Pathogen Clearance Research Articles

Rutin Synergizes with Colistin to Eradicate Salmonellosis in Mice by Enhancing the Efficacy and Reducing the Toxicity.

The wide dissemination of multidrug-resistant (MDR) Gram-negative bacteria poses a significant global health and security concern. As developing new antibiotics is generally costly, fastidious, and time-consuming, there is an urgent need for alternative therapeutic strategies to address the gap in antibiotic discovery void. This study aimed to investigate the activity of colistin (CS) in combination with a natural product, rutin (RT), to combat against Salmonella Typhimurium (S. Tm) in vitro and in vivo. The results showed that a combination with RT enabled the potentiation of CS efficacy. Further mechanistic analysis indicated that RT disrupted iron homeostasis to inactivate the PmrA/PmrB system, thereafter reducing the bacterial membrane modifications for enhancing CS binding. Besides enhancing bactericidal activity of CS, RT was also observed to mitigate the CS-induced nephrotoxicity, by which the dosing limitation of CS was overcome for better pathogen clearance. The animal trial eventually confirmed the in vivo synergistic interaction of RT with CS to treat the bacterial infection. To sum up, the present study uncovered the potential of RT as a viable adjuvant of CS to eradicate the infection and protect the hosts, which might serve as a promising alternative to combat infections caused by MDR Gram-negative bacteria.

Clearance of Intracellular Pathogens with Hyaluronic Acid Nanomicelles Responsive to H2S and pH

Hyaluronic acid (HA) is an acidic mucopolysaccharide of animal origin composed of repeating disaccharide units of N-acetylglucosamine and glucuronic acid. Due to its excellent biocompatibility, biodegradability, and selective affinity for CD44 receptors on cell surfaces, HA is widely employed as a drug carrier. In our study, we aimed to target subcellular bacteria by grafting cystamine onto HA scaffolds through an amide reaction, producing a linker responsive to H2S and pH changes. Subsequently, hydrophobic dodecylamine was attached to HA, forming amphiphilic molecules. These amphiphilic entities can self-assemble into nanomicelles in an aqueous solution, thereby encapsulating the antibacterial agent triclosan (TCS). The resulting HA-based system (HASS-TCS) can be internalized via CD44-mediated endocytosis, releasing substantial amounts of streptomycin and TCS in H2S-rich and acidic environments. Additionally, HASS-TCS has demonstrated effectiveness in eradicating biofilms and addressing intracellular infections caused by Salmonella. This study underscores a novel pH-sensitive hyaluronic acid-based drug delivery system with significant potential for the effective treatment of intracellular infections.

Long-term Memory in Immune Cells: An Overview

Long-term memory in immune cells is a pivotal aspect of the adaptive immune response, enabling the host to mount rapid and effective defenses against previously encountered pathogens. This review explores the mechanisms underlying the development and maintenance of immune memory, focusing on memory T cells, memory B cells, and long-lived plasma cells. Following primary infections or vaccinations, a subset of activated lymphocytes transitions into memory cells, which persist long after pathogen clearance. Factors influencing memory cell longevity, such as antigen persistence, cytokine signaling, and homeostatic proliferation, are discussed. Moreover, the review addresses the challenges posed by chronic infections and the potential for immune exhaustion, which can impair memory function. Additionally, the clinical implications of understanding immune memory are highlighted, particularly in vaccine development, cancer immunotherapy, and the management of autoimmune diseases. By synthesizing current knowledge on long-term memory in immune cells, this review aims to provide insights into future research directions and therapeutic strategies to enhance immune responses and improve public health outcomes. Keywords: Long-term memory, immune cells, memory T cells, memory B cells, immune exhaustion, vaccine development.

The Role of the Complement System in Autoimmune Diseases and Therapeutic Targeting

The complement system, a critical component of the innate immune system, plays a dual role in immune defense and pathogenesis, particularly in autoimmune diseases. Comprising over 30 proteins, the complement system facilitates pathogen clearance, inflammation, and immune modulation. However, its dysregulation can lead to uncontrolled activation and contribute to the development and progression of various autoimmune disorders, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), antiphospholipid syndrome (APS), and vasculitis. In these diseases, excessive complement activation triggers inflammation, immune cell recruitment, and tissue damage, exacerbating the autoimmune response. This review provides an in-depth analysis of the complement system’s role in autoimmune diseases, exploring how its three activation pathways—classical, lectin, and alternative—contribute to disease pathogenesis. It also discusses key complement proteins such as C3, C5, and the membrane attack complex (MAC) in promoting inflammatory responses in these conditions. Moreover, the review highlights recent advances in therapeutic strategies targeting the complement system, including the development of C5 inhibitors like eculizumab and C3 inhibitors, which show promise in treating complement-mediated autoimmune diseases. These therapies aim to reduce inflammation and tissue destruction, offering new approaches for managing autoimmune disorders. Understanding complement dysregulation is crucial for the development of more effective treatments in the future. Keywords: Complement system, Autoimmune diseases, Complement activation, Inflammation, Therapeutic targeting

Temperature-Responsive Hydrogel System Integrating Wound Temperature Monitoring and On-demand Drug Release for Sequentially Inflammatory Process Regulation of Wound Healing.

Wound healing faces challenges like inflammation, infection, and limited monitoring capabilities, and traditional dressings often lack the ability to promote healing or provide real-time wound status updates. Early pro-inflammatory responses help clear pathogens and damaged tissue, while timely anti-inflammatory modulation aids tissue regeneration, making sequential inflammation regulation crucial. Additionally, wound temperature, a key infection biomarker, enables real-time monitoring for effective management. We propose a temperature-responsive hydrogel dressing capable of two-stage sequential drug release and wound temperature monitoring. The hydrogel, composed of poly(N-isopropylacrylamide) (PNIPAM) and dopamine/methacrylated-modified hyaluronic acid (HA-MA-DA), allows temperature-based drug release control, sequential regulating pro-inflammatory and anti-inflammatory stages in wound healing. Interleukin-8 (IL-8), a pro-inflammatory molecule, is encapsulated into hydrogel matrix and rapidly released to trigger the initial inflammatory response. Furthermore, photothermally responsive and erastin-loaded polydopamine@PNIPAM nanoparticles (E-PD NPs) are incorporated to release the anti-inflammatory drug erastin upon near-infrared light exposure, terminating inflammation through cytosolic burial, and thus achieve anti-inflammatory effects at the second stage of wound healing. Furthermore, a bluetooth module enables real-time wound temperature monitoring. Combining sequential drug release with temperature monitoring, our hydrogel dressing addresses significant gaps in current wound healing technologies and offers new insights into personalized therapeutic interventions.

The complement system in lipid-mediated pathologies.

The complement system, a coordinator and facilitator of the innate immune response, plays an essential role in maintaining host homeostasis. It promotes clearance of pathogen- and danger-associated molecular patterns, regulates adaptive immunity, and can modify various metabolic processes such as energy expenditure, lipid metabolism, and glucose homeostasis. In this review, we will focus on the intricate interplay between complement components and lipid metabolism. More precisely, we will display how alterations in the activation and regulation of the complement system affect pathological outcome in lipid-associated diseases, such as atherosclerosis, obesity, metabolic syndrome, age-related macular degeneration, and metabolic dysfunction-associated steatotic liver disease. In addition to that, we will present and evaluate underlying complement-mediated physiological mechanisms, observed both in vitro and in vivo. Our manuscript will demonstrate the clinical significance of the complement system as a bridging figure between innate immunity and lipid homeostasis.

Assessment of Glutamine as a Fuel Source for Alveolar Macrophages Exposed to Chronic Ethanol Using an Extracellular Flux Bioanalyzer.

Alveolar macrophages (AMs) are the first line of cellular defense in the lower airway against pathogens. However, chronic and excessive alcohol use impairs the ability of AMs to phagocytize and clear pathogens from the alveolar space, in part through dysregulated fuel metabolism and bioenergetics. Our prior work has shown that chronic ethanol (EtOH) consumption impairs mitochondrial bioenergetics and increases lactate levels in AMs. Further, we recently demonstrated that EtOH increases glutamine dependency and glutamine-dependent maximal respiration while decreasing flexibility, shifting away from pyruvate-dependent respiration and towards glutamine-dependent respiration. Glutaminolysis is an important compensatory pathway for mitochondrial respiration when pyruvate is used for lactic acid production or when other fuel sources are insufficient. Using a mouse AM cell line, MH-S cells, exposed to either no EtOH or EtOH (0.08%) for 72 h, we determined the dependency of mitochondrial respiration and bioenergetics on glutamine as a fuel source using an extracellular flux bioanalyzer. Real-time measures were done in response to bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES), an inhibitor of glutaminase 1, which prevents the enzymatic conversion of glutamine to glutamate, in media vehicle or in response to vehicle alone, followed by testing mitochondrial stress. The step-by-step protocol provided herein describes our methods and calculations for analyzing average levels of glutamine-dependent basal mitochondrial respiration, mitochondrial ATP-linked respiration, maximal mitochondrial respiration, and mitochondrial spare respiratory capacity across multiple biological and experimental replicates.

Plant derived bioactive compounds for the treatment of neurodegeneration and neuroimmune disorders associated with the complement system

The complement system is a key component of the innate immune system that mediates the clearance of pathogens, apoptotic cells, and cellular debris. However, the complement system also has diverse roles in the central nervous system (CNS), where it regulates synaptic pruning, neural plasticity, and neuroinflammation. Dysregulation of the complement system has been implicated in various neurodegenerative disorders such as Alzheimer’s disease, multiple sclerosis, epilepsy, stroke, and traumatic brain injury. In these conditions, excessive or chronic activation of the complement system may lead to synaptic loss, neuronal damage, immune dysregulation, and inflammation, which leads to exacerbating the disease’s progression and severity. Moreover, the complement system may interact with infectious agents that invade the CNS, such as bacteria, viruses, fungi, and parasites, and modulate their pathogenicity and host response. Therefore, understanding the complex interplay between the complement system and the CNS is crucial for developing novel therapeutic strategies to prevent or treat neurodegenerative and neuroimmune disorders. Natural compounds, such as plant extracts, phytochemicals, and nutraceuticals, have emerged as promising candidates for modulating the complement system and its effects on the CNS. These compounds may exert anti-inflammatory, antioxidant, neuroprotective, and immunomodulatory effects by regulating the expression of various complement components and pathways. In this review, we summarized the current knowledge on the roles of the complement system in human neurodegenerative disorders and the benefits of natural compounds for complement-targeted therapy.

Harnessing Bacillus subtilis Spore Surface Display (BSSD) Technology for Mucosal Vaccines and Drug Delivery: Innovations in Respiratory Virus Immunization

Respiratory viruses present significant global health challenges due to their rapid evolution, efficient transmission, and zoonotic potential. These viruses primarily spread through aerosols and droplets, infecting respiratory epithelial cells and causing diseases of varying severity. While traditional intramuscular vaccines are effective in reducing severe illness and mortality, they often fail to induce sufficient mucosal immunity, thereby limiting their capacity to prevent viral transmission. Mucosal vaccines, which specifically target the respiratory tract’s mucosal surfaces, enhance the production of secretory IgA (sIgA) antibodies, neutralize pathogens, and promote the activation of tissue-resident memory B cells (BrMs) and local T cell responses, leading to more effective pathogen clearance and reduced disease severity. Bacillus subtilis spore surface display (BSSD) technology is emerging as a promising platform for the development of mucosal vaccines. By harnessing the stability and robustness of Bacillus subtilis spores to present antigens on their surface, BSSD technology offers several advantages, including enhanced stability, cost-effectiveness, and the ability to induce strong local immune responses. Furthermore, the application of BSSD technology in drug delivery systems opens new avenues for improving patient compliance and therapeutic efficacy in treating respiratory infections by directly targeting mucosal sites. This review examines the potential of BSSD technology in advancing mucosal vaccine development and explores its applications as a versatile drug delivery platform for combating respiratory viral infections.

Insect immunity in the Anthropocene.

Anthropogenic activities result in global change, including climate change, landscape degradation and pollution, that can alter insect physiology and immune defences. These changes may have contributed to global insect decline and the dynamics of insect-transmitted diseases. The ability of insects to mount immune responses upon infection is crucial for defence against pathogens and parasites. Suppressed immune defences reduce fitness by causing disease-driven mortality and elevated immune responses reduce energy available to invest in other fitness traits such as reproduction. Understanding the impact of anthropogenic factors on insect-pathogen interactions is therefore key to determining the contribution of anthropogenic global change to pathogen-driven global insect decline and the emergence and transmission of insect-borne diseases. Here, we synthesise evidence of the impact of anthropogenic factors on insect immunity. We found evidence that anthropogenic factors, such as insecticides and heavy metals, directly impacting insect immune responses by inhibiting immune activation pathways. Alternatively, factors such as global warming, heatwaves, elevated CO2 and landscape degradation can indirectly reduce insect immune responses via reducing the energy available for immune function. We further review how anthropogenic factors impact pathogen clearance and contribute to an increase in vector-borne diseases. We discuss the fitness cost of anthropogenic factors via pathogen-driven mortality and reduced reproductive output and how this can contribute to species extinction. We found that most research has determined the impact of a single anthropogenic factor on insect immune responses or pathogen resistance. We recommend studying the combined impact of multiple stressors on immune response and pathogen resistance to understand better how anthropogenic factors affect insect immunity. We conclude by highlighting the importance of initiatives to mitigate the impact of anthropogenic factors on insect immunity, to reduce the spread of vector-borne diseases, and to protect vulnerable ecosystems from emerging diseases.

Cell Death Mechanisms

Cells and their building blocks ensure the maintenance of life by performing complex tasks such as taking in nutrients, excreting waste materials, producing energy, growth, division and reproduction. The form of intercellular communication and coordination is critical for the organism to grow, develop, and adapt to its environment optimally. The numerical balance of the cells that make up the organism is very important for it to survive in a healthy way. While new cells are being created in the living being, some of the existing cells are also eliminated through cell death, thus ensuring a stable balance. As new cells are generated within the organism, a portion of the existing cells undergoes elimination through the process of cell death, thereby maintaining a stable balance. To uphold this mechanism, various forms of cell death mechanisms are activated. Cell death occurs spontaneously, genetically or by other factors that are a part of the life of living things. It basically exists in two main forms. These are programmed and unprogrammed cell death. Cell death mechanisms are critical for the development, survival and health of living organisms. This process, which is basically divided into two main categories, is called programmed cell death (apoptosis) and unprogrammed cell death (necrosis). Programmed and unprogrammed cell death mechanisms are very important for the proper functioning of biological systems and the continuation of life. While programmed cell death (apoptosis) plays very important roles in the regulation and development of tissues, homeostasis, immune response and prevention of diseases, unprogrammed cell death (necrosis) is important in the rapid repair of tissue by clearing damaged cells and the clearance of pathogens. Understanding the way death mechanisms work is very important in terms of understanding the effects that may occur on a healthy continuation of life and in developing more effective methods in the treatment of diseases that may arise as a result. For these reasons, what death mechanisms are, their types, differences and working principles have been tried to be summarized in this study.

Analysis of the c.1135G > A, c.1993A > G, c.2059T > C TAP2 gene variants and their relationship with latent tuberculosis infection in Mexico

Tuberculosis (TB) is a worldwide public health problem with 10.6 million people falling ill and 1.5 million deaths every year. Latent tuberculosis infection (LTBI) is a condition in which an individual has been infected with Mycobacterium tuberculosis (Mtb) but does not show clinical signs and symptoms. The transporter associated with antigen processing (TAP2) protein plays a fundamental role in the immune response promoting the clearance of intracellular pathogens, such as Mtb. Our study aimed to determine the association between c.1135G > A (rs1800454), c.1993A > G (rs241447) and c.2059 T > C (rs241448) TAP2 gene variants with LTBI susceptibility. In this case-control study, 180 individuals (90 were LTBI-positive and 90 were controls) from shelters were analyzed. Genotyping of the polymorphisms was performed using the Applied Biosystems Step One Thermal Cycler Real-Time PCR allelic discrimination technology. The haplotypic analyses were performed with the Arlequin 3.5 software. The G allele (OR = 1.732, CI = 1.125–2.667, p = 0.012) and AG genotype of the c.1993A > G variant (p=<0.001) were associated with susceptibility to LTBI (p=<0.001), as well as the GAT, AAT, AAC, AGT haplotypes (p=<0.001). The c.1135G > A and c.2059 T > C variants were not associated with LTBI risk.

The involvement of endogenous melatonin in LPS-induced M1-like macrophages and its underlying synthesis mechanism regulated by IRF3

Melatonin (MLT) has been shown to induce polarization of macrophages towards M2-like phenotype and inhibit polarization of macrophages towards M1-like phenotype through exogenous administration, which affects the development of many macrophage polarization-related diseases, such as infectious diseases, cardiovascular diseases, bone diseases, and tumors. However, whether endogenous melatonin has similar influences on macrophage polarization as exogenous melatonin is still under investigation. This study revealed that the process of lipopolysaccharide (LPS) inducing macrophages to polarize towards M1-like phenotype was accompanied by an increase in endogenous MLT secretion. To explore the role of increased endogenous MLT in the polarization process of macrophages, whether similar to the function of exogenous MLT in inhibiting polarization of macrophages towards M1-like phenotype, we established LPS-induced MLT deficiency models in vitro to investigate the effects of endogenous MLT on the secretion of cytokines, co-stimulatory molecules, ROS, and phagocytic function in LPS-induced M1-like macrophages. Additionally, we aimed to elucidate the mechanism by which LPS affects the secretion of endogenous MLT by macrophages. Our results confirm that LPS induces transcription of Aanat through the TLR4/TRIF pathway, consequently facilitating the secretion of MLT by macrophages. In this way, IRF3 is the main transcription factor that regulates Aanat transcription. Endogenous MLT plays a role in inhibiting the polarization of macrophages towards M1 phenotype and delaying cell apoptosis during LPS-induced polarization towards M1 phenotype. This phenomenon may be a form of self-protection that occurs when macrophages engulf pathogens while avoiding oxidative stress and apoptosis caused by LPS. This conclusion clarifies the role of endogenous MLT in the clearance of pathogens by macrophages, providing a theoretical basis for understanding its role in innate immunity.

NKp46+ ILC3s promote early neutrophil defense against Clostridioides difficile infection through GM-CSF secretion

Clostridioides difficile infection (CDI) is a common cause of antibiotic-associated colitis. C. difficile proliferates and produces toxins that damage the colonic epithelium, leading to symptoms ranging from mild diarrhea to severe pseudomembranous colitis. The host's innate response to CDI occurs in two phases: an early phase in which neutrophils reduce the bacterial load and a late phase involving repair mechanisms to restore epithelial integrity. Group 3 innate lymphoid cells (ILC3s) are crucial in protecting the gut from CDI. Previous studies have shown that ILC3-derived IL-22 is essential in the late phase of CDI for epithelial repair and maintaining an intestinal microbiota that competes with C. difficile, preventing its expansion. Our study finds that ILC3s also protect during the early stages of CDI by sustaining neutrophils through GM-CSF. Less neutrophil production, accumulation, and activation was evident in ILC3-deficient mice than in wild-type (WT) mice, which led to exacerbated symptoms, impaired pathogen clearance, a compromised epithelial barrier, and increased mortality. The adoptive transfer of ILC3s into ILC3-deficient mice restored neutrophil responses and improved disease outcomes. Both in vitro and in vivo experiments revealed that GM-CSF production by ILC3s is crucial for neutrophil production and effective resistance during CDI. Using mice lacking NKp46+ ILC3s, we found that this subset significantly contributes to GM-CSF production in CDI. These findings highlight the critical role of the ILC3-neutrophil connection in early innate responses to CDI. Enhancing ILC3 production of GM-CSF could be a promising strategy for improving host defense against CDI and other enteric infections.

Metabolic pathways fueling the suppressive activity of myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSC) are considered an aberrant population of immature myeloid cells that have attracted considerable attention in recent years due to their potent immunosuppressive activity. These cells are typically absent or present in very low numbers in healthy individuals but become abundant under pathological conditions such as chronic infection, chronic inflammation and cancer. The immunosuppressive activity of MDSC helps to control excessive immune responses that might otherwise lead to tissue damage. This same immunosuppressive activity can be detrimental, particularly in cancer and chronic infection. In the cancer setting, tumors can secrete factors that promote the expansion and recruitment of MDSC, thereby creating a local environment that favors tumor progression by inhibiting the effective immune responses against cancer cells. This has made MDSC a target of interest in cancer therapy, with researchers exploring strategies to inhibit their function or reduce their numbers to improve the efficacy of cancer immunotherapies. In the context of chronic infections, MDSC can lead to persistent infections by suppressing protective immune responses thereby preventing the clearance of pathogens. Therefore, targeting MDSC may provide a novel approach to improve pathogen clearance during chronic infections. Ongoing research on MDSC aims to elucidate the exact processes behind their expansion, recruitment, activation and suppressive mechanisms. In this context, it is becoming increasingly clear that the metabolism of MDSC is closely linked to their immunosuppressive function. For example, MDSC exhibit high rates of glycolysis, which not only provides energy but also generates metabolites that facilitate their immunosuppressive activity. In addition, fatty acid metabolic pathways, such as fatty acid oxidation (FAO), have been implicated in the regulation of MDSC suppressive activity. Furthermore, amino acid metabolism, particularly arginine metabolism mediated by enzymes such as arginase-1, plays a critical role in MDSC-mediated immunosuppression. In this review, we discuss the metabolic signature of MDSC and highlight the therapeutic implications of targeting MDSC metabolism as a novel approach to modulate their immunosuppressive functions.

Metapopulation model of phage therapy of an acute Pseudomonas aeruginosa lung infection.

Phage therapy is increasingly employed as a compassionate treatment for severe infections caused by multidrug-resistant (MDR) bacteria. However, the mixed outcomes observed in larger clinical studies highlight a gap in understanding when phage therapy succeeds or fails. Previous research from our team, using in vivo experiments and single-compartment mathematical models, demonstrated the synergistic clearance of acute P. aeruginosa pneumonia by phage and neutrophils despite the emergence of phage-resistant bacteria. In fact, the lung environment is highly structured, prompting the question of whether immunophage synergy explains the curative treatment of P. aeruginosa when incorporating realistic physical connectivity. To address this, we developed a metapopulation network model mimicking the lung branching structure to assess phage therapy efficacy for MDR P. aeruginosa pneumonia. The model predicts the synergistic elimination of P. aeruginosa by phage and neutrophils but emphasizes potential challenges in spatially structured environments, suggesting that higher innate immune levels may be required for successful bacterial clearance. Model simulations reveal a spatial pattern in pathogen clearance where P. aeruginosa are cleared faster at distal nodes of the bronchial tree than in primary nodes. Interestingly, image analysis of infected mice reveals a concordant and statistically significant pattern: infection intensity clears in the bottom before the top of the lungs. The combined use of modeling and image analysis supports the application of phage therapy for acute P. aeruginosa pneumonia while emphasizing potential challenges to curative success in spatially structured in vivo environments, including impaired innate immune responses and reduced phage efficacy.

Macrophages and autophagy: partners in crime.

Macrophages and autophagy are intricately linked, both playing vital roles in maintaining homeostasis and responding to disease. Macrophages, known for their 'eating' function, rely on a sophisticated digestion system to process a variety of targets, from apoptotic cells to pathogens. The connection between macrophages and autophagy is established early in their development, influencing both differentiation and mature functions. Autophagy regulates essential immune functions, such as inflammation control, pathogen clearance, and antigen presentation, linking innate and adaptive immunity. Moreover, it modulates cytokine production, ensuring a balanced inflammatory response that prevents excessive tissue damage. Autophagy also plays a critical role in macrophage polarization, influencing their shift between pro-inflammatory and anti-inflammatory states. This review explores the role of autophagy in macrophages, emphasizing its impact across various tissues and pathological conditions, and detailing the cellular and molecular mechanisms by which autophagy shapes macrophage function.

A triple-mode strategy combining low-temperature photothermal, photodynamic, and chemodynamic therapies for treating infectious skin wounds.

The skin is the first natural barrier of the human body. Bacterial infections severely hinder the healing process of skin wounds and pose a great threat to human health. Therefore, it is particularly urgent to develop new antimicrobial strategies for bacterial pathogen clearance and wound healing. In this study, a metal-organic framework (MOF), Fe-MIL88B-NH2, was incorporated with the photosensitizer indocyanine green (ICG) to construct composite nanoparticles (MOF@ICG NPs) with multiple antibacterial activities. Under mild near-infrared (NIR) irradiation, the photosensitizer ICG in the MOF@ICG NPs undergoes photothermal conversion (∼45 °C) and photodynamic reactions to generate heat and singlet oxygen (1O2). In addition, the Fenton reaction of the NPs with hydrogen peroxide (H2O2) in the bacterial infection microenvironment resulted in the generation of hydroxyl radicals (˙OH), thus achieving the three-mode combination of low-temperature photothermal therapy (PTT)/photodynamic therapy (PDT)/chemodynamic therapy (CDT). The in vitro experimental results showed that MOF@ICG MPs had excellent antibacterial properties and good cytocompatibility, with some ability to promote the migration of L-929 fibroblasts. Furthermore, under NIR irradiation, MOF@ICG NPs could significantly kill bacteria and promote skin wound healing according to the results of animal experiments. The wound healing rate reached 87.1% after 7 days of treatment. The research results break through the limitations of single-mode antibacterial technology and provide certain theoretical guidance and technical support for the research and development of new antibacterial materials.

Development of a humanized mouse model with functional human materno-fetal interface immunity.

Materno-fetal immunity possesses specialized characteristics to ensure pathogen clearance while maintaining tolerance to the semiallogeneic fetus. Most of our understanding on human materno-fetal immunity is based on conventional rodent models that may not precisely represent human immunological processes owing to the huge evolutionary divergence. Herein, we developed a pregnant human immune system (HIS) mouse model through busulfan preconditioning, which hosts multilineage human immune subset reconstitution at the materno-fetal interface. Human materno-fetal immunity exhibits a tolerogenic feature at the midgestation stage (embryonic day [E] 14.5), and human immune regulatory subsets were detected in the decidua. However, the immune system switches to an inflammatory profile at the late gestation stage (E19). A cell-cell interaction network contributing to the alternations in the human materno-fetal immune atmosphere was revealed based on single-cell RNA-Seq analysis, wherein human macrophages played crucial roles by secreting several immune regulatory mediators. Furthermore, depletion of Treg cells at E2.5 and E5.5 resulted in severe inflammation and fetus rejection. Collectively, these results demonstrate that the pregnant HIS mouse model permits the development of functional human materno-fetal immunity and offers a tool for human materno-fetal immunity investigation to facilitate drug discovery for reproductive disorders.

From fat storage to immune hubs: the emerging role of adipocytes in coordinating the immune response to infection.

Adipose tissue is a rich source of diverse cell populations, including immune cells, adipocytes and stromal cells. Interactions between these different cell types are now appreciated to be critical for maintaining tissue structure and function, by governing processes such as adipogenesis, lipolysis and differentiation of white to beige adipocytes. Interactions between these cells also drive inflammation in obesity, leading to an expansion of adipose tissue immune cells, and the secretion of proinflammatory cytokines from immune cells and from adipocytes themselves. However, in evolutionary terms, obesity is a recent phenomenon, raising the question of why adipocytes evolved to express factors that influence the immune response. Studies of various pathogens indicate that adipocytes are highly responsive to infection, altering their metabolic profiles in a way that can be used to release nutrients and fuel the immune response. In the case of infection with the extracellular parasite Trypanosoma brucei, attenuating the ability of adipocytes to sense the cytokine IL-17 results in a loss of control of the local immune response and an increased pathogen load. Intriguingly, comparisons of the adipocyte response to infection suggest that the immune responses of these cells occur in a pathogen-dependent manner, further confirming their complexity. Here, with a focus on murine adipose tissue, we discuss the emerging concept that, in addition to their canonical function, adipocytes are immune signalling hubs that integrate and disseminate signals from the immune system to generate a local environment conducive to pathogen clearance.