Innate Response Research Articles

Identification of a novel antimicrobial peptide from amphioxus ribosomal protein L27

Antimicrobial peptides (AMPs), derived from a variety of proteins such as ribosomal proteins, play a pivotal role in the innate immune system. However, information regarding ribosomal protein-derived AMPs is currently limited and their mechanisms of action remain poorly defined. Here we identified and characterized the antibacterial activity of amphioxus RPL27 (BjRPL27) and its core functional region located at residues 51-72 (termed BjRPL2751-72). We found that BjRPL27 expression was upregulated in the hepatic caecum following bacterial infection. Both the recombinant protein rBjRPL27 and the synthetic peptide BjRPL2751-72 effectively killed the Gram-positive bacterium Staphylococcus aureus and the Gram-negative bacterium Aeromonas hydrophila via a combined action of disrupting cell membrane integrity, inducing membrane depolarization, and increasing intracellular reactive oxygen species (ROS) production. Additionally, the sequence of BjRPL2751-72 was highly conserved among all eukaryotic RPL27s, implying an ancient origin for the antibacterial activity of the RPL27 family. In vivo assays showed that BjRPL2751-72 not only efficiently protected zebrafish from A. hydrophila infection, but also killed the bacterium S. aureus on the skin wound of rats. Furthermore, neither BjRPL27 nor BjRPL2751-72 exhibited hemolytic activity towards human red blood cells, making them promising lead molecules for designing novel AMPs. These findings highlight the potential of BjRPL2751-72 as a novel AMP with selective bactericidal properties.

Comparison of transcriptome responses in blood cells of Atlantic salmon infected by three genotypes of Piscine orthoreovirus.

Piscine orthoreovirus (PRV) infection is common in aquaculture of salmonids. The three known PRV genotypes (PRV-1-3) have host species specificity and cause different diseases, but all infect and replicate in red blood cells (RBCs) in early infection phase. PRV-1 is the causative agent of heart and skeletal muscle inflammation (HSMI) in farmed Atlantic salmon (Salmo salar), PRV-2 causes erythrocytic inclusion body syndrome (EIBS) in coho salmon (Oncorhynchus kisutch), while PRV-3 induces HSMI-like disease in farmed rainbow trout (Oncorhynchus mykiss). PRV-3 can also infect A. salmon without causing clinical disease and has been shown to cross-protect against PRV-1 infection and HSMI, while PRV-2 or inactivated adjuvanted PRV-1 vaccine only partially reduced HSMI pathologic changes. In the present work, we studied the transcriptional responses in blood cells of A. salmon two- and five-weeks post infection with PRV-1, PRV-2, PRV-3, or post injection with inactivated PRV-1 vaccine. PRV-1 and PRV-3 replicated well in A. salmon blood cells, and both induced the typical innate antiviral responses triggered by dsRNA viruses. Two weeks post infection, PRV-3 triggered stronger antiviral responses than PRV-1, despite their similar viral RNA replication levels, but after five weeks the induced responses were close to equal. PRV-2 and the InPRV-1 vaccine did not trigger the same typical antiviral responses as the replicating PRV-1 and PRV-3 genotypes, but induced genes involved in membrane trafficking and signaling pathways that may regulate physiological functions. These findings propose that the protection mediated by PRV-3 against a secondary infection by PRV-1 occur due to a potent and early activation of the same type of innate immune responses. The difference in the timing of antiviral responses may give PRV-1 an evolutionary edge, facilitating its dissemination to A. salmon heart, a critical step for HSMI development.

The Activation of Microglia by the Complement System in Neurodegenerative Diseases.

Neurodegenerative diseases (NDDs) are a group of neurological disorders characterized by the progressive loss of neuronal structure and function, leading to cognitive and behavioral impairments. Despite significant research advancements, there is currently no definitive cure for NDDs. With global aging on the rise, the burden of these diseases is becoming increasingly severe, highlighting the urgency of understanding their pathogenesis and developing effective therapeutic strategies. Microglia, specialized macrophages in the central nervous system, play a dual role in maintaining neural homeostasis. They are involved in clearing cellular debris and apoptotic cells, but in their activated state, they release inflammatory factors that contribute significantly to neuroinflammation. The complement system (CS), a critical component of the innate immune system, assists in clearing damaged cells and proteins. However, excessive or uncontrolled activation of the CS can lead to chronic neuroinflammation, exacerbating neuronal damage. This review aims to explore the roles of microglia and the CS in the progression of NDDs, with a specific focus on the mechanisms through which the CS activates microglia by modulating mitochondrial function. Understanding these interactions may provide insights into potential therapeutic targets for mitigating neuroinflammation and slowing neurodegeneration.

Enhanced Macrophage Uptake of Spray-Dried Phosphatidylserine-Loaded Microparticles for Pulmonary Drug Delivery Applications.

Macrophages are an integral part of the innate immune system and act as a first line of defense to pathogens; however, macrophages can be reservoirs for pathogens to hide and replicate. Tuberculosis, influenza virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are common diseases whose pathogens are uptaken into macrophages. Current treatments for diseases such as these are limited by the therapeutic delivery method, which typically involves systemic delivery in large, frequent doses. This study aims to overcome this limitation via the development of an inhalable dry powder microparticle (MP) formulation capable of targeted drug delivery to alveolar macrophages in addition to controlled release of a therapeutic. A simple one-step spray drying method was used to synthesize acetalated dextran (Ac-Dex) MP loaded with the model therapeutic, curcumin, and 1,2-dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS), which is a phospholipid that induces ligand-receptor mediated macrophage phagocytosis. The resulting MP exhibited significantly more uptake by RAW 264.7 macrophages in comparison to MP without DPPS, and it was shown that DPPS-mediated uptake was macrophage specific. The particles exhibited pH-responsive release and in vitro aerosol dispersion analysis confirmed the MP can be effectively aerosolized for pulmonary delivery. Overall, the described MP has the potential to improve treatment efficacy for macrophage-associated diseases.

Macrophage Polarisation in the Tumour Microenvironment: Recent Research Advances and Therapeutic Potential of Different Macrophage Reprogramming.

Macrophages are a critical component of the innate immune system, derived from monocytes, with significant roles in anti-inflammatory and anti-tumour activities. In the tumour microenvironment, however, macrophages are often reprogrammed into tumour-associated macrophages (TAMs), which promote tumour growth, metastasis, and therapeutic resistance. To review recent advancements in the understanding of macrophage polarisation and reprogramming, highlighting their role in tumour progression and potential as therapeutic targets. This is a review article synthesising findings from recent studies on macrophage polarisation and reprogramming in tumour biology. Not applicable (review of existing literature). Key studies were identified and summarised to explore mechanisms of macrophage polarisation and reprogramming, focusing on M1/M2 polarisation, metabolic and epigenetic changes, and pathway regulation. Macrophage reprogramming in the tumour microenvironment involves complex mechanisms, including phenotypic and functional alterations. These processes are influenced by M1/M2 polarisation, metabolic and epigenetic reprogramming, and various signalling pathways. TAMs play a pivotal role in tumour progression, metastasis, and therapy resistance, making them prime targets for combination therapies. Understanding the mechanisms underlying macrophage polarisation and reprogramming offers promising avenues for developing therapies to counteract tumour progression. Future research should focus on translating these insights into clinical applications for effective cancer treatment.

Biopeptide-rich fermented hemp seeds: Boosting anti-inflammatory and immune responses through Lactiplantibacillus plantarum probiotic fermentation.

Cannabis sativa L. (hemp) seeds are increasingly recognized as a promising food source rich in phytochemicals that support inflammatory and immunological reactions. This study investigates whether fermentation with Lactiplantibacillus plantarum can further enhance these functional properties, paving the way for hemp seeds to be developed into potent functional food ingredients. Aqueous, 70% ethanol, and ethyl acetate extracts from both L. plantarum-fermented (FHS) and unfermented hemp seeds (HS) were evaluated for their anti-inflammatory activities using cell-based assays. The 70% ethanol extract of FHS exhibited marked inhibitory effects on cytokines, including TNF-α, IL-1β, and IL-10, with fermentation significantly enhancing these effects by 25%, 39.3%, and 29.6%, respectively, compared to the unfermented extracts. Additionally, mRNA expression analysis confirmed the strong immunomodulatory potential of the fermented extracts. Intracellular metabolomic analysis revealed that the 'antifolate resistance', 'nicotine addiction', 'aminoacyl-tRNA biosynthesis', and 'D-amino acid metabolism' are highlighted in the reasons for this enhancement. Furthermore, FHS significantly prolonged the survival of C. elegans exposed to pathogens, with gene expression analysis indicating modulation of the innate immune system via regulation of genes such as gcs-1, lys-1, dbl-1, pmk-1, elt-2, and dod-22. A comprehensive metabolomic and correlation analysis identified five novel bioactive peptides (AAELIGVP, AAVPYPQ, VFPEVAP, DVIGVPLG, PVPKVL) and bioactive acids (indoleacetic acid and homovanillic acid) that were enriched during fermentation, which are strongly linked to the enhanced anti-inflammatory and immunomodulatory effects observed. These findings suggest that L. plantarum-fermented hemp seeds hold significant promise as functional ingredients in anti-inflammatory and immunomodulatory food products, with potential applications in health and wellness industries.

Study of cathelicidin (LL-37) immunoexpression in the skin of vitiligo patients.

Vitiligo is a pigmentary disorder acquired and caused by the loss or destruction of melanocytes from the epidermis. There is strong proof that vitiligo is mainly an autoimmune disease. Cathelicidin (LL37), an antimicrobial polypeptide, is an important part of the innate immune system and has a role in different skin autoimmune diseases. The present work aimed to study the immunoexpression of cathelicidin in the vitiligo patients' skin to elucidate its possible role in vitiligo pathogenesis. Twenty vitiligo patients and 20 controls of matched sex and age were included. A 3mm punch biopsy was taken from the non-lesional and lesional skin of each patient and controlled subjects. Each was stained with hematoxylin and eosin (H&E) and subjected to cathelicidin immunostaining detection. A significant difference was detected between the two studied groups regarding cathelicidin immunohistochemical expression (Pvalue < 0.001). The lesional immunohistochemical expression of cathelicidin showed a mean of 2.85 ± 0.67. The non-lesional immunohistochemical expression of cathelicidin showed a mean of 2.05 ± 0.51 with a statistically significant higher mean value in the patients' group than the controls (P < 0.001) which recommends that cathelicidin may play a role in the vitiligo pathogenesis. The immunohistochemical scores of the lesional and non-lesional cathelicidin levels were significantly related to the VIDA score (p < 0.001 and = 0.016, respectively) which suggests a role of cathelicidin in vitiligo activity. A significant elevation was indicated in the non-lesional cathelicidin expression, indicating that cathelicidin may be able to predict the appearance of future lesions in non-lesional skin, this requires further longitudinal studies to be confirmed.

Non-Immune Functions of Innate Immunity Acting on Physiological Processes: Insights from Drosophila

As the first line of host immune defense, innate immunity plays a key role in warding off foreign pathogens and damage. Drosophila melanogaster, as a classical model animal for more than 100 years, is an important research model for studying innate immunity. In recent years, scientists have made remarkable progress in the recognition mechanisms of innate immunity, the mechanisms of effector molecules, and the modes of their response at the cellular and tissue levels. However, the interaction between innate immunity and other physiological functions remains relatively novel and has yet to be systematically explored. Here, we first briefly discuss the link between the innate immunity system and physiological regulation, from several representative perspectives such as sleep, insulin, and brain function. Then, using Drosophila as a model, we provide an overview of the physiological system and specifically summarize the research on the regulation of physiology by innate immunity, covering sleep, lipid metabolism, development, neurodegenerative diseases, memory, feeding, lifespan, movement, and antioxidation. This review provides valuable perspectives into how innate immunity influences other physiological processes, providing a deeper understanding of the complex roles underlying innate immunity.

PRRSV-2 nsp2 Ignites NLRP3 inflammasome through IKKβ-dependent dispersed trans-Golgi network translocation.

The NLRP3 inflammasome is a fundamental component of the innate immune system, yet its excessive activation is intricately associated with viral pathogenesis. Porcine reproductive and respiratory syndrome virus type 2 (PRRSV-2), belonging to the family Arteriviridae, triggers dysregulated cytokine release and interstitial pneumonia, which can quickly escalate to acute respiratory distress and death. However, a mechanistic understanding of PRRSV-2 progression remains unclear. Here, we screen that PRRSV-2 nsp2 activates the NLRP3 inflammasome, thereby instigating a state of hyperinflammation. Mechanistically, PRRSV-2 nsp2 interacts with the nucleotide-binding and oligomerization (NACHT) domain of NLRP3, augmenting IKKβ recruitment to driving NLRP3 translocation to the dispersed trans-Golgi network (dTGN) for oligomerization. This process facilitates ASC polymerization, culminating in the activation of the NLRP3 inflammasome. In addition, the IKKβ-dependent NLRP3 translocation to the dTGN is pivotal for pseudorabies virus (PRV) and encephalomyocarditis virus (EMCV)-induced inflammatory responses. Collectively, these results elucidate a novel mechanism of NLRP3 inflammasome activation during PRRSV-2 infection, providing valuable insights into PRRSV-2 pathogenesis.

Photoresponsive Bio‐Heterojunctions Eliciting Immunogenicity to Prevent Infection Recurrence and Accelerating Chronic Wound Regeneration

AbstractDynamic therapy utilizes reactive oxygen species (ROS) to antibacterial and enhance the innate immune system to treat bacterial infections. If ROS levels are too low, the elimination of pathogens and the enhancement of innate immunity cannot be achieved. However, excess accumulation of ROS may impact intracellular glutathione (GSH) levels, hindering T cell maturation and the establishment of immune memory. Herein, a multifunctional nanofiber membrane is designed, consisting of a polymer scaffold, MXene/CeO2 bio‐heterojunctions (MX@Ce bio‐HJs), and lactate oxidase (Lox) to balance the production of ROS, for the treatment of recurrent bacterial infections. In this system, MX@Ce bio‐HJs upon near‐infrared ray (NIR) generate photodynamic therapy, while Lox responds to the wound microenvironment exert chemodynamic therapy, synergistically produce ROS to rapidly eradicate bacteria, amplify the ability of dendritic cells to recognize and present antigens of bacterial fragments, and enhance innate immunity. Without NIR, MX@Ce bio‐HJs showcase catalase‐like and superoxide dismutase‐like activities, scavenging subsequent ROS accumulation, promoting T cell maturation to form acquired immune memory, and combating recurrent bacterial infection. Such work highlights the potential to combat in situ bacterial infections and recurrent bacterial infections and inspires the development of future antibacterial therapies.

An Iron‐Polyphenol Decorated siRNA‐Encapsulated Nanomedicine Multifacetedly Promoted Macrophage Phagocytosis for Synergistic Ferroptosis‐Immunotherapy

AbstractMacrophages are vital components of the innate immune system, capable of directly engulfing tumor cells. However, tumor cells can cunningly evade recognition and phagocytosis by macrophages. In light of this, an iron‐polyphenol‐decorated poly(ethylene glycol)‐poly(lactic‐co‐glycolic acid (PEG‐PLGA) nanoparticle has been developed with efficient siRNA encapsulation (NPsiCD47@Fe‐TA) to trigger the ferroptosis in tumor cell and also elicit the macrophage‐mediated immunotherapy. The Fe‐TA (Tannic acid) shell of NPsiCD47@Fe‐TA induces the ferroptosis in tumor cell, which consequently produces oxygenated phosphatidylethanolamine 1‐steaoryl‐2‐15‐HpETE‐sn‐glycero‐3‐phosphatidylethanolamine (SAPE‐OOH) in the cell membrane and achieve the surface exposure of calreticulin (CRT). Meanwhile, the encapsulated siCD47 of NPsiCD47@Fe‐TA efficiently down‐regulates the CD47 receptor in the tumor cell membrane. The exposure of SAPE‐OOH and CRT in the cell membrane and down‐regulation of CD47 receptor remarkably promoted the phagocytosis of tumor cells by macrophage and elicited the systemic anticancer immune response. Eventually, the NPsiCD47@Fe‐TA can efficiently suppress the tumor growth. Moreover, after combination with immune checkpoint blockade (ICB) antibody, NPsiCD47@Fe‐TA remarkably inhibits tumor progress and metastasis in the cold triple‐negative 4T1 breast cancer model.

Effects of sugars on the gustatory response, longevity and realized fecundity of the egg parasitoid Trissolcus basalis

AbstractParasitoids are widely used as biological control agents to manage insect pest populations in greenhouses. To meet their energetic and nutritional requirements, adult parasitoids consume carbohydrate‐rich sources such as (extra‐)floral nectar and honeydew. However, these sugar sources are often scarce or even absent in greenhouses, compromising the effectiveness of parasitoids as biological control agents. To remedy this, artificial sugar solutions can be provided to sustain parasitoid populations. To develop an artificial sugar solution that supports parasitoids, proper selection of sugars is critical. In this study, we investigated the innate gustatory response and survival of the egg parasitoid Trissolcus basalis (Wollaston) on eight plant‐ and/or insect‐derived sugars (fructose, glucose, maltose, mannose, melezitose, rhamnose, sucrose and trehalose). Our results show that T. basalis can consume a wide range of sugars and survive on them. Five sugars (sucrose, fructose, maltose, melezitose and trehalose) increased its longevity more than seven‐fold compared to the water control. For two sugars, sucrose and trehalose, the parasitoid's realized fecundity was monitored after various time periods during which the parasitoids were fed with the sugars (1 day, 1 week, 2 weeks, and 3 weeks). The results indicate a prolonged period of parasitism compared to the water control because of a longer lifespan when fed on the sugars. Altogether, our findings provide valuable insights for the development of an artificial sugar solution that supports the performance of T. basalis, potentially enhancing the biological control of important pest species such as Nezara viridula (Linnaeus).

Unlocking Antimicrobial Peptides: In Silico Proteolysis and Artificial Intelligence-Driven Discovery from Cnidarian Omics

Overcoming the growing challenge of antimicrobial resistance (AMR), which affects millions of people worldwide, has driven attention for the exploration of marine-derived antimicrobial peptides (AMPs) for innovative solutions. Cnidarians, such as corals, sea anemones, and jellyfish, are a promising valuable resource of these bioactive peptides due to their robust innate immune systems yet are still poorly explored. Hence, we employed an in silico proteolysis strategy to search for novel AMPs from omics data of 111 Cnidaria species. Millions of peptides were retrieved and screened using shallow- and deep-learning models, prioritizing AMPs with a reduced toxicity and with a structural distinctiveness from characterized AMPs. After complex network analysis, a final dataset of 3130 Cnidaria singular non-haemolytic and non-toxic AMPs were identified. Such unique AMPs were mined for their putative antibacterial activity, revealing 20 favourable candidates for in vitro testing against important ESKAPEE pathogens, offering potential new avenues for antibiotic development.

The TLR7/9 adaptors TASL and TASL2 mediate IRF5-dependent antiviral responses and autoimmunity in mouse

Endosomal nucleic acid sensing by Toll-like receptors (TLRs) is central to antimicrobial immunity and several autoimmune conditions such as systemic lupus erythematosus (SLE). The innate immune adaptor TASL mediates, via the interaction with SLC15A4, the activation of IRF5 downstream of human TLR7, TLR8 and TLR9, but the pathophysiological functions of this axis remain unexplored. Here we show that SLC15A4 deficiency results in a selective block of TLR7/9-induced IRF5 activation, while loss of TASL leads to a strong but incomplete impairment, which depends on the cell type and TLR engaged. This residual IRF5 activity is ascribed to a previously uncharacterized paralogue, Gm6377, named here TASL2. Double knockout of TASL and TASL2 (TASLDKO) phenocopies SLC15A4-deficient feeble mice showing comparable impairment of innate and humoral responses. Consequently, TASLDKO mice fail to control chronic LCMV infection, while being protected in a pristane-induced SLE disease model. Our study thus demonstrates the critical pathophysiological role of SLC15A4 and TASL/TASL2 for TLR7/9-driven inflammatory responses, further supporting the therapeutic potential of targeting this complex in SLE and related diseases.

The success of the tumor immunotherapy: neutrophils from bench to beside

The present immune therapy was focused on the immune checkpoint blockade or Chimeric Antigen Receptor T-Cell Immunotherapy (CART) transfer, but how to activate the innate immune system to antitumor still lags out. Neutrophils are the most abundant circulating leukocytes in human, and heterogeneous neutrophils have been increasingly recognized as important players in tumor progression. They play double “edge-sward” by either supporting or suppressing the tumor growth, including driving angiogenesis, extracellular matrix remodeling to promote tumor growth, participating in antitumor adaptive immunity, or killing tumor cells directly to inhibit the tumor growth. The complex role of neutrophils in various tumors depends on the tumor microenvironment (TME) they are located, and emerging evidence has suggested that neutrophils may determine the success of tumor immunotherapy in the context of the immune checkpoint blockade, innate immune training, or drug-loaded extracellular microvesicles therapy, which makes them become an exciting target for tumor immunotherapy, but still with challenges. Here, we summarize the latest insights on how to activate neutrophils in antitumor immunity and discuss the advances of neutrophil-targeted immunotherapy strategies.

Recent Advances on Immunity and Hypertension: The New Cells on the Kidney Block.

Over the last 50 years, contribution of the immune system has been identified in the development of hypertension and renal injury. Both human and experimental animal models of hypertension have demonstrated that innate and adaptive immune cells, along with their cytokines and chemokines, modulate blood pressure fluctuations and end organ renal damage. Numerous cell types of the innate immune system, specifically monocytes, macrophages, and dendritic cells present antigenic peptides to T cells promoting inflammation and the elevation of blood pressure. These T cells and other adaptive immune cells, migrate to vascular and tubular cells of the kidney and promote end-organ fibrosis, damage, and ultimately hypertensive injury. Through the development of high throughput screening, novel renal and immune cell subsets have been identified as possible contributors and regulators of renal injury and hypertension. In this review, we will consider classical immunological cells and their contribution to renal inflammation, and novel cell subsets, including renal stromal cells, that could potentially shed new light on renal injury and hypertension. Lastly, we will discuss how interorgan inflammation contributes to the development of hypertension and hypertension-related multi-organ damage, and the clinical implications of the immunological components of renal injury and hypertension.

Bacterial expression, purification and characterization of the human Dectin-1 lectin domain for structural and functional studies.

Dectin-1 (CLEC7A), a C-type lectin-like receptor that recognizes β-1,3 glucans, has a key role in the innate immune system. While the lectin domain of mouse Dectin-1 has been solubilized and refolded from inclusion bodies in Escherichia coli, similar refolding of the human Dectin-1 lectin domain is hindered by the formation of misfolded multimers with aberrant intermolecular disulfide bonds. The aim of this study was to develop a method for the large-scale production of the human Dectin-1 lectin domain. Based on a protocol for the murine domain, the human Dectin-1 lectin domain was expressed as a fusion protein with Protein G B1, a solubility-enhancing tag. The refolding and purification conditions were then optimized by testing a range of buffers with and without Ca2+ ions. The inclusion of 1 mM Ca2+ ions in both the refolding and purification buffers resulted in high yields of a monomeric form of the human Dectin-1 lectin. The resulting recombinant protein was demonstrated to be functional, showing specific binding to the β-glucan laminarin as verified by thermal shift assays, gel filtration chromatography and NMR. Furthermore, NMR experiments revealed that the human Dectin-1 lectin domain binds Ca2+ ions. The recombinant protein will support structural biology studies to clarify differences in β-glucan binding specificity between human and mouse Dectin-1, and to explore the effects of mutations on the functionality of human Dectin-1.

Endocrine and molecular regulation of seasonal avian immune function.

Birds have evolved seasonal adaptations in multiple aspects of the innate and adaptive immune systems. Seasonal immunological adaptations are crucial for survival in harsh environmental conditions and in response to increased prevalence of acute and chronic diseases. Similar to other vertebrates, birds exhibit remarkable plasticity in cytokine production, chemotaxis, phagocytosis and inflammation across the year. In this review, we provide a comparative perspective on seasonal rhythms in bird immune function. We describe advances in our understanding of annual changes in immune cells and responses to innate and adaptive immune challenges. Then, the role of glucocorticoids, sex steroids, thyroid hormones (THs) and melatonin to act as immunomodulators is described. We then discuss the impact of a major and emerging disease, the high pathogenicity avian influenza, as one of the most critical seasonal diseases with significant implications for poultry and wild bird populations. The review identifies the need to enhance our knowledge of annual rhythms in immune cells and tissues in birds, at molecular, cellular and hormonal levels across the year. Moreover, there is a significant absence of information on sex-specific seasonal variation in immune function. Understanding seasonal immune system dynamics will aid in addressing the negative impacts of pathogenic diseases, minimize global economic losses and aid conservation efforts.This article is part of the Theo Murphy meeting issue 'Circadian rhythms in infection and immunity'.

Modeling Innate Immunity Causing Chronic Inflammation and Tissue Damage

Mathematical models of immune responses have traditionally focused on adaptive immunity and pathogen-immune dynamics. However, recent advances in immunology have highlighted the critical role of innate immunity. In response to physical damage or pathogen attacks, innate immune cells circulating throughout the body rapidly migrate from blood vessels and accumulate at the site of injury, triggering inflammation. These cells engulf, break down, and eliminate pathogens. This innate immune response occurs much faster than adaptive immune responses, which require time for cell activation and proliferation. While inflammation helps eliminate pathogens, it can sometimes lead to chronic inflammation by triggering excessive immune responses, ultimately causing tissue damage. In this study, we examine a simple dynamical model of innate immunity. The analysis indicates that when an infection occurs, it triggers inflammation, which activates the innate immune system and initiates the activation cycle. Consequently, pathogens may be eradicated, leaving behind persistent chronic inflammation. Alternatively, the pathogens may not be eradicated, with their abundance either stabilizing at a positive level or oscillating indefinitely. The dynamics exhibit both transcritical and Hopf bifurcations. When innate immunity is activated in the absence of inflammation, pathogens are eradicated more easily, and the likelihood of oscillations in inflammation, immune responses, and pathogen abundance is reduced.

Investigation of genes expression of the JAK/STAT signalling pathway and AMPs in the presence of Borrelia spirochetes in Ixodes ricinus

Multicellular animals need to control the spread of invading pathogens. This is a particular challenge for blood-feeding vectors such as ticks, which ingest large amounts of blood potentially laden with harmful microorganisms. Ticks have a basic innate immune system and protect themselves from infection through innate immune responses involving pathways such as Janus kinase (JAK) or the signalling transducer activator of transcription (STAT). Direct antimicrobial defence occurs through the rapid synthesis of numerous antimicrobial agents including antimicrobial peptides (AMPs). The tick Ixodes ricinus is one of the main vectors of the Lyme disease pathogen, the spirochete Borrelia burgdorferi sensu lato. Data suggest that the JAK/STAT signalling pathway controls the expression of AMPs and regulates the infection of the pathogen in the tick body. The innate immune system during the off-host period keeps the level of spirochete infection in check. Spirochetes may influence the innate immune response in ticks. Therefore, the aim of this study was to analyse the expression of the genes related to the JAK/STAT pathway and selected AMPs in questing ticks in which B. burgorferi s.l. was detected. In the ticks infected with spirochetes, overexpression of genes related to the JAK/STAT signalling pathway was observed in the case of STAM and SOCS genes. AMPs genes such as def1, ric, lzs were overexpressed with different expression patterns. The results obtained suggest that AMPs may be involved in infection management in ticks.