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

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.

Rhodococcus equifoal pneumonia: Update on epidemiology, immunity, treatment and prevention

“…86 Additionally, there is evidence that intracellular killing after in vitro infection with R. equi was negatively associated with the ratio of IFNγ/IL-10. 87 These results suggest that balance between pro-inflammatory (i.e. IFNγ) and anti-inflammatory cytokines (i.e.…”

“…In vitro treatment (priming) of monocyte‐derived macrophages (MDMs) from adult horses with IFN‐γ (or other cytokines such as TNF‐α and IL‐6) before in vitro infection with R. equi significantly decreased intracellular replication of R. equi when compared to unprimed MDMs 86 . Additionally, there is evidence that intracellular killing after in vitro infection with R. equi was negatively associated with the ratio of IFN‐γ/IL‐10 87 . These results suggest that balance between pro‐inflammatory (i.e.…”

Serum Antibody Activity against Poly- N -Acetyl Glucosamine (PNAG), but Not PNAG Vaccination Status, Is Associated with Protecting Newborn Foals against Intrabronchial Infection with Rhodococcus equi

“…Foals were infected with a virulent strain of R. equi originally isolated from a pneumonic foal from Texas (strain EIDL 5-331) that we have used previously to infect foals at age 28 days ( 19 , 41 , 42 ). This strain was streaked onto a brain heart infusion (BHI) agar plate (Bacto brain heart infusion; BD, Becton, Dickinson and Company, Sparks, MD, USA).…”

“…Approximately 200 μl of challenge dose was saved to confirm the concentration (dose) administered and to verify virulence of the isolate using multiplex PCR ( 43 ). This challenge dose was based on evidence that younger foals are more susceptible to infection ( 23 ), being 5-fold greater than that reported to cause pneumonia in 50% of foals infected at 4 to 7 days of age ( 23 ) and being 200-fold less than the dose we have used reliably to cause pneumonia in foals infected at approximately 28 days of age ( 19 , 41 , 42 ).…”

A Comprehensive Investigation Regarding the Differentiation of the Procurable COVID-19 Vaccines

“…PUL-042 is a solution containing Pam2CSK4 acetate (Pam2) and a synthetic diacylated lipopeptide (LP), which serves as a toll-like receptor (TLR) 2 agonist and TLR6 agonist and the oligodeoxynucleotide (ODN) M362 containing unmethylated CpG-based dinucleotides which is a TLR9 agonist possessing potential immunostimulating activity. Administration of PUL-042 via inhalation route has shown potential therapeutic activity against various major classes of pathogens like bacteria, fungus, and virus ( 88 – 90 ). It is currently in clinical trial, and phase 2 [Clinical Trial Identifier number NCT04312997] of it will be run by Pulmotect Inc. the manufacturer of PUL-042 ( 79 ).…”