First Line Of Defense Research Articles

D-sodium lactate promotes the activation of NF-κB signaling pathway induced by lipopolysaccharide via histone lactylation in bovine mammary epithelial cells.

Lactate is a glycolytic end product that is further metabolized as an energy source. This end product has been associated with certain diseases, including sepsis and tumors, and it can regulate the transition of macrophages to an anti-inflammatory state. This study aimed to explore the effects of lactate on the inflammatory responses of mammary gland epithelial cells, which constitute the first line of defense against pathogens in mammary glands. Bovine mammary epithelial cells (BMECs) were challenged with lipopolysaccharide (LPS) in the presence or absence of D-sodium lactate (D-nala). LPS exposure increased the concentration of lactate both inside and outside the cells. Further, inhibiting glycolysis diminished the LPS-induced production of proinflammatory cytokines. Treatment with LPS, exogenous D-nala, and their combination upregulated the expression levels of MCT1, increased the intracellular levels of lactate and histone H3 lysine 18 lactylation (H3K18la), and activated the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling pathway. The lactylation of H3K18 was mediated by p300/CBP. The p300/CBP inhibitor C646 decreased the level of H3K18la, reversing the activation of the NF-κB signaling pathway and release of proinflammatory cytokines. Therefore, LPS increased the intracellular level of lactate by upregulating MCT1 and glycolysis. D-nala exacerbated the LPS-induced inflammatory responses in BMECs. Moreover, intracellular lactate enhanced the activation of the NF-κB signaling pathway through the p300/CBP-mediated lactylation of H3K18. Thus, the findings of this study expand our understanding of lactate function in immune regulation.

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.

Novel vaccine strategies to induce respiratory mucosal immunity: advances and implications.

Rapid advances in vaccine technology are becoming increasingly important in tackling global health crises caused by respiratory virus infections. While traditional vaccines, primarily administered by intramuscular injection, have proven effective, they often fail to provide the broad upper respiratory tract mucosal immunity, which is urgently needed for first-line control of respiratory viral infections. Furthermore, traditional intramuscular vaccines may not adequately address the immune escape of emerging virus variants. In contrast, respiratory mucosal vaccines developed using the body's mucosal immune response mechanism can simultaneously establish both systemic and mucosal immunity. This dual action effectively allows the respiratory mucosal immune system to function as the first line of defense, preventing infections at the entry points. This review highlights the efficacy of respiratory mucosal vaccines, including innovative delivery methods such as nasal and oral formulations, in enhancing local and systemic immune barriers. Notably, respiratory mucosal vaccines offer potential advantages in protecting against emerging virus variants and maintaining long-term and multidimensional immune memory in the upper respiratory tract. In addition, a combination of intramuscular and respiratory mucosal delivery of vaccines largely improves their coverage and effectiveness, providing valuable insights for future vaccine development and public inoculation strategies.

Long non-coding RNA MMTP mediates necroptosis in alveolar macrophages during Mycoplasma hyopneumoniae infection by enhancing TNF-α transcription.

Mycoplasma hyopneumoniae (M. hyo), a major respiratory pathogen in swine, causes chronic respiratory diseases characterized by severe lung inflammation. Alveolar macrophages, which serve as the first line of defense in the respiratory immune system, undergo necroptosis in response to M. hyo infection. This form of programmed cell death amplifies pulmonary inflammation and leads to impaired lung function, yet the precise molecular mechanisms remain poorly understood. Long non-coding RNAs (lncRNAs), known for their regulatory roles in transcriptional and epigenetic processes, have been linked to various inflammatory and infectious diseases. In this study, we identified a novel lncRNA, lncRNA-MMTP, as a critical regulator of necroptosis during M. hyo infection. Mechanistically, lncRNA-MMTP interacts with the transcription factor TFII-I to enhance c-Fos promoter activity, leading to increased transcription of TNF-α and activation of the RIPK1/RIPK3/MLKL necroptotic pathway. Importantly, knockdown of lncRNA-MMTP or inhibition of TFII-I significantly reduced TNF-α levels and necroptosis in alveolar macrophages. These findings not only elucidate a new molecular pathway underlying M. hyo-induced lung inflammation but also suggest potential therapeutic targets for managing pathogen-induced inflammatory responses in the respiratory system.

Nucleotide analogues and mpox: Repurposing the repurposable.

While the COVID-19 crisis is still ongoing, a new public health threat has emerged with recent outbreaks of monkeypox (mpox) infections in Africa. Mass vaccination is not currently recommended by the World Health Organization (WHO), and antiviral treatments are yet to be specifically approved for mpox, although existing FDA-approved drugs (Tecovirimat, Brincidofovir, and Cidofovir) may be used in severe cases or for immunocompromised patients. A first-line of defense is thus drug repurposing, which was heavily attempted against SARS-CoV-2 - albeit with limited success. This review focuses on nucleoside analogues as promising antiviral candidates for targeting of the viral DNA-dependent DNA polymerase. In contrast to broad-spectrum screening approaches employed for SARS-CoV-2, we emphasize the importance of understanding the structural specificity of viral polymerases for rational selection of potential candidates. By comparing DNA-dependent DNA polymerases with other viral polymerases, we highlight the unique features that influence the efficacy and selectivity of nucleoside analogues. These structural insights provide a framework for the preselection, repurposing, optimization, and design of nucleoside analogues, aiming to accelerate the development of targeted antiviral therapies for mpox and other viral infections.

State of the Art and Emerging Technologies in Vaccine Design for Respiratory Pathogens.

In this review, we present the efforts made so far in developing effective solutions to prevent infections caused by seven major respiratory pathogens: influenza virus, respiratory syncytial virus (RSV), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Bordetella pertussis, Streptococcus pneumoniae (pneumococcus), Mycobacterium tuberculosis, and Pseudomonas aeruginosa. Advancements driven by the recent coronavirus disease 2019 (COVID-19) crisis have largely focused on viruses, but effective prophylactic solutions for bacterial pathogens are also needed, especially in light of the antimicrobial resistance (AMR) phenomenon. Here, we discuss various innovative key technologies that can help address this critical need, such as (a) the development of Lung-on-Chip ex vivo models to gain a better understanding of the pathogenesis process and the host-microbe interactions; (b) a more thorough investigation of the mechanisms behind mucosal immunity as the first line of defense against pathogens; (c) the identification of correlates of protection (CoPs) which, in conjunction with the Reverse Vaccinology 2.0 approach, can push a more rational and targeted design of vaccines. By focusing on these critical areas, we expect substantial progress in the development of new vaccines against respiratory bacterial pathogens, thereby enhancing global health protection in the framework of the increasingly concerning AMR emergence.

Airway Basal Stem Cells Inflammatory Alterations in COVID-19 and Mitigation by Mesenchymal Stem Cells.

SARS-CoV-2 infection and the resultant COVID-19 pneumonia cause significant damage to the airway and lung epithelium. This damage manifests as mucus hypersecretion, pulmonary inflammation and fibrosis, which often lead to long-term complications collectively referred to as long COVID or post-acute sequelae of COVID-19 (PASC). The airway epithelium, as the first line of defence against respiratory pathogens, depends on airway basal stem cells (BSCs) for regeneration. Alterations in BSCs are associated with impaired epithelial repair and may contribute to the respiratory complications observed in PASC. Given the critical role of BSCs in maintaining epithelial integrity, understanding their alterations in COVID-19 is essential for developing effective therapeutic strategies. This study investigates the intrinsic properties of BSCs derived from COVID-19 patients and evaluates the modulatory effects of mesenchymal stem cells (MSCs). Through a combination of functional assessments and transcriptomic profiling, we identified key phenotypic and molecular deviations in COVID-19 patient-derived BSCs, including goblet cell hyperplasia, inflammation and fibrosis, which may underlie their contribution to PASC. Notably, MSC co-culture significantly mitigated these adverse effects, potentially through modulation of the interferon signalling pathway. This is the first study to isolate BSCs from COVID-19 patients in the Chinese population and establish a COVID-19 BSC-based xenograft model. Our findings reveal critical insights into the role of BSCs in epithelial repair and their inflammatory alterations in COVID-19 pathology, with potential relevance to PASC and virus-induced respiratory sequelae. Additionally, our study highlights MSC-based therapies as a promising strategy to address respiratory sequelae and persistent symptoms.

Candidiasis: Insights into Virulence Factors, Complement Evasion and Antifungal Drug Resistance

Invasive fungal infections constitute a substantial global health burden, with invasive candidiasis representing approximately 70% of reported cases worldwide. The emergence of antifungal resistance among Candida species has further exacerbated this challenge to healthcare systems. Recent epidemiological studies have documented a concerning shift towards non-albicans Candida species, exhibiting reduced antifungal susceptibility, in invasive candidiasis cases. The complement system serves as a crucial first-line defence mechanism against Candida infections. These fungal pathogens can activate the complement cascade through three conventional pathways—classical, lectin, and alternative—in addition to activation through the coagulation system. While these pathways are initiated by distinct molecular triggers, they converge at C3 convertase formation, ultimately generating biologically active products and the membrane attack complex. Candida species have evolved sophisticated mechanisms to evade complement-mediated host defence, including the masking of cell wall components, proteolytic cleavage and inhibition of complement proteins, recruitment of complement regulators, and acquisition of host proteins. This review examines the intricate interplay between Candida species and the host complement system, with emphasis on complement evasion strategies. Furthermore, we highlight the importance of exploring the crosstalk between antifungal resistance and immune evasion strategies employed by Candida species. Understanding these interactions may facilitate the development of novel therapeutic approaches and strategies to overcome treatment failures in Candida species infections.

The Role of Innate Immunity in Healthy Aging Through Antimicrobial Peptides.

In a super-aging society, the increase in the elderly population is closely tied to a rise in infectious diseases due to factors such as weakened immune systems and decreased vaccine efficacy in older adults. Various opportunistic pathogens commonly encountered in everyday life can cause infections and diseases when an individual's immune defence is weakened due to aging. These factors underscore the importance of preventive measures against pathogenic infections and the aging of immune systems in the elderly. The immune response acts as the defence mechanism against foreign substances, including pathogens and abnormal cells. Specifically, the innate immune response is the body's first line of defence, offering a rapid and nonspecific response to pathogens. Advances in the study of innate immunity's regulatory functions in both immune and non-immune cells have broadened our understanding of innate immune responses' impact on health. This includes a focus on immune effectors like antimicrobial peptides (AMPs) and their potential implications for health and longevity. This review summarises the common principles and evolutionary adaptations of innate immunity via AMPs, in mammals and invertebrates. Especially, this review discusses the conserved mechanisms regulating AMP production and the role of AMPs in modulating aging and diseases from invertebrate to human. Therefore, it highlights the potential role of innate immunity in addressing aging through AMPs.

Living Microneedles for Intradermal Delivery of Beneficial Bacteria.

The skin, our first line of defense against external threats, combines a physical barrier and a rich microbial community. Disruptions of this community, for example, due to infectious injury, have been linked to a decrease in bacteria diversity and to mild to severe pathological conditions. Although some progress has been made in the field, possibilities/procedures for restoring the skin microbiome are still far from ideal. The objective of this study was to design and evaluate a dissolvable poly(vinyl alcohol)/polyvinylpyrrolidone microneedle (MN) patch containing live Bacillus subtilis. According to the plan, bacteria were distributed equally throughout the patch without compromising the morphology and mechanical properties of the needles. B. subtilis was successfully released from the MNs, reaching a logarithmic growth phase after 5 h. These MNs demonstrated remarkable antibacterial activity against the Gram-positive pathogenic S. pyogenes, S. aureus, and C. acnes, while the empty control MNs showed no such activity. Finally, mice were inserted with a single MN patch loaded with GFP-B. subtilis presented significantly higher total radiance efficiency (TRE) values compared to the empty-MN mice throughout the entire experiment. This concept of incorporating live, secreting bacteria within a supportive MN patch shows great promise as a bacterial delivery system, offering a potential shift from conventional pharmacological approaches to more sustainable and symbiotic therapies.

Chitosan Nanoparticles for Enhanced Immune Response and Delivery of Multi-Epitope Helicobacter pylori Vaccines in a BALB/c Mouse Model.

Background/Objectives: Helicobacter pylori is the leading cause of chronic gastritis, peptic ulcer, gastric adenocarcinoma, and mucosal-associated lymphoma. Due to the emerging problems with antibiotic treatment against H. pylori in clinical practice, H. pylori vaccination has gained more interest. Oral immunization is considered a promising approach for preventing initial colonization of this bacterium in the gastrointestinal tract, establishing a first line of defense at gastric mucosal surfaces. Chitosan nanoparticles can be exploited effectively for oral vaccine delivery due to their stability, simplicity of target accessibility, and beneficial mucoadhesive and immunogenic properties. Methods: In this study, new multi-epitope pDNA- and recombinant protein-based vaccines incorporating multiple H. pylori antigens were produced and encapsulated in chitosan nanoparticles for oral and intramuscular administration. The induced immune response was assessed through the levels of antigen-specific IgGs, secreted mucosal SIgA, and cytokines (IL-2, IL-10, and IFN-γ) in immunized BALB/C mice. Results: Intramuscular administration of both pDNA and recombinant protein-based vaccines efficiently stimulated the production of specific IgG2a and IgG1, which was supported by cytokines levels. Oral immunizations with either pDNA or recombinant protein vaccines revealed high SIgA levels, suggesting effective gastric mucosal immunization, contrasting with intramuscular immunizations, which did not induce SIgA. Conclusions: These findings indicate that both pDNA and recombinant protein vaccines encapsulated into chitosan nanoparticles are promising candidates for eradicating H. pylori and mitigating associated gastric diseases in humans.

Resolving spatially distinct phytohormone response zones in Arabidopsis thaliana roots colonized by Fusarium oxysporum.

Jasmonic acid (JA), ethylene (ET) and salicylic acid (SA) are the three major phytohormones coordinating plant defense responses, and all three are implicated in the defense against the fungal pathogen Fusarium oxysporum. However, their distinct modes of action and possible interactions remain unknown, in part because all spatial information on their activity is lacking. Here, we set out to probe this spatial aspect of plant immunity by using live-microscopy with newly developed fluorescence-based transcriptional reporter lines. We have created a GreenGate vector collection of Plant Immune system Promoters (GG-PIPs) that allow us to image local activation of immune pathways with single-cell resolution. Using this system, we demonstrate that SA and JA act spatially separate from each other in distinct sets of root cells neighboring the fungal colonization site, while ET contributes to both sets. SA & ET induce the hypersensitive response as a first line of defense, while JA & ET govern active defense against the pathogen in a separate, second line of defense. Such an approach to resolve the plant's immune responses on an individual cell level has been lacking, and this work demonstrates that this microscopy-based approach can contribute to understanding plant immune responses in detail.

IgA class switching enhances neutralizing potency against SARS-CoV-2 by increased antibody hinge flexibility.

IgA antibodies are critical components of the mucosal immune barrier, providing essential first-line defense against viral infections. In this study, we investigated the impact of antibody class switching on neutralization efficacy by engineering recombinant antibodies of different isotypes (IgA1, IgG1) with identical variable regions from SARS-CoV-2 convalescent patients. A potent, broad-spectrum neutralizing monoclonal antibody CAV-C65 exhibited a ten-fold increase in neutralization potency upon switching from IgG1 to IgA1 monomer. Structural analysis revealed that this antibody binds to two adjacent receptor binding domains on the spike protein. Enhanced neutralization by IgA1 was attributed to the combined effects of increased affinity, unique hinge region properties, and potential cross-linking of viral particles. Inhaled CAV-C65 IgA1 demonstrated prophylactic efficacy against lethal SARS-CoV-2 infection in hACE2 mice. These findings highlight the pivotal role of IgA in antiviral immunity and inform the development of IgA-based therapeutics.

Fun in the sun: ribosomes defend against UV irradiation.

The concept that ribosomes are sensors of translational distress has sparked significant interest, although much of the research has been conducted in vitro. A new study by Vind et al. provides in vivo evidence that the ribotoxic stress response (RSR) serves as the first line of defense against ultraviolet (UV) radiation.

Computational and experimental approaches to explore defense related enzymes conferring resistance in Fusarium infected chilli plants by regulating plant metabolism through nutritional products.

Nutritional status being the first line of defense for host plants, determines their susceptibility or resistance against invading pathogens. In recent years, the applications of plant nutrient related products have been documented as one of the best performers and considered as alternatives or/and supplements in plant disease management compared to traditional chemicals. However, knowledge about application of plant nutrient related products for the management of destructive fungal pathogen Fusarium oxysporum f.sp. capsici and their impact on the components of the antioxidant defense system, especially in chilli plants, still needs to be discovered. Therefore, in this current study, we aimed to evaluate two nutrient fertilizers viz. Krystafeed and Micro Plus at three different concentrations by soil drenching method for their effects against the Fusarium wilt of chilli and investigate the components of the antioxidant defense system of chilli plants. Correlation and computational analysis on the components of antioxidant defense system in various pathways were performed to predict the suitable binding sites of mineral ions. Results indicated that the combination of Krystafeed and Micro Plus was found the most effective with (27.01, 26.59%) disease incidence, followed by Micro Plus (29.56, 32.35%) and Krystafeed (38.21, 41.15%), both in greenhouse and field conditions, respectively. Moreover, the combination of Krystafeed and Micro Plus significantly increased the concentration of SOD (27.53, 108.96)%, POD (37.29, 45.65)%, CAT (19.33, 95.33)%, H2O2 (22.13, 118.98)%, TPC (27.39, 17.37)%, chlorophyll a (21.80, 35.74)%, chlorophyll b (57.57, 18.25)%, total chlorophyll (30.21, 19.83)%, Tocopherol (13.08, 33.66)%, TrxR (5.03, 36.56)%, MDA (13.84, 54.79)%, ascorbate (4.72, 17.28)%, Proline (5.94, 59.31)%, and phytoalexin (Capsidiol) (11.33, 55.08)% in the treated plants of resistant and susceptible chilli varieties, respectively, as compared to the untreated plants. Pearson's correlation heat-map analysis showed that all the enzymes of antioxidant defense system were found positively correlated with each other. It is concluded that the improvement of crop resistance by the application of plant nutrient related products may be viable alternatives to synthetic chemicals for managing Fusarium wilt disease of chilli and potentially other pathogens.

Iron improves the antiviral activity of NK cells.

Natural killer (NK) cells are innate immune cells that play a crucial role as a first line of defense against viral infections and tumor development. Iron is an essential nutrient for immune cells, but it can also pose biochemical risks such as the production of reactive oxygen species. The importance of iron for the NK cell function has gained increasing recognition. We have previously shown that NK cells require iron to efficiently eliminate virus-infected target cells; however, the impact of nutritional iron deficiency on NK cell function and the therapeutic benefits of iron supplementation remain unclear. Here, we demonstrate that diet-related low iron levels lead to increased retroviral loads due to functional NK cell impairment, while iron supplementation enhances NK cell proliferation, as well as their cytotoxic efficacy. Notably, iron-treated NK cells exhibited significant metabolic changes, including mitochondrial reorganization. Interestingly, although iron supplementation decreased the NK cell's cytokine production, it significantly improved NK cell degranulation and the expression of cytotoxicity-associated proteins. These findings highlight the critical role of iron in maintaining NK cell immunity and suggest that iron supplementation may hold therapeutic potential for supporting the treatment of viral infections and immunodeficiency disorders.

DAMPs, PAMPs, NLRs, RIGs, CLRs and TLRs - Understanding the Alphabet Soup in the Context of Bone Biology.

The purpose of this review is to summarize the current understanding of cell-autonomous innate immune pathways that contribute to bone homeostasis and disease. Germ-line encoded pattern recognition receptors (PRRs) are the first line of defense against danger and infections. In the bone microenvironment, PRRs and downstream signaling pathways, that mount immune defense, interface intimately with the core cellular processes in bone cells to alter bone formation and resorption. The role of PRR engagement on bone remodeling has been best described as a result of activated macrophages secreting effector molecules that reshape the characteristics of bone-resident cells. However, it is being increasingly recognized that local bone resident-cells like osteoclasts and osteoblasts possess an arsenal of PRRs. The engagement of these PRRs by stimuli in the bone niche can drive cell-autonomous (aka cell-intrinsic) responses that, in turn, impact bone-remodeling dramatically, irrespective of immune cell effectors. Indeed, this vital role for cell-autonomous innate immune responses is evident in how reduced PRR activity within osteoclast progenitors correlates with their reduced differentiation and abnormal bone remodeling. Further, cell-intrinsic PRR activity has now been shown to influence the behavior of osteoblasts, osteocytes and other local immune/non-immune cell populations. However, distinct PRR families have varying impact on bone homeostasis and inflammation, emphasizing the importance of investigating these different nodes of innate immune signaling in bone cells to better identify how they synergistically and/or antagonistically regulate bone remodeling in the course of an immune response. Innate immune sensing within bone resident cells is a critical determinant for bone remodeling in health and disease.

Omics-Based Interaction Analysis Reveals Interplay of Chemical Pollutant (Ozone) and Photoradiation (UVSSR) Stressors in Skin Damage.

The skin acts as the first line of defense against various environmental stressors, such as solar ultraviolet radiation, visible light, pollution particles and ozone. Simultaneous exposure to different stressors is common in everyday life but has been less studied than exposure to single stressors. Herein, the combined effects of a chemical pollutant (ozone) and a UV radiation stressor (UVSSR) were investigated on a 3D pigmented living skin equivalent model. Our results demonstrate that skin lightness (L* value) was significantly decreased by exposure to either UVSSR or ozone alone and that co-exposure to UVSSR and ozone further exacerbated surface darkness, suggesting that these stressors had a significant joint effect. Conventional differential expression analysis showed that, among exposure groups, co-exposure dysregulated the most genes, followed by ozone and UVSSR alone. Omics-based interaction framework (OBIF) analysis showed that most interactive genes following ozone and UVSSR exposure displayed a cooperative effect and had functions related to the skin barrier; these genes with synergistic effects were enriched in biological pathways such as the chronic inflammatory response and the apoptotic signaling pathway. In summary, exposure to ozone in combination with UVSSR showed a joint effect on UVSSR-induced phenotypic changes in the skin; the underlying mechanism was determined by using transcriptome analysis, showing the additive impacts of ozone on UVSSR-induced skin damage, such as cellular stress and inflammatory responses. These findings shed light on how ozone exacerbates UVSSR damage and indicate that the synergistic response genes identified using OBIF analysis may drive the progression of skin damage induced by chemical/photoradiation stress co-exposure.

A gut instinct for childhood leukemia prevention: microbiome-targeting recommendations aimed at parents and caregivers.

Childhood leukemia accounts for 30% of all pediatric cancer cases with acute lymphoblastic leukemia (ALL) being the most common subtype. Involvement of the gut microbiome in ALL development has recently garnered interest due to an increasing recognition of the key contribution the microbiome plays in maintaining the immune system's homeostatic balance. Commensal gut microbiota provide a first line of defense against different pathogens and gut microbiome immaturity has been implicated in ALL pathogenesis. Several environmental factors such as nutrition, mode of delivery, breastfeeding and, early social or livestock contacts are known to alter the composition of the gut microbiota. Variations in these factors influence the risk of childhood leukemia onset. This review aims to elucidate the risk factors influencing microbial composition in the context of childhood ALL. The link between gut microbiome diversity and childhood ALL offers the opportunity to develop risk-reducing strategies that can be communicated to a broad target population of (future) parents and caregivers for childhood leukemia prevention. Here, we summarize evidence on how promoting a diverse gut microbiome in newborns through simple measures such as increasing social contacts early in life may decrease the risk of developing ALL in these children later on.

Altered microRNA Expression Correlates with Reduced TLR2/4-Dependent Periodontal Inflammation and Bone Resorption Induced by Polymicrobial Infection.

Periodontitis is the most prevalent chronic immuno-infectious multispecies dysbiotic disease of the oral cavity. The Toll-like receptors (TLR) provide the first line of defense, one of the best-characterized pathogens-detection systems and play a vital role in recognizing multiple microbial products. Multispecies infection with periodontal bacteria S. gordonii, F. nucleatum, P. gingivalis, T. denticola, and T. forsythia induced gingival inflammation, alveolar bone resorption (ABR) and miRNA expression in the C57BL6/J wild-type mice and whereas infection did not increase significant ABR in the TLR2/4 deficient mice. Among the 15 miRNAs investigated, miR-146a - 5p, miR-15a-5p were upregulated in wild-type and TLR2 -/- mice and miR-146a-5p, miR-30c-5p, let-7c-5p were upregulated in the TLR4 -/- mice compared to sham-infected controls. Notably, inflammatory miRNA miR-146a-5p was upregulated uniquely among the three different infection groups. The upregulated miRNAs (miR-146a, miR-15-a-5p, let-7c-5p) and downregulated miRNAs could be markers for TLRs-mediated induction of periodontitis.