Host-directed therapy in foals can enhance functional innate immunity and reduce severity of Rhodococcus equi pneumonia

Steve Giguère,Angela I. Bordin,Jocelyne M. Bray,Noah D. Cohen,Brenton Scott,Londa J. Berghaus,Magnus Hook,Rena Johnson

doi:10.1038/s41598-021-82049-y

Steve Giguère, Angela I. Bordin + Show 6 more

Open Access

https://doi.org/10.1038/s41598-021-82049-y

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Abstract

Pneumonia caused by the intracellular bacterium Rhodococcus equi is an important cause of disease and death in immunocompromised hosts, especially foals. Antibiotics are the standard of care for treating R. equi pneumonia in foals, and adjunctive therapies are needed. We tested whether nebulization with TLR agonists (PUL-042) in foals would improve innate immunity and reduce the severity and duration of pneumonia following R. equi infection. Neonatal foals (n = 48) were nebulized with either PUL-042 or vehicle, and their lung cells infected ex vivo. PUL-042 increased inflammatory cytokines in BAL fluid and alveolar macrophages after ex vivo infection with R. equi. Then, the in vivo effects of PUL-042 on clinical signs of pneumonia were examined in 22 additional foals after intrabronchial challenge with R. equi. Foals infected and nebulized with PUL-042 or vehicle alone had a shorter duration of clinical signs of pneumonia and smaller pulmonary lesions when compared to non-nebulized foals. Our results demonstrate that host-directed therapy can enhance neonatal immune responses against respiratory pathogens and reduce the duration and severity of R. equi pneumonia.

Highlights

Pneumonia caused by the intracellular bacterium Rhodococcus equi is an important cause of disease and death in immunocompromised hosts, especially foals
We demonstrate that: (1) a combination of TLR2/6 and TLR9 agonists (PUL-042) administered via nebulization at various doses and on multiple occasions is safe for neonatal foals; (2) aerosol treatment of neonatal foals with PUL-042 increased interleukin (IL)-6 and IFN-γ concentration in the supernatant of alveolar macrophages (AMs) upon ex vivo infection; (3) nebulization of PUL-042 in foals challenged intrabronchially with live virulent R. equi reduced the duration of fever, clinical pneumonia, and cough, as well as reduced the size of pulmonary lesions compared to foals that were not nebulized
Because the balance of pro- and anti-inflammatory cytokines is more important than their individual concentrations, we examined the ratio of stimulated IFN-γ expression and IL-10 expression, and found that it was associated with killing of R. equi (Fig. 5C; R value − 0.4740)

Summary

Introduction

Pneumonia caused by the intracellular bacterium Rhodococcus equi is an important cause of disease and death in immunocompromised hosts, especially foals. The objective of our research was to test whether nebulization with PUL-042 in foals would improve innate immune responses and reduce the severity and duration of pneumonia due to intrabronchial challenge with R. equi of foals at 28 days of age. We demonstrate that: (1) a combination of TLR2/6 and TLR9 agonists (PUL-042) administered via nebulization at various doses and on multiple occasions is safe for neonatal foals; (2) aerosol treatment of neonatal foals with PUL-042 increased interleukin (IL)-6 and IFN-γ concentration in the supernatant of alveolar macrophages (AMs) upon ex vivo infection; (3) nebulization of PUL-042 in foals challenged intrabronchially with live virulent R. equi reduced the duration of fever, clinical pneumonia, and cough, as well as reduced the size of pulmonary lesions compared to foals that were not nebulized. Our results indicate that nebulization with PUL-042 enhanced functional responses by AMs and reduced the severity of clinical pneumonia compared to non-nebulized foals

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