventional exposure systems commonly used to replicate human RT infections: liquid endotracheal instillation (IT), facemask (FM) aerosol inhalation, and head-only exposure (HOE) aerosol inhalation. Using PET/CT imaging with [¹⁸F] fluorodeoxyglucose ([¹⁸F]FDG) as the radiotracer, we quantified deposition across the upper respiratory tract (URT), lower respiratory tract (LRT), and digestive tract in anesthetized, spontaneously breathing cynomolgus macaques. A 98.0 ± 1.4 % deposited dose in the LRT was obtained with IT, whereas FM gave only 28.2 ± 6.4 % (MMAD: 3.1 μm GSD 2.2) and HOE gave 40.4 ± 19.0 % (MMAD: 1.9 μm GSD 2.0). This variability of deposition rates highlights the need for precise metrology tools. The homogeneity of lung deposition was improved and ratio between peripheral deposition/central deposition (P/C ratio) were higher with FM, and particularly with the HOE device, than with IT. An in vivo study of macaques inhaling Bacillus atrophaeus spore suspensions tracked with [¹⁸F]FDG revealed a correlation between radioactivity and spore concentration in respiratory samples (nasal/tracheal swabs, bronchoalveolar lavage) after inhalation. In conclusion, pathogen exposure systems significantly affect dose deposition and distribution within NHP airways which may thus impact vaccines and therapeutics efficacy trial in challenge models. PET/CT imaging provides a robust tool for monitoring and controlling exposure to respiratory pathogens, decreasing the number of animals required for studies through precise dose control and tissue targeting. Exposure systems should be tailored to inhalation scenarios such as close contact or accumulated aerosol exposure, to reproduce improve relevance of preclinical models.