Vaccination inducing durable and robust antigen-specific Th1/Th17 immune responses contributes to prophylactic protection against Mycobacterium avium infection but is ineffective as an adjunct to antibiotic treatment in chronic disease

Abstract

Mycobacterium avium complex (MAC) causing pulmonary disease in humanshas emerged worldwide. Thus, effective strategies simultaneously aiming to prevent MAC infection and accelerate therapeutic efficacy are required. To this end, subunit vaccine-induced protection against a well-defined virulent Mycobacterium avium (Mav) isolate was assessed as a preventative and therapeutic modality in murine models. Mav-derived culture filtrate antigen (CFA) was used as a vaccine antigen with glucopyranosyl lipid A stable emulsion (GLA-SE) or GLA-SE plus cyclic-di-GMP (GLA-SE/CDG), and we compared the immunogenicities, protective efficacies and immune correlates. Interestingly, CFA+GLA-SE/CDG immunization induced greater CFA-specific Th1/Th17 responses in both the lung and spleen than among the tested groups. Consequently, protective efficacy was optimally achieved with CFA+GLA-SE/CDG by significantly reducing bacterial loads along with long-lasting maintenance of antigen-specific Th1/Th17 cytokine-producing multifunctional T cell responses and relevant cytokine productions. Thus, we employed this subunit vaccine as an adjunct to antibiotic treatment. However, this vaccine was ineffective in further reducing bacterial loads. Collectively, our study demonstrates that strong Mav CFA-specific Th1/Th17 responses are critical for preventative protection against Mav infection but may be ineffective or even detrimental in an established and progressive chronic disease, indicating that different approaches to combating Mav infection are necessary according to vaccination purposes.

Protein-energy restriction-induced lipid metabolism disruption causes stable-to-progressive disease shift in Mycobacterium avium-infected female mice

“… 31 , 65 , 66 Intriguingly, even though αCD36 treatment did not restore Th1/Th17 responses in LPD-fed mice, it effectively reduced the bacterial burden. This indicates that while Th1/Th17 responses are crucial for initial protection against M. avium infection, as suggested by the recent study, 36 their roles might be overshadowed by innate immunity mechanisms in the context of chronic nutrient-limited conditions.…”

“…In a recent study, our group successfully established chronic progressive pulmonary infection models in BALB/c and C57BL/6 mice using aerosolised M. avium SMC #7. 36 We extended this research to evaluate disease progression in three inbred mouse strains following infection with M. avium , including A/J mice, which are notably susceptible to Mtb infection. 37 , 38 Each mouse group received a high dose of aerosolised M. avium SMC #7.…”

Next Generation Mucosal Vaccine Strategy for Respiratory Pathogens

“…Multiple studies report the successful generation of robust immune responses by intranasal administration of TLR4 agonists [163][164][165]. Administration of a synthetic TLR4 agonist, Glucopyranosyl Lipid Adjuvant-stable emulsion (GLA-SE)induced Th1/Th17-biased systemic and mucosal antibody responses when administered intramuscularly [166] or intranasally [167]. Other TLR ligands tested in mucosal vaccines have been (a) TLR3-specific double-stranded RNA analog polyinosine: polycytosine acid (poly I: C) [168,169], (b) TLR5-specific flagellins [170,171], (c) TLR7 agonists like imidazoquinoline derivatives [172], and TLR9 agonists like CpG-oligodeoxynucleotides [173].…”