Evaluation of host immune responses to Mycobacteriophage Fionnbharth by route of delivery.

Publication date: Jan 20, 2025

For much of the last decade, tuberculosis (TB) was the leading cause of mortality due to an infectious pathogen (Mycobacterium tuberculosis, M. tb). Approximately 1. 3 million deaths in 2023 worldwide were attributed to TB disease. Focused intervention strategies to block transmission would significantly reduce the global health burden of TB. Mycobacteriophages (phages) are a sorely underutilized biologic therapy for the pathogen M. tb, and here we aimed to address outstanding questions about their utility for clinical applications. We aimed to determine the impact of repeated mucosal or intravenous (IV) delivery of representative anti-M. tb phage FionnbharthΔ45Δ47 (Fionnbharth) in a preclinical mouse model. In addition, we specifically sought to understand which route induced anti-phage antibodies, which may reduce the long-term impact of phage therapy. C57BL/6 mice were dosed weekly for 6 weeks by either route and serum and bronchoalveolar lavage fluid (BALf) were evaluated for anti-phage humoral responses by ELISA. We found that aerosol delivery disperses phage across all lung lobes where M. tb is also found after experimental infection by the same route. Repeated aerosol delivery was well tolerated and did not induce robust neutralizing humoral immunity. In contrast, Mice receiving IV phage developed increasing magnitude and neutralizing total IgG and IgA responses over time. To determine whether pre-treatment environmental exposure to Fionnbharth-like phages could induce antibody responses that are potentially neutralizing, ~ 500 human plasma samples from normal donors were evaluated by ELISA. We observed that 5% of samples had antibodies to Fionnbharth (with end point titers > 10 dilution), although none were neutralizing. Furthermore, we found that highly-purified phage preparations did not activate mouse or human derived toll like receptor (TLR) 4 or TLR9 in HEKblue reporter assays. These data together support using Fionnbharth in anti-M. tb therapy phage cocktail strategies and that aerosol delivery should be prioritized for further efficacy testing.

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Concepts Keywords
3million Administration, Intravenous
Fionnbharth4547 Aerosol delivery
Host Animals
Mycobacteriophages Antibodies, Viral
Tuberculosis Antibodies, Viral
Bronchoalveolar Lavage Fluid
Disease Models, Animal
Female
Humans
Humoral immunity
Lung
Mice
Mycobacteriophage
Mycobacteriophages
Mycobacterium tuberculosis
Phage Therapy
Tuberculosis
Tuberculosis

Semantics

Type Source Name
disease IDO host
disease MESH tuberculosis
pathway KEGG Tuberculosis
disease IDO pathogen
disease IDO intervention
disease MESH infection
pathway REACTOME Reproduction
disease MESH COVID 19 pandemic
drug DRUGBANK Coenzyme M
drug DRUGBANK BCG vaccine
disease MESH infection transmission
disease IDO infection incidence
disease MESH emergency
disease IDO colony
drug DRUGBANK Flunarizine
drug DRUGBANK Tromethamine
drug DRUGBANK Magnesium sulfate
drug DRUGBANK Albendazole
disease IDO facility
disease IDO bacteria
drug DRUGBANK Tretamine
disease IDO assay
drug DRUGBANK Iron
drug DRUGBANK Aspartame
drug DRUGBANK Glutamic Acid
disease IDO blood
drug DRUGBANK Dextrose unspecified form
drug DRUGBANK Streptomycin
disease MESH histocompatibility
drug DRUGBANK Amino acids
drug DRUGBANK Water
drug DRUGBANK Indoleacetic acid
disease IDO protein
disease MESH colitis
drug DRUGBANK Guanosine
pathway REACTOME Immune System
disease IDO immune response
drug DRUGBANK Trestolone
disease MESH inflammation
disease IDO reagent
disease MESH Allergy
disease MESH Infectious Diseases
disease MESH Mycobacterium Infections
disease IDO susceptibility
disease MESH Mycobacterium abscessus infection
pathway REACTOME Innate Immune System
disease IDO cell
disease MESH Lung Disease
disease MESH Disease Models Animal

Original Article

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