Antimicrobial Peptides In Response Research Articles

Enhanced Antimicrobial Peptide Response Following Bacillus Calmette-Guerin Vaccination in Elderly Individuals.

Antimicrobial peptides are an important component of host defense against Mycobacterium tuberculosis. However, the ability of BCG to induce AMPs as part of its mechanism of action has not been investigated in detail. We investigated the impact of Bacillus Calmette-Guerin (BCG) vaccination on circulating plasma levels and TB-antigen stimulated plasma levels of AMPs in a healthy elderly population. We assessed the association of AMPs, including Human Beta Defensin 2 (HBD-2), Human Neutrophil Peptide 1-3 (HNP1-3), Granulysin, and Cathelicidin (LL37), in circulating plasma and TB-antigen stimulated plasma (using IGRA supernatants) at baseline (pre-vaccination) and at Month 1 and Month 6 post vaccination. Post BCG vaccination, both circulating plasma levels and TB-antigen stimulated plasma levels of AMPs significantly increased at Month 1 and Month 6 compared to pre-vaccination levels in the elderly population. However, the association of AMP levels with latent TB (LTB) status did not exhibit statistical significance. Our findings indicate that BCG vaccination is linked to heightened circulating levels of AMPs in the elderly population, which are also TB-antigen-specific. This suggests a potential mechanism underlying the immune effects of BCG in enhancing host defense against TB.

The ncRNA-mediated regulatory networks of defensins and lysozymes in Riptortus pedestris: involvement in response to gut bacterial disturbances.

Insects depend on humoral immunity against intruders through the secretion of antimicrobial peptides (AMPs) and immune effectors via NF-κB transcription factors, and their fitness is improved by gut bacterial microbiota. Although there are growing numbers of reports on noncoding RNAs (ncRNAs) involving in immune responses against pathogens, comprehensive studies of ncRNA-AMP regulatory networks in Riptortus pedestris, which is one of the widely distributed pests in East Asia, are still not well understood under feeding environmental changes. The objective of this study employed the whole-transcriptome sequencing (WTS) to systematically identify the lncRNAs (long noncoding RNA) and circRNAs (circular RNA) and to obtain their differential expression from the R. pedestris gut under different feeding conditions. Functional annotation indicated that they were mainly enriched in various biological processes with the GO and KEGG databases, especially in immune signaling pathways. Five defensin (four novel members) and eleven lysozyme (nine novel members) family genes were identified and characterized from WTS data, and meanwhile, phylogenetic analysis confirmed their classification. Subsequently, the miRNA-mRNA interaction network of above two AMPs and lncRNA-involved ceRNA (competing endogenous RNA) regulatory network of one lysozyme were predicted and built based on bioinformatic prediction and calculation, and the expression patterns of differentially expressed (DE) defensins, and DE lysozymes and related DE ncRNAs were estimated and selected among all the comparison groups. Finally, to integrate the analyses of WTS and previous 16S rRNA amplicon sequencing, we conducted the Pearson correlation analysis to reveal the significantly positive or negative correlation between above DE AMPs and ncRNAs, as well as most changes in the gut bacterial microbiota at the genus level of R. pedestris. Taken together, the present observations provide great insights into the ncRNA regulatory networks of AMPs in response to rearing environmental changes in insects and uncover new potential strategies for pest control in the future.

Hepcidin and dicentracin peptides show preventive antiviral applications against NNV infection in European sea bass through immunomodulatory roles

Aquaculture is an extremely prosperous market threatened by pathogen outbreaks, including viruses as nodavirus (NNV), which infect fish species with special interest in trading such as European sea bass. Antimicrobial peptides (AMPs) might constitute potential antiviral agents, which had been previously evaluated in fish with positive prospects, based on their properties as immunomodulators or directly killing pathogens. In this line, we aimed to evaluate this dual role by administering two European sea bass synthetic AMPs (Hamp or Dic) prior to NNV infection. Both treatments conferred partial protection against NNV though viral replication and load were not affected. Both AMPs elicited, prior to infection, AMP response and leukocyte mobilization whilst down-regulated pro-inflammatory markers. Upon infection, Hamp and Dic peptides abrogated the inflammatory response provoked by NNV as well as avoid NNV-induced disturbance of the leucocyte distribution in the brain, mainly neutrophils, macrophages and CD8+ T cells. This study points that preventive applications of synthetic Hamp and Dic peptides exert their antiviral actions through the immunomodulatory role and not by a direct action of the antimicrobial on NNV. This work opens the door to the use of AMPs as potential prophylactic tools against NNV as well as immunostimulant in fish farms.

Hirudomacin: a Protein with Dual Effects of Direct Bacterial Inhibition and Regulation of Innate Immunity.

Hirudomacin (Hmc) belongs to the Macin family of antimicrobial peptides, which can be used for bactericidal purposes in vitro by cleaving cell membranes. Although the Macin family has broad-spectrum antibacterial properties, few studies have been reported on bacterial inhibition by enhancing innate immunity. To further investigate the mechanism of Hmc inhibition, we chose the classical innate immune model organism Caenorhabditis elegans as the study subject. In this investigation, we found that Hmc treatment directly reduced the number of Staphylococcus aureus and Escherichia coli in the intestine of infected wild-type nematodes and infected pmk-1 mutant nematodes. Hmc treatment significantly prolonged the life span of infected wild-type nematodes and increased the expression of antimicrobial effectors (clec-82, nlp-29, lys-1, lys-7), and Hmc treatment still significantly increased the expression of antimicrobial effectors (clec-82, nlp-29, lys-7) in wild-type nematodes in the absence of bacterial stimulation. In addition, Hmc treatment significantly increased the expression of key genes of the pmk-1/p38 MAPK pathway (pmk-1, tir-1, atf-7, skn-1) under both infected and uninfected conditions but failed to increase the life span of infected pmk-1 mutant nematodes as well as the expression of antimicrobial effector genes. Western blot results further demonstrated that Hmc treatment significantly elevated pmk-1 protein expression levels in infected wild-type nematodes. In conclusion, our data suggest that Hmc has both direct bacteriostatic and immunomodulatory effects and may upregulate antimicrobial peptides in response to infection via the pmk-1/p38 MAPK pathway. It has the potential to serve as a new antibacterial agent and immune modulator. IMPORTANCE In today's world, bacterial drug resistance is becoming increasingly serious, and natural antibacterial proteins are attracting attention because of advantages such as their diverse and complex antibacterial modes, lack of residue, and harder-to-develop drug resistance. Notably, there are few antibacterial proteins with multiple effects such as direct antibacterial and innate immunity enhancement at the same time. We believe that an ideal antimicrobial agent can be developed only through a more comprehensive and in-depth study of the bacteriostatic mechanism of natural antibacterial proteins. The significance of our study is that based on the known in vitro bacterial inhibition of Hirudomacin (Hmc), we further clarified its mechanism in vivo, which can be subsequently developed as a natural bacterial inhibitor for various applications in medicine, food, farming, and daily chemicals.

Ageing leads to reduced specificity of antimicrobial peptide responses in Drosophila melanogaster.

Evolutionary theory predicts a late-life decline in the force of natural selection, possibly leading to late-life deregulations of the immune system. A potential outcome of such deregulations is the inability to produce specific immunity against target pathogens. We tested this possibility by infecting multiple Drosophila melanogaster lines (with bacterial pathogens) across age groups, where either individual or different combinations of Imd- and Toll-inducible antimicrobial peptides (AMPs) were deleted using CRISPR gene editing. We show a high degree of non-redundancy and pathogen-specificity of AMPs in young flies: in some cases, even a single AMP could confer complete resistance. However, ageing led to drastic reductions in such specificity to target pathogens, warranting the action of multiple AMPs across Imd and Toll pathways. Moreover, use of diverse AMPs either lacked survival benefits or even accompanied survival costs post-infection. These features were also sexually dimorphic: females required a larger repertoire of AMPs than males but extracted equivalent survival benefits. Finally, age-specific expansion of the AMP-repertoire was accompanied with ageing-induced downregulation of negative-regulators of the Imd pathway and damage to renal function post-infection, as features of poorly regulated immunity. Overall, we could highlight the potentially non-adaptive role of ageing in producing less-specific AMP responses, across sexes and pathogens.

Self-Assembly of Linear, Natural Antimicrobial Peptides: An Evolutionary Perspective.

Antimicrobial peptides are an ancient and innate system of host defence against a wide range of microbial assailants. Mechanistically, unstructured peptides undergo a secondary structure transition into amphipathic α-helices, upon contact with membrane surfaces. This leads to peptide binding and removal of the membrane components in a detergent-like manner or via self-organisation into trans-membrane pores (either barrel-stave or toroidal pore) thereby destroying the microbe. Self-assembly of antimicrobial peptides into oligomers and ultimately amyloid has been mostly examined in parallel, however recent findings link diseases, such as Alzheimer's disease as an aberrant activity of a protective neuropeptide with antimicrobial activity. These self-assembled oligomers can also interact with membranes. Here, we review those antimicrobial peptides reported to self-assemble into amyloid, where supported by structural evidence. We consider their membrane activities as antimicrobial peptides and present evidence of consistent self-assembly patterns across major evolutionary groups. Trends are apparent across these groups, supporting the mounting data that self-assembly of antimicrobial peptides into amyloid should be considered as synergistic to the antimicrobial peptide response.

The colonisation of saline waters is associated with lowered immune responses in aquatic beetles

Abstract The immune response represents a suite of evolved traits that can involve energetic and evolutionary trade‐offs with other energy‐demanding and fitness‐related processes. Here, we tested the hypothesis that aquatic beetles living in inland hypersaline habitats have lower immune capacity than freshwater congeners. Phenoloxidase activity, encapsulation response and antimicrobial peptide activity were compared in freshwater/hypersaline species pairs with differing osmoregulatory capacity and cuticular waterproofing properties in the genera Nebrioporus (Dytiscidae) and Enochrus (Hydrophilidae), independent evolutionary lineages that have colonised saline media separately. Hypersaline species (N. ceresyi and E. jesusarribasi) showed significantly lower phenoloxidase activity and antimicrobial peptide responses than their freshwater relatives (N. clarkii and E. salomonis). Encapsulation responses in freshwater species also appeared to be higher than in hypersaline relatives. Our results reinforce the complex nature of immune responses and suggest that adaptation to saline environments may have involved a trade‐off between osmoregulation and investment in immune defences, but also are consistent with relaxed selection pressures on basal immune responses resulting from lower microbial infection load in saline habitats. In addition, the more resistant cuticle of species occupying such habitats may protect against the entry of parasites, reducing selection pressure on immunity. Because the evolution of salinity tolerance is associated with reduced immune capacity, saline specialists may be particularly vulnerable to the dilution of saline waters and consequent changes in pathogen communities and load following colonisation by more generalist microorganisms.

Antimicrobial Peptide Combination Can Hinder Resistance Evolution.

ABSTRACTAntibiotic-resistant microbial pathogens are becoming a major threat to human health. Therefore, there is an urgent need to develop new alternatives to conventional antibiotics. One such promising alternative is antimicrobial peptides (AMPs), which are produced by virtually all organisms and typically inhibit bacteria via membrane disruption. However, previous studies demonstrated that bacteria can rapidly develop AMP resistance. Here, we study whether combination therapy, known to be able to inhibit the evolution of resistance to conventional antibiotics, can also hinder the evolution of AMP resistance. To do so, we evolved the opportunistic pathogen Staphylococcus aureus in the presence of individual AMPs, AMP pairs, and a combinatorial antimicrobial peptide library. Treatment with some AMP pairs indeed hindered the evolution of resistance compared with individual AMPs. In particular, resistance to pairs was delayed when resistance to the individual AMPs came at a cost of impaired bacterial growth and did not confer cross-resistance to other tested AMPs. The lowest level of resistance evolved during treatment with the combinatorial antimicrobial peptide library termed random antimicrobial peptide mixture, which contains more than a million different peptides. A better understanding of how AMP combinations affect the evolution of resistance is a crucial step in order to design “resistant proof” AMP cocktails that will offer a sustainable treatment option for antibiotic-resistant pathogens.IMPORTANCE The main insights gleaned from this study are the following. (i) AMP combination treatment can delay the evolution of resistance in S. aureus. Treatment with some AMP pairs resulted in significantly lower resistance then treatment with either of the individual AMPs. Treatment with a random AMP library resulted in no detectable resistance. (ii) The rate at which resistance to combination arises correlates with the cost of resistance to individual AMPs and their cross-resistance. In particular, combinations to which the least resistance arose involved AMPs with high fitness cost of resistance and low cross-resistance. (iii) No broad-range AMP resistance evolved. Strains that evolved resistance to some AMPs typically remained sensitive to other AMPs, alleviating concerns regarding the evolution of resistance to immune system AMPs in response to AMP treatment.

Molecular Identification of Two DNA Methyltransferase Genes and Their Functional Characterization in the Anti-Bacterial Immunity of Antheraea pernyi.

Under different physiological conditions, such as microbial infection, epigenetic mechanisms regulate genes at the transcription level in living organisms. DNA methylation is a type of epigenetic mechanism in which DNA methyltransferases modify the expression of target genes. Here, we identified a full-length sequence of DNMT-1 and DNMT-2 from the Chinese oak silkworm, A. pernyi, which was highly similar to the homologous sequences of Bombyx mori. ApDNMT-1 and ApDNMT-2 have unique domain architectures of insect DNMTs, highlighting their conserved functions in A. pernyi. ApDNMT-1 and ApDNMT-2 were found to be widely expressed in various tissues, with the highest levels of expression in hemocytes, the ovary, testis, and fat bodies. To understand the biological role of these genes in microbial resistance, we challenged the fifth instar larvae of A. pernyi by administrating Gram-positive and Gram-negative bacteria and fungi. The results revealed that transcript levels of ApDNMT-1 and ApDNMT-2 were increased compared to the control group. The inhibition of these genes by a DNMTs inhibitor [5-azacytidine (5-AZA)] significantly reduced bacterial replication and larvae mortality. In addition, 5-AZA treatment modified the expression patterns of antimicrobial peptides (AMPs) in the A. pernyi larvae. Our results suggest that ApDNMT-1 and ApDNMT-2 seem to have a crucial role in innate immunity, mediating antimicrobial peptide responses against bacterial infection in A. pernyi.

Antimicrobial Peptide and Lipid Response of Alveolar Type II Model Cells to Cytokines of TH17 Signature

Abstract Mycobacterium tuberculosis (Mtb) causes ~ 10 million deaths each year worldwide. The current BCG vaccine that targets TH1 cells and anti-tuberculosis drugs have limited efficacy. Novel preventative measures are in dire need. Epithelial cells in the lungs are among the first host cells to encounter inhaled Mtb. Epithelial cells produce antimicrobial peptides (AMPs) like human beta-defensins (HBDs) and antimicrobial lipids (AMLs). Microbial products such as lipopolysaccharide (LPS), IL-1β made by macrophages, and IL-17 and IL-22 secreted by TH17 cells are all known to increase production of AMPs in epithelial cells. However, their effect on the production of AMLs is unknown. We hypothesized that TH17 cytokines increase the production of AMPs and AMLs in lung alveolar type II cells, leading to increased antimycobacterial activity. As determined by immunofluorescence, IL-17 combined with IL-22 (IL-17/22) significantly increased intracellular HBD2 in A549 cells after 48 h. Using the lipid sensitive fluoroprobes Bodipy and Nile Red, we found that IL-1β combined with LPS significantly increased intracellular neutral lipids, while IL-17/22, IL-1β/LPS, and LPS alone significantly increased neutral and polar lipid secretion after 24h stimulation. To assess the antimycobacterial effect of A549 secretions, we developed a qPCR-based assay employing Mycolicibacterium smegmatis (Ms), an avirulent model organism for Mtb, bacterial cell lysis with TRI reagent and bead beating, gDNA extraction with Direct-zol™ DNA Miniprep, SYBR Green chemistry, and 16S rRNA gene targeting primers, and testing is ongoing. This research may lead to novel vaccine approaches for Mtb based on TH17-induced antimycobacterial activity of lung epithelial cells. This research was supported by NIH R25GM061331, NIH T34GM08228, and CalStateLA Provost’s Research Restart Grant.

The Prepropalustrin-2CE2 and Preprobrevinin-2CE3 Gene from Rana chensinensis: Gene Expression, Genomic Organization and Functional Analysis of the Promoter Activity.

For amphibians, antimicrobial peptides are innate immune molecules that resist adverse external environmental stimuli. However, the regulation mechanism of antimicrobial peptide gene expression in frogs is still unclear. The two antimicrobial peptides, palustrin-2CE2 and brevinin-2CE3, are produced under external stimulation in Rana chensinensis. Using this model, we analyzed the gene structure and regulatory elements of the two antimicrobial peptide genes and explored the regulatory effects of related transcription factors on the two genes. Different stimuli such as E. coli, S. aureus, and chemical substance lipopolysaccharide (LPS) were applied to Rana chensinensis tadpoles at different developmental stages, and antimicrobial peptide expression levels were detected by RT-PCR. Bioinformatics analysis and 5'-RACE and genome walking technologies were employed to analyze the genome structure and promoter region of the antimicrobial peptide genes. With dual-luciferase reporter gene assays, yeast one-hybrid experiment and EMSA assays, we assessed the regulatory effect of the endogenous regulators of the cell on the antimicrobial peptide promoter. The transcription levels of prepropalustrin-2CE2 and preprobrevinin-2CE3 were significantly upregulated after different stimulations. Genomic structure analysis showed that both genes contained three exons and two introns. Promoter analysis indicated that there are binding sites for regulatory factors of the NF-κB family in the promoter region, and experiments showed that endogenous NF-κB family regulatory factors in frog cells activate the promoters of the antimicrobial peptide genes. Yeast one-hybrid experiment and EMSA assay demonstrated that RelA and NF-κB1 might interact with specific motifs in the prepropalustrin-2CE2 promoter. In this paper, we found that the gene expression levels of the antimicrobial peptides, palustrin-2CE2 and brevinin-2CE3, in R. chensinensis will increase under environmental stimuli, and we verified that the changes in gene expression levels are affected by the transcription factors RelA and NF-κB1. The yeast one-hybrid experiment and EMSA assay confirmed that RelA and NF-κB1 could directly interact with the frog antimicrobial peptide gene promoter, providing new data for the regulatory mechanism of antimicrobial peptides in response to environmental stimuli.

Activin and BMP Signaling Activity Affects Different Aspects of Host Anti-Nematode Immunity in Drosophila melanogaster.

The multifaceted functions ranging from cellular and developmental mechanisms to inflammation and immunity have rendered TGF-ß signaling pathways as critical regulators of conserved biological processes. Recent studies have indicated that this evolutionary conserved signaling pathway among metazoans contributes to the Drosophila melanogaster anti-nematode immune response. However, functional characterization of the interaction between TGF-ß signaling activity and the mechanisms activated by the D. melanogaster immune response against parasitic nematode infection remains unexplored. Also, it is essential to evaluate the precise effect of entomopathogenic nematode parasites on the host immune system by separating them from their mutualistic bacteria. Here, we investigated the participation of the TGF-ß signaling branches, activin and bone morphogenetic protein (BMP), to host immune function against axenic or symbiotic Heterorhabditis bacteriophora nematodes (parasites lacking or containing their mutualistic bacteria, respectively). Using D. melanogaster larvae carrying mutations in the genes coding for the TGF-ß extracellular ligands Daw and Dpp, we analyzed the changes in survival ability, cellular immune response, and phenoloxidase (PO) activity during nematode infection. We show that infection with axenic H. bacteriophora decreases the mortality rate of dpp mutants, but not daw mutants. Following axenic or symbiotic H. bacteriophora infection, both daw and dpp mutants contain only plasmatocytes. We further detect higher levels of Dual oxidase gene expression in dpp mutants upon infection with axenic nematodes and Diptericin and Cecropin gene expression in daw mutants upon infection with symbiotic nematodes compared to controls. Finally, following symbiotic H. bacteriophora infection, daw mutants have higher PO activity relative to controls. Together, our findings reveal that while D. melanogaster Dpp/BMP signaling activity modulates the DUOX/ROS response to axenic H. bacteriophora infection, Daw/activin signaling activity modulates the antimicrobial peptide and melanization responses to axenic H. bacteriophora infection. Results from this study expand our current understanding of the molecular and mechanistic interplay between nematode parasites and the host immune system, and the involvement of TGF-ß signaling branches in this process. Such findings will provide valuable insight on the evolution of the immune role of TGF-ß signaling, which could lead to the development of novel strategies for the effective management of human parasitic nematodes.

Amyloid beta’s antimicrobial properties protect elderly mice from succumbing to infection with the neurotropic parasite Toxoplasma gondii

Data suggest that amyloid beta (Aβ) is a major initiator of Alzheimer's disease (AD) and a highly conserved anti-microbial peptide. Although Aβ accumulation is thought to be detrimental to the brain as a trigger of pathology, like neuroinflammation, efforts to cure AD by clearing Aβ have failed in part because the reactivation of latent disease. Thus, more work is needed to understand how Aβ may be necessary to the brain, where the actions of the adaptive immune system are more restricted compared to other organs in the body. Using the intracellular T.gondii, we are exploring how infection impacts Aβ levels in the brain, how Aβ may combat the parasite, and whether Aβ's importance may change as organisms age.To address whether Aβ is an effective antimicrobial peptide in response to T.gondii infection, in vitro experiments were performed to determine if and how Aβ may protect against infection. Further, in vivo infection studies were performed to assess whether the presence of excess Aβ is helpful during infection with respect to age.We found that exposure to Aβ is effective at protecting cells from invasion by the parasite and those parasites replicate more slowly within cells once they do invade. In vivo, mice with excess Aβ have a lower parasite burden in the brain, indicating that Aβ may either help protect the brain from colonization by an invading pathogen or can help clear the brain of pathogens that have breached the blood-brain barrier. Further, we have found that these protective effects are only beneficial to elderly mice as aged (18mo+) mice with excess Aβ are able to survive T.gondii infection, while their WT littermates are not.These data support the idea that the Aβ could be beneficial as we age. Current work is focused on whether Aβ is toxic to T.gondii or if, as seen in viruses, Aβ traps the pathogen, making it more vulnerable to clearance by the immune system. Future work will include examining how Aβ impacts the functions of the immune system and how pathogens like T.gondii may have evolved ways to subvert the antimicrobial actions of Aβ.

The Cooperation of Bifidobacterium longum and Active Vitamin D3 on Innate Immunity in Salmonella Colitis Mice via Vitamin D Receptor.

Salmonella spp. remains a major public health problem for the whole world. Intestinal epithelial cells serve as an essential component of the mucosal innate immune system to defend against Salmonella infection. Our in vitro studies showed probiotics and active vitamin D have similar effects on innate immunity in Salmonella-infected intestinal epithelial cells, including antimicrobial peptide and inflammatory responses, to protect the host against infection while downregulating detrimental overwhelming inflammation. Hence, we investigated the synergistic effects of probiotics and active vitamin D on Salmonella colitis and translocation to liver and spleen by in vitro and in vivo studies. The Salmonella colitis model is conducted with 6–8 w/o male C57BL/6 mice: Streptomycin (20 mg/mouse p.o.)-pretreated C57BL/6 mice are mock infected with sterile PBS or infected orally with 1 × 108 CFU of a S. Typhimurium wild-type strain SL1344 for 48 h. The mice in the treated groups received 1, 25D daily (0.2 ug/25 g/d) and/or 1 × 108 CFU of probiotics, Lactobacillus rhamnosus GG (LGG) and Bifidobacterium longum (BL) by intragastric administration for 14 days. The in vivo study demonstrated the combination of probiotic Bifidobacterium longum and active vitamin D3 had the synergistic effects on reducing the severity of Salmonella colitis and body weight loss in C57BL/6 mice by reducing cecal inflammatory mIL-6, mIL-8, mTNF-α and mIL-1β mRNA responses, blocking the translocation of bacteria while enhancing the antimicrobial peptide mhBD-3 mRNA in comparison to the infection only group. However, LGG did not have the same synergistic effects. It suggests the synergistic effects of Bifidobacterium longum and active vitamin D on the antibacterial and anti-inflammatory responses in Salmonella colitis. Therefore, our in vivo studies demonstrated that the combination of probiotic Bifidobacterium longum and active vitamin D3 has the synergistic effects on reducing the severity of Salmonella colitis via the suppression of inflammatory responses, and blocking the translocation of bacteria through the enhancement of antimicrobial peptides.

Yin and Yang: A disrupted skin microbiome and an aberrant host immune response in hidradenitis suppurativa.

The skin microbiome plays an important role in maintaining skin homeostasis by controlling inflammation, providing immune education and maintaining host defense. However, in many inflammatory skin disorders the skin microbiome is disrupted. This dysbiotic community may contribute to disease initiation or exacerbation through the induction of aberrant immune responses in the absence of infection. Hidradenitis suppurativa (HS) is a complex, multifaceted disease involving the skin, innate and adaptive immunity, microbiota and environmental stimuli. Herein, we discuss the current state of HS skin microbiome research and how microbiome components may activate pattern recognition receptor (PRR) pathways, metabolite sensing pathways and antigenic receptors to drive antimicrobial peptide, cytokine, miRNA and adaptive immune cell responses in HS. We highlight the major open questions that remain to be addressed and how antibiotic therapies for HS likely influence both microbial burden and inflammation. Ultimately, we hypothesize that the two-way communication between the skin microbiome and host immune response in HS skin generates a chronic positive feed-forward loop that perpetuates chronic inflammation, tissue destruction and disease exacerbation.

Potential role of Vitamin D as an antiviral agent

Vitamin D has potential antimicrobial activity, the deficiency of which has deleterious effects on the general well-being and longevity, predisposing major public health problem worldwide. About 1 billion people have Vitamin D deficiency, which is prevalent among all ethnicities and age groups throughout the world. In addition, the incidence of antimicrobial resistance has emerged as a major threat to public health, and it is estimated to cause 10 million deaths annually by 2050 throughout the world. Vitamin D, as a mighty antimicrobial agent, may decrease the occurrence of infection through numerous pathways. Vitamin D strengthens innate immunity by modulating the production of various anti-microbial peptide (AMPs), cytokine, chemokines and interleukin responses. Vitamin D is responsible for the regulation of >200 genes, including cell proliferation, differentiation, and apoptotic genes. It acts as the key holder for modulating systemic inflammation, oxidative stress, and mitochondrial respiratory functions. Thus, a Vitamin D replete state appears to benefit most infections. As an antiviral agent, Vitamin D may constitute an inexpensive prophylactic option either by itself or as a synergistic agent during the treatment of different viral infections. The present review stipulates the importance of Vitamin D and its possible mechanisms against treating any kind of viruses. Relevant published articles were summarized by performing computerized literature searches (searches were made in PubMed/Medline, EMBASE, ScienceDirect, and Scirus) of different authentic databases using the following keywords: Vitamin D, VDR, infections, antimicrobial peptides, viruses, and COVID-19. The future for the sunshine vitamin as an antiviral agent looks brighter. More scientific proposition entailing in vitro, in vivo, or genomic studies are required to understand how important Vitamin D is against viral infections.

Mosquito defensin facilitates Japanese encephalitis virus infection by downregulating the C6/36 cell-surface antiviral protein HSC70B

Japanese encephalitis virus (JEV) is a viral zoonosis that can cause viral encephalitis, death and disability whose primary vector is the Culex mosquito. Viral infection induces a series of antimicrobial peptide responses in mosquitoes, and the effector defensin enhances JEV replication in mosquitoes. However, the underlying mechanisms by which defensin enhances JEV are not fully understood. Here, we found that mosquito defensin could downregulate the antiviral protein HSC70B and enhance virus infection in mosquitoes. The cell-surface protein HSC70B was significantly downregulated by JEV infection and defensin treatment. Low levels of HSC70B were beneficial to JEV infection in mosquitoes. Taken together, these findings show that defensin and HSC70B axis facilitates JEV infection in the mosquito.

Respiratory Effects of Exposure to Aerosol From the Candidate Modified-Risk Tobacco Product THS 2.2 in an 18-Month Systems Toxicology Study With A/J Mice.

Smoking cessation is the most effective measure for reducing the risk of smoking-related diseases. However, switching to less harmful products (modified-risk tobacco products [MRTP]) can be an alternative to help reduce the risk for adult smokers who would otherwise continue to smoke. In an 18-month chronic carcinogenicity/toxicity study in A/J mice (OECD Test Guideline 453), we assessed the aerosol of Tobacco Heating System 2.2 (THS 2.2), a candidate MRTP based on the heat-not-burn principle, compared with 3R4F cigarette smoke (CS). To capture toxicity- and disease-relevant mechanisms, we complemented standard toxicology endpoints with in-depth systems toxicology analyses. In this part of our publication series, we report on integrative assessment of the apical and molecular exposure effects on the respiratory tract (nose, larynx, and lungs). Across the respiratory tract, we found changes in inflammatory response following 3R4F CS exposure (eg, antimicrobial peptide response in the nose), with both shared and distinct oxidative and xenobiotic responses. Compared with 3R4F CS, THS 2.2 aerosol exerted far fewer effects on respiratory tract histology, including adaptive tissue changes in nasal and laryngeal epithelium and inflammation and emphysematous changes in the lungs. Integrative analysis of molecular changes confirmed the substantially lower impact of THS 2.2 aerosol than 3R4F CS on toxicologically and disease-relevant molecular processes such as inflammation, oxidative stress responses, and xenobiotic metabolism. In summary, this work exemplifies how apical and molecular endpoints can be combined effectively for toxicology assessment and further supports findings on the reduced respiratory health risks of THS 2.2 aerosol.

Diminished Systemic and Mycobacterial Antigen Specific Anti-microbial Peptide Responses in Low Body Mass Index-Latent Tuberculosis Co-morbidity.

Low body mass index (BMI) is a risk factor for progression from latent Mycobacterium tuberculosis infection to active tuberculosis (TB) disease. Anti-microbial peptides (AMPs) are multifunctional molecules that play a crucial role in the mammalian host innate defense mechanism. AMPs have been shown to have an important role in host immunity to TB infection. The association of antimicrobial peptides with low BMI–latent tuberculosis (LTBI) co-morbidity has not been explored. To study the association of AMPs with LTBI-BMI, we examined the systemic, baseline, and mycobacterial antigen stimulated levels of human neutrophil peptides 1–3, (HNP1-3), granulysin, human beta defensin–2 (HBD-2), and cathelicidin (LL-37) in individuals with LTBI and low BMI (LBMI) and compared them with individuals with LTBI and normal BMI (NBMI). LBMI was characterized by diminished systemic levels of HNP1-3, granulysin, HBD-2 and cathelicidin in comparison with NBMI. Similarly, LBMI was also characterized by diminished unstimulated levels of HNP1-3 and granulysin and diminished mycobacterial antigen stimulated levels of HNP1-3, granulysin, and HBD-2. In addition, certain AMPs exhibited a positive correlation with BMI. Our data, therefore, demonstrates that coexistent LBMI in LTBI is characterized by the diminished levels of HNP1-3, granulysin, HBD-2, and cathelicidin, thereby potentially increasing the risk of progression to active TB.

TmSpz4 Plays an Important Role in Regulating the Production of Antimicrobial Peptides in Response to Escherichia coli and Candida albicans Infections.

Spätzle family proteins activate the Toll pathway and induce antimicrobial peptide (AMP) production against microbial infections. However, the functional importance of Tmspätzle4 (TmSpz4) in the immune response of Tenebrio molitor has not been reported. Therefore, here, we have identified and functionally characterized the role of TmSpz4 against bacterial and fungal infections. We showed that TmSpz4 expression was significantly induced in hemocytes at 6 h post-injection with Escherichia coli, Staphylococcus aureus, and Candida albicans. TmSpz4 knock-down significantly reduced larval survival against E. coli and C. albicans. To understand the reason for the survivability difference, the role of TmSpz4 in AMP production was examined in TmSpz4-silenced larvae following microbe injection. The AMPs that are active against Gram-negative bacteria, including TmTenecin-2, TmTenecin-4, TmAttacin-1a, TmDefensin-2, and TmCecropin-2, were significantly downregulated in response to E. coli in TmSpz4-silenced larvae. Similarly, the expression of TmTenecin-1, TmTenecin-3, TmThaumatin-like protein-1 and -2, TmDefensin-1, TmDefensin-2, and TmCecropin-2 were downregulated in response to C. albicans in TmSpz4-silenced larvae. In addition, the transcription factor NF-κB (TmDorX1 and TmDorX2) expression was significantly suppression in TmSpz4-silenced larvae. In conclusion, these results suggest that TmSpz4 plays a key role in regulating immune responses of T. molitor against to E. coli and C. albicans.