Non-specific protection from respiratory tract infections in cattle generated by intranasal administration of an innate immune stimulant

Abstract

Alternatives to antibiotics for prevention of respiratory tract infections in cattle are urgently needed given the increasing public and regulatory pressure to reduce overall antibiotic usage. Activation of local innate immune defenses in the upper respiratory tract is one strategy to induce non-specific protection against infection with the diverse array of viral and bacterial pathogens associated with bovine respiratory disease complex (BRDC), while avoiding the use of antibiotics. Our prior studies in rodent models demonstrated that intranasal administration of liposome-TLR complexes (LTC) as a non-specific immune stimulant generated high levels of protection against lethal bacterial and viral pathogens. Therefore, we conducted studies to assess LTC induction of local immune responses and protective immunity to BRDC in cattle. In vitro, LTC were shown to activate peripheral blood mononuclear cells in cattle, which was associated with secretion of INFγ and IL-6. Macrophage activation with LTC triggered intracellular killing of Mannheimia hemolytica and several other bacterial pathogens. In studies in cattle, intranasal administration of LTC demonstrated dose-dependent activation of local innate immune responses in the nasopharynx, including recruitment of monocytes and prolonged upregulation (at least 2 weeks) of innate immune cytokine gene expression by nasopharyngeal mucosal cells. In a BRDC challenge study, intranasal administration of LTC prior to pathogen exposure resulted in significant reduction in both clinical signs of infection and disease-associated euthanasia rates. These findings indicate that intranasal administration of a non-specific innate immune stimulant can be an effective method of rapidly generating generalized protection from mixed viral and bacterial respiratory tract infections in cattle.

The innate immune stimulant Amplimune® is safe to administer to young feedlot cattle

“…Other studies have also investigated the ability of different types of innate immune stimulants to enhance immune system function in cattle. Liposome‐toll‐like receptor complexes delivered intranasally to beef calves induced significant increases in the percentage of CD14+ monocytes in nasal mucosal samples and upregulated expression of interferon‐gamma, interleukin‐8 and monocyte chemoattractant protein‐1 gene transcripts in nasopharyngeal samples 16 . Fermentation products from the yeast Saccharomyces cerevisiae (SCFP) have been fed to dairy calves, reducing the incidence of diarrhoea 23 .…”

“…Research is being done to improve the overall disease resistance of livestock by selecting animals with enhanced immune competence or general immune system performance 2,14 ; the efficacy of current vaccines is being improved through the use of new adjuvants like glycoprotein subunits 15 ; and livestock producers are adapting the way animals are handled in order to reduce pathogen exposure 5 . In addition, many different innate immune stimulants are being investigated for their ability to enhance immune system health, and growth and production 16,17 . The action of these immune stimulants has been linked with the concept of trained immunity.…”

“… 5 In addition, many different innate immune stimulants are being investigated for their ability to enhance immune system health, and growth and production. 16 , 17 The action of these immune stimulants has been linked with the concept of trained immunity. Trained immunity describes a recently discovered ability of innate immune cells to be ‘trained’ through repeated exposure to the same pathogen.…”

Early Activation of the Innate Immunity and Specific Cellular Immune Pathways after Vaccination with a Live Intranasal Viral Vaccine and Challenge with Bovine Parainfluenza Type 3 Virus

“…The protection seen can occur due to several mechanisms. Firstly, by induction of the non-specific, innate immune response, described by Wheat et al [20] using intranasal administration of liposome-TLR complexes. This mechanism is also known as trained innate immunity, which has memory-like traits and could be boosted by challenge with BPIV3.…”

FeedingSaccharomyces cerevisiaefermentation products lessens the severity of a viral–bacterial coinfection in preweaned calves

“…Twenty-seven, 1- to 2-d-old Holstein × Angus calves (12 males and 15 females) were enrolled in the trial. A statistical power analysis was performed for sample size estimation based upon published results (including our own; Castrucci et al, 1996 , 1998 ; Nickell et al, 2016 ; Guerra-Maupome et al, 2019 ; Mahmoud et al, 2020 ; Wheat et al, 2020 ; Díaz et al, 2021 ) for in vivo innate immunostimulant activity in cattle. Given a medium effect size (following Cohen’s criteria, Cohen, 1988 ), an α = 0.05, and power = 0.7, the projected samples size to measure a significant effect of SCFP supplementation on gross lung pathology scores (in challenge studies, Mann–Whitney test) was n = 12, calculated using the G*Power 3.1 software.…”