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Wound healing is a complex physiological process essential for restoring tissue integrity following various injuries, ranging from minor, everyday incidents to post-surgical complications. Emerging studies have demonstrated that lactic acid bacteria (LAB) can offer benefits beyond gut health, extending their positive effects on skin health. This study investigated the potential of Lactobacillus reuteri NCHBL-005, a honeybee-derived probiotic strain, to enhance fibroblast-mediated wound healing. L929 cells and mouse embryonic fibroblasts (MEFs) were utilized as models to specifically target fibroblasts. To assess the wound healing potential in vitro, a scratch assay was performed, providing insights into wound closure. Additionally, we created wound models in mice to evaluate the in vivo effects of the treatment. Our results showed that L. reuteri NCHBL-005 significantly accelerated wound closure in L929 fibroblast compared to other lactobacilli and exhibited superior efficacy in activating the mitogen-activated protein kinase (MAPK) pathway. Through MAPK inhibition assays, we confirmed that the wound healing effects of L. reuteri NCHBL-005 were MAPK-dependent, promoting fibroblast proliferation and differentiation. Notably, L. reuteri NCHBL-005 treatment did not facilitate wound healing in MEF cells derived from Toll-like-receptor 2 knockout (TLR2 ) mice, highlighting the critical role of TLR2 in this mechanism. In vivo studies further corroborated these findings, in which topical administration of L. reuteri NCHBL-005 enhanced wound healing and stimulated fibroblast proliferation and activation, as confirmed by histopathological analysis. These findings revealed that L. reuteri NCHBL-005 activates fibroblasts through TLR2 stimulation and subsequent MAPK pathway activation, suggesting its potential as a promising therapeutic candidate for wound management.

The Bacillus Calmette-Guérin (BCG) vaccine, the only licensed vaccine against tuberculosis (TB), has played a crucial role in mitigating severe manifestations of the disease, particularly in children. However, its effectiveness against pulmonary TB in adults remains variable, largely due to its limited ability to elicit a sustained antigen-specific T H 1 immune response and to generate long-lived tissue-resident memory T cells (T RM ) within the lungs. Consequently, innovative strategies that address these immunological shortcomings are needed to enhance BCG immunogenicity and efficacy against pulmonary TB. Recent studies on intravenous (IV)-BCG have emerged as a promising alternative, achieving near-sterilizing immunity in preclinical models such as nonhuman primates by strengthening pulmonary defenses against Mycobacterium tuberculosis (Mtb). This review examines how IV-BCG enhances BCG efficacy through a synergistic network of immunological factors, including trained immunity, effector T H 1 cells, lung T RM , inducible bronchus-associated lymphoid tissue (iBALT), and antibody responses. Systemic delivery of IV-BCG induces durable trained immunity, primes robust T H 1 and T RM responses in the lungs, may foster iBALT formation for localized protection, and enhances antibody production to reinforce humoral defenses. Drawing on data from preclinical studies, this review highlights how these components interconnect to sustain long-lasting pulmonary protection and offers insights into optimizing BCG-based TB vaccines.

IntroductionAlveolar macrophages (AMs) are the first line of defence against pathogens that initiate an inflammatory response in the lungs and exhibit a strong affinity for surfactant protein A (SP-A). Extracellular vesicles (EVs) have emerged as a promising drug delivery platform due to their minimal cytotoxicity. However, precise targeting of specific cell types and the rapid lysosomal degradation of EVs within recipient cells remain persistent challenges.MethodIn this study, we explored the biological significance of SP-A-EVs as novel drug delivery systems for combating lung inflammation. We first verified that respiratory EVs express SP-A receptor (SP-R210), facilitating the conjugation of SP-A with EVs. The delivery efficiency, cellular internalisation pathways and therapeutic effects were evaluated using an in vivo mouse model.ResultsSP-A-EVs were robustly internalised into AMs both in vitro and in vivo. Furthermore, our investigation revealed that the toll-like receptor 4-mediated endocytosis pathway was employed for the uptake of SP-A-EVs, significantly delaying their degradation compared with natural EVs, which primarily followed the conventional lysosomal degradation pathway within AMs. In a functional study, we successfully loaded anti-inflammatory microRNA (let-7b) into SP-A-EVs, leading to the suppression of AM activation and the alleviation of lung inflammation induced by lipopolysaccharide.ConclusionThese findings underscore the potential of SP-A-EVs as highly effective drug delivery systems for targeted therapeutics in lung-related disorders, capitalising on the strong affinity between AMs and SP-A and the modulation of cellular internalisation.

Severe fever with thrombocytopenia syndrome virus was first discovered in 2009 as the causative agent of severe fever with thrombocytopenia syndrome. Despite its potential threat to public health, no prophylactic vaccine is yet available. This study developed a heterologous prime-boost strategy comprising priming with recombinant replication-deficient human adenovirus type 5 (rAd5) expressing the surface glycoprotein, Gn, and boosting with Gn protein. This vaccination regimen induced balanced Th1/Th2 immune responses and resulted in potent humoral and T cell-mediated responses in mice. It elicited high neutralizing antibody titers in both mice and non-human primates. Transcriptome analysis revealed that rAd5 and Gn proteins induced adaptive and innate immune pathways, respectively. This study provides immunological and mechanistic insight into this heterologous regimen and paves the way for future strategies against emerging infectious diseases.

Diabetic retinopathy (DR) is a prevalent complication of diabetes, often resulting in vision loss and blindness. Existing treatments primarily aim to control blood sugar levels and inhibit angiogenesis. However, current therapies for DR, such as anti-VEGF and laser photocoagulation, are frequently invasive, and can cause adverse side effects. Consequently, there is a critical need for new preventive therapeutics to address DR more effectively. This study aimed to examine the therapeutic potential of a histamine H 4 receptor (HRH4) antagonist as a preventive treatment for DR in mice. A mouse model of DR was established by intraperitoneally injecting 200 mg/kg of streptozotocin (STZ). Immune cell infiltration into the retina of mice with STZ-induced diabetes was measured using fluorescence-activated cell sorting (FACS) 12 weeks after STZ injection. The preventive effects of the HRH4 antagonist on inflammation and pathological retinal vessel leakage were determined in a mouse model of DR. Infiltration of HRH4-expressing macrophages increased in the retina of mice with STZ-induced DR. The HRH4 antagonist prevented macrophage infiltration and retinal vascular leakage to prevent STZ-induced DR in mice without causing any retinal toxicity. The infiltration of macrophages increased in the retina of mice with STZ-induced diabetes through HRH4, indicating that HRH4 is potentially a novel preventative therapeutic target in DR. These findings suggest that targeting HRH4 is a promising strategy for the prevention and treatment of DR.

NADPH oxidase 2 (NOX2) is an enzyme responsible for generating reactive oxygen species, primarily found in phagocytes. Chronic Granulomatous Disease (CGD), along with bacterial infections such as Mycobacterium tuberculosis (Mtb), is a representative NOX2-deficient X-linked disease characterized by uncontrolled inflammation. However, the precise roles of host-derived factors that induce infection-mediated hyperinflammation in NOX2-deficient condition remain incompletely understood. To address this, we compared Mtb-induced pathogenesis in Nox2 -/- and wild type (WT) mice in a sex-dependent manner. Among age- and sex-matched mice subjected to Mtb infection, male Nox2 -/- mice exhibited a notable increase in bacterial burden and lung inflammation. This was characterized by significantly elevated pro-inflammatory cytokines such as G-CSF, TNF-α, IL-1α, IL-1β, and IL-6, excessive neutrophil infiltration, and reduced pulmonary lymphocyte levels as tuberculosis (TB) progressed. Notably, lungs of male Nox2 -/- mice were predominantly populated with CD11b int Ly6G int CXCR2 lo CD62L lo immature neutrophils which featured mycobacterial permissiveness. By diminishing total lung neutrophils or reducing immature neutrophils, TB immunopathogenesis was notably abrogated in male Nox2 -/- mice. Ultimately, we identified G-CSF as the pivotal trigger that exacerbates the generation of immature permissive neutrophils, leading to TB immunopathogenesis in male Nox2 -/- mice. In contrast, neutralizing IL-1α and IL-1β, which are previously known factors responsible for TB pathogenesis in Nox2 -/- mice, aggravated TB immunopathogenesis. Our study revealed that G-CSF-driven immature and permissive pulmonary neutrophils are the primary cause of TB immunopathogenesis and lung hyperinflammation in male Nox2 -/- mice. This highlights the importance of quantitative and qualitative control of pulmonary neutrophils to alleviate TB progression in a phagocyte oxidase-deficient condition.

ImmunoPET/CT imaging using a labeled SIV-specific antibody can identify sites of viralinfection in SIV-infected macaques without the need for tissue biopsies, even if viral load in the blood is below the detection limit. The detection of viral dynamics and localization in the context of controlled HIV infection remains a challenge and is limited to blood and biopsies. We developed a method to capture total-body simian immunodeficiency virus (SIV) replication using immunoPET (antibody-targeted positron emission tomography). The administration of a poly(ethylene glycol)-modified, 64 Cu-labeled SIV Gp120–specific antibody led to readily detectable signals in the gastrointestinal and respiratory tract, lymphoid tissues and reproductive organs of viremic monkeys. Viral signals were reduced in aviremic antiretroviral-treated monkeys but detectable in colon, select lymph nodes, small bowel, nasal turbinates, the genital tract and lung. In elite controllers, virus was detected primarily in foci in the small bowel, select lymphoid areas and the male reproductive tract, as confirmed by quantitative reverse-transcription PCR (qRT-PCR) and immunohistochemistry. This real-time, in vivo viral imaging method has broad applications to the study of immunodeficiency virus pathogenesis, drug and vaccine development, and the potential for clinical translation.