Impact of Hypoxia-Inducible Factor-1α on Host Immune Metabolism and Tissue Damage During Mycobacterium bovis Infection.

HIF-1α is a pivotal regulator of metabolic and inflammatory responses. This study investigated the role of HIF-1α in M. bovis infection and its effects on host immune metabolism and tissue damage. We evaluated the expression of immunometabolism markers and MMPs infected with M. bovis, and following HIF-1α inhibition in vitro. To understand the implications of HIF-1α inhibition on disease progression, mice at different infection stages were treated with the HIF-1α inhibitor, YC-1. Our results revealed an upregulation of the HIF-1α in macrophages post-M. bovis infection, facilitating enhanced M1 macrophage polarization. The blockade of HIF-1α moderated these responses but escalated MMP activity, hindering bacterial control. Consistent with our in vitro results, early-stage treatment of mice with YC-1 aggravated pathological alterations and tissue damage, while late-stage HIF-1α inhibition proved beneficial in managing the disease. Overall, our findings underscored the nuanced role of HIF-1α across varying phases of M. bovis infection.

Multicomponent Pathogen-Mimicking Nanoparticles Induce Intestinal Immune Responses against Paratuberculosis.

Given the worldwide problem posed by enteric pathogens, the discovery of safe and efficient intestinal adjuvants combined with novel antigen delivery techniques is essential to the design of mucosal vaccines. In this work, we designed poly (lactic-co-glycolic acid) (PLGA)-based nanoparticles (NPs) to codeliver all-trans retinoic acid (atRA), novel antigens, and CpG. To address the insolubility of the intestinal adjuvant atRA, we utilized PLGA to encapsulate atRA and form a "nanocapsid" with polydopamine. By leveraging polydopamine, we adsorbed the water-soluble antigens and the TLR9 agonist CpG onto the NPs' surface, resulting in the pathogen-mimicking PLPCa NPs. In this study, the novel fusion protein (HBf), consisting of the Mycobacterium avium subspecies paratuberculosis antigens HBHA, Ag85B, and Bfra, was coloaded onto the NPs. In vitro, PLPCa NPs were shown to promote the activation and maturation of bone marrow-derived dendritic cells. Additionally, we found that PLPCa NPs created an immune-rich microenvironment at the injection site following intramuscular administration. From the results, the PLPCa NPs induced strong IgA levels in the gut in addition to enhancing powerful systemic immune responses. Consequently, significant declines in the bacterial burden and inflammatory score were noted in PLPCa NPs-treated mice. In summary, PLPCa can serve as a novel and safe vaccine delivery platform against gut pathogens, such as paratuberculosis, capable of activating both systemic and intestinal immunity.

Chitosan-alginate/R8 ternary polyelectrolyte complex as an oral protein-based vaccine candidate induce effective mucosal immune responses.

Vaccination is the most effective method for preventing infectious diseases. Oral vaccinations have attracted much attention due to the ability to boost intestinal and systemic immunity. The focus of this study was to develop a poly (lactide-co-glycolide) acid (PLGA)-based ternary polyelectrolyte complex (PEC) with chitosan, sodium alginate, and transmembrane peptides R8 for the delivery of antigen proteins. In this study, the antigen protein (HBf), consisting of the Mycobacterium avium subspecies paratuberculosis (MAP) antigens HBHA, Ag85B, and Bfra, was combined with R8 to generate self-assembled conjugates. The results showed that PEC presented a cross-linked reticular structure to protect the encapsulated proteins in the simulated gastric fluid. Then, the nanocomposite separated into individual nanoparticles after entering the simulated intestinal fluid. The ternary PEC with R8 promoted the in vivo uptake of antigens by intestinal lymphoid tissue. Moreover, the ternary PEC administered orally to mice promoted the secretion of specific antibodies and intestinal mucosal IgA. In addition, in the mouse models of MAP infection, the ternary PEC enhanced splenic T cell responses, thus reducing bacterial load and liver pathology score. These results suggested that this ternary electrolyte complex could be a promising delivery platform for oral subunit vaccine candidates, not limited to MAP infection.