Induction of innate cytokine responses by respiratory mucosal challenge with R848 in zebrafish, mice, and humans

Fränze Progatzky,Akhilesh Jha,Madina Wane,Ryan S Thwaites,Spyridon Makris,Robin J Shattock,Cecilia Johansson,Peter J Openshaw,Laurence Bugeon,Trevor T Hansel,Margaret J Dallman

doi:10.1016/j.jaci.2019.04.003

Fränze Progatzky, Akhilesh Jha + Show 9 more

Open Access

https://doi.org/10.1016/j.jaci.2019.04.003

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Abstract

Development of new therapies and vaccines to combat viral respiratory tract infections is slow, partly because of the limited understanding of innate immune responses at the respiratory mucosal site of disease. Detailed characterization of such responses might facilitate biomarker definition for respiratory diseases and provide novel mechanistic insights and a platform for the testing of novel therapeutics. Recently, noninvasive serial nasosorption of mucosal lining fluid has been used to study immune responses to experimental live human rhinovirus.

Highlights

We developed parallel live zebrafish, mouse, and human challenge models to study the effects of viral RNA mimic TLR agonists with relevance to respiratory viral infection
The mouse nasal cavity is inaccessible for repetitive sampling, and we developed a mucosal tissue sampling technique ex vivo by applying an absorption approach similar to that used for human subjects
An early response was observed for TNF-a, whereas IFN-g levels increased later. These results suggest that R848 can be administered to human subjects as a noninfectious virus-type challenge of the innate immune system, whereas complementary studies in mice and zebrafish could allow mechanistic insight

Summary

LETTERS TO THE EDITOR

We have used zebrafish gills to assess respiratory inflammation, and our results suggest zebrafish are a relevant model to study mechanisms of respiratory mucosal innate immune responses.[8] we developed parallel live zebrafish, mouse, and human challenge models to study the effects of viral RNA mimic TLR agonists with relevance to respiratory viral infection. These comparative studies allow assessment of cytokine responses at comparable and accessible sites of the respiratory mucosa (Fig 1, A-C). Development of a human nasal mucosal model is of special interest because the nose is the portal for viral respiratory tract infections that cause widespread winter morbidity and mortality, and there are advantages in studying a complex multicellular mucosal system directly in human subjects

Nasosorption of mucosal fluid

Human studies

Mouse studies

Zebrafish studies