Recent Advances in the Discovery and Function of Antimicrobial Molecules in Platelets.

The conventional function described for platelets is maintaining vascular integrity. Nevertheless, increasing evidence reveals that platelets can additionally play a crucial role in responding against microorganisms. Activated platelets release molecules with antimicrobial activity. This ability was first demonstrated in rabbit serum after coagulation and later in rabbit platelets stimulated with thrombin. Currently, multiple discoveries have allowed the identification and characterization of PMPs (platelet microbicidal proteins) and opened the way to identify kinocidins and CHDPs (cationic host defense peptides) in human platelets. These molecules are endowed with microbicidal activity through different mechanisms that broaden the platelet participation in normal and pathologic conditions. Therefore, this review aims to integrate the currently described platelet molecules with antimicrobial properties by summarizing the pathways towards their identification, characterization, and functional evaluation that have promoted new avenues for studying platelets based on kinocidins and CHDPs secretion.

Calreticulin functions in antimicrobial immunity of obscure puffer Takifugu obscurus.

Calreticulin (Crt) is a highly conserved and multi-functional protein with lectin-like properties and important immunological activities. In this study, a Crt homolog, namely, ToCrt, was cloned and characterized from the obscure puffer Takifugu obscurus with an open reading frame of 1278 bp encoding a putative protein of 425 amino acids. The deduced amino acid sequence of ToCrt consisted of three conserved structural domains: N-domain, P-domain, and C-terminal domain. In the phylogenetic tree, ToCrt formed a separate cluster with three Crts from other pufferfish species (Takifugu rubripes, Takifugu flavidus, and Takifugu bimaculatus). The mRNA transcript of ToCrt was ubiquitously expressed in all the examined tissues in a decreasing order: liver, spleen, kidney, gills, intestine, and heart. After Vibrio harveyi, Edwardsiella tarda, and Aeromonas hydrophila stimulations, the levels of ToCrt mRNA in the kidney and spleen were significantly upregulated compared with that in the control group. The recombinant calreticulin domain of ToCrt (rToCrt) could bind three Gram-negative bacteria (V. harveyi, E. tarda, and A. hydrophila) and polysaccharides from bacterial cell walls such as lipopolysaccharide and peptidoglycan. Meanwhile, rToCrt could agglutinate different kinds of microorganisms and exhibit antimicrobial activity. These results suggested that T. obscurus ToCrt could serve as an antimicrobial effector in the host immune response against invading microorganisms.

Antimicrobial immunity impedes CNS vascular repair following brain injury.

Traumatic brain injury (TBI) and cerebrovascular injury are leading causes of disability and mortality worldwide. Systemic infections often accompany these disorders and can worsen outcomes. Recovery after brain injury depends on innate immunity, but the effect of infections on this process is not well understood. Here, we demonstrate that systemically introduced microorganisms and microbial products interfered with meningeal vascular repair after TBI in a type I interferon (IFN-I)-dependent manner, with sequential infections promoting chronic disrepair. Mechanistically, we discovered that MDA5-dependent detection of an arenavirus encountered after TBI disrupted pro-angiogenic myeloid cell programming via induction of IFN-I signaling. Systemic viral infection similarly blocked restorative angiogenesis in the brain parenchyma after intracranial hemorrhage, leading to chronic IFN-I signaling, blood-brain barrier leakage and a failure to restore cognitive-motor function. Our findings reveal a common immunological mechanism by which systemic infections deviate reparative programming after central nervous system injury and offer a new therapeutic target to improve recovery.

Immunomodulatory Properties of Host Defence Peptides in Skin Wound Healing.

Cutaneous wound healing is a vital biological process that aids skin regeneration upon injury. Wound healing failure results from persistent inflammatory conditions observed in diabetes, or autoimmune diseases like psoriasis. Chronic wounds are incurable due to factors like poor oxygenation, aberrant function of peripheral sensory nervature, inadequate nutrients and blood tissue supply. The most significant hallmark of chronic wounds is heavily aberrant immune skin function. The immune response in humans relies on a large network of signalling molecules and their interactions. Research studies have reported on the dual role of host defence peptides (HDPs), which are also often called antimicrobial peptides (AMPs). Their duality reflects their potential for acting as antibacterial peptides, and as immunodulators that assist in modulating several biological signalling pathways related to processes such as wound healing, autoimmune disease, and others. HDPs may differentially control gene regulation and alter the behaviour of epithelial and immune cells, resulting in modulation of immune responses. In this review, we shed light on the understanding and most recent advances related to molecular mechanisms and immune modulatory features of host defence peptides in human skin wound healing. Understanding their functional role in skin immunity may further inspire topical treatments for chronic wounds.

PACAP modulates the transcription of TLR-1/TLR-5/MyD88 pathway genes and boosts antimicrobial defenses in Clarias gariepinus.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a multifunctional neuropeptide that belongs to the secretin/glucagon/GHRH/VIP superfamily. Some of these molecules have antimicrobial activity and they are capable of stimulating the immune system. The present work studied the antibacterial and immunostimulatory activity of PACAP-38 from African catfish Clarias gariepinus against the Gram-negative bacterium Pseudomonas aeruginosa in an in vivo test. PACAP-38 improved antimicrobial activity of skin mucus molecules against P. aeruginosa. The peptide modulates the gene expression profile of TLR-1, TLR-5, MyD88, IL-1ß, TNF-ɑ, IL-8, pardaxin, hepcidin and G/C-type lysozymes in skin, spleen and head kidney. The influenced exerted depended on the time after infection and tissue analyzed. This study provides the first evidence of a link between PACAP and antimicrobial peptides hepcidin and pardaxin. Our results suggest further use of PACAP as antimicrobial agent that could potentially be used to control disease in aquaculture.

Short-Chain Fatty Acids as a Potential Treatment for Infections: a Closer Look at the Lungs.

Short-chain fatty acids (SCFAs) are the main metabolites produced by the gut microbiota via the fermentation of complex carbohydrates and fibers. Evidence suggests that SCFAs play a role in the control of infections through direct action both on microorganisms and on host signaling. This review summarizes the main microbicidal effects of SCFAs and discusses studies highlighting the effect of SCFAs in the virulence and viability of microorganisms. We also describe the diverse and complex modes of action of the SCFAs on the immune system in the face of infections with a specific focus on bacterial and viral respiratory infections. A growing body of evidence suggests that SCFAs protect against lung infections. Finally, we present potential strategies that may be leveraged to exploit the biological properties of SCFAs for increasing effectiveness and optimizing patient benefits.

Structure and antimicrobial activity of NCR169, a nodule-specific cysteine-rich peptide of Medicago truncatula.

A model legume, Medicago truncatula, has over 600 nodule-specific cysteine-rich (NCR) peptides required for symbiosis with rhizobia. Among them, NCR169, an essential factor for establishing symbiosis, has four cysteine residues that are indispensable for its function. However, knowledge of NCR169 structure and mechanism of action is still lacking. In this study, we solved two NMR structures of NCR169 caused by different disulfide linkage patterns. We show that both structures have a consensus C-terminal ß-sheet attached to an extended N-terminal region with dissimilar features; one moves widely, whereas the other is relatively stapled. We further revealed that the disulfide bonds of NCR169 contribute to its structural stability and solubility. Regarding the function, one of the NCR169 oxidized forms could bind to negatively charged bacterial phospholipids. Furthermore, the positively charged lysine-rich region of NCR169 may be responsible for its antimicrobial activity against Escherichia coli and Sinorhizobium meliloti. This active region was disordered even in the phospholipid bound state, suggesting that the disordered conformation of this region is key to its function. Morphological observations suggested the mechanism of action of NCR169 on bacteria. The present study on NCR169 provides new insights into the structure and function of NCR peptides.

Eficácia de óleos vegetais no controle do biofilme dental: revisão integrativa / Efficacy of vegetable oils in control of dental biofilm: integrative review / Eficacia de los aceites vegetales en el control de biofilm dental: revision integrativa

Introdução:A terapia de bochecho com óleos vegetais é uma cultura tradicional na Índia com intuito de prevenir afecções bucais, como cárie e doença periodontal. Atualmente, com as mudanças nos padrões alimentares da sociedade, tem-se empregado com maior valor o uso de óleos naturais, já que estudos demonstram sua importância para saúde.Objetivo:Esta revisão integrativa teve como objetivo selecionar evidências que mostrassem a utilização de óleos vegetais, com ação antimicrobiana, no controle do biofilme dental. Metodologia:O levantamento bibliográfico foi realizado nos meses de julho e agosto de 2020, por meio de pesquisa por via eletrônica, consultando-se o banco de dados Pubmed e SciELO (Scientific Electronic Library Online). Foram utilizados os descritores: Óleos vegetais, agentes antimicrobianos, Placa dental, Odontologia preventiva e Odontologia, os descritores foram usados separadamente e em cruzamento com o operador boleano AND. Utilizou-se os seguintes critérios de inclusão: Estudos clínicos, artigos completos e disponíveis gratuitamente, publicados no período de 2010 a 2020 em português e/ou inglês, e indexados nas bases de dados já citadas. Foram excluídos os trabalhos de conclusão de curso, dissertações, teses, livros e capítulos de livros, além de artigos duplicados e que não abordaram o tema do estudo.Resultados:Atenderam os critérios da pesquisa 04 estudos do tipo clínico randomizado, os quais mostraram eficiência dos óleos vegetais utilizados no controle do biofilme dental. A realização de pesquisas envolvendo e motivando a industrialização de produtos naturaiscontribui para a Política Nacional de Práticas Integrativas e Complementares.Conclusões:Os artigos analisados mostraram eficácia na utilização de óleos vegetais no controle do biofilme dental, sendo esses aplicados clinicamente,não mostrando prejuízo aos participantes e indicados como coadjuvante na manutenção da saúde bucal (AU).

Introduction:Mouthwash therapy with vegetable oils is a traditional culture in India with the aim of preventing oral diseases, such as caries and periodontal disease. Currently, with the changes in the dietary patterns of society, the use of natural oils has been used with greater value, since studies demonstrate its importance for health.Objective:This integrative review aimed to select evidence that showed the use of vegetable oils, with antimicrobial action, in the control of dental biofilm. Methodology:Thebibliographic survey was carried out in July and August 2020, through electronic research, consulting the Pubmed and SciELO database (Scientific Electronic Library Online). The descriptors were used: Vegetable oils, antimicrobial agents, dental plaque, preventive dentistry and dentistry, the descriptors were used separately and in cross-section with the Boolean operator AND. The following inclusion criteria were used: Clinical studies, complete and freely available articles, published between 2010 and 2020in Portuguese and / or English, and indexed in the databases already cited. Course completion papers, dissertations, theses, books and book chapters were excluded, as well as duplicate articles that did not address the subject of the study. Results:Four studies of randomized clinical type met the research criteria, which showed efficiency of vegetable oils used in the control of dental biofilm. Conducting research involving and motivating the industrialization of natural products contributes to the National Policy on Integrative and Complementary Practices.Conclusions:The analyzed articles showed efficacy in the use of vegetable oils in the control of dental biofilm, which were applied clinically without showing any harm to the participants and indicatedas an adjunct in maintaining oral health (AU).

Introducción: La terapia de enjuague bucal con aceites vegetales es una cultura tradicional en India con el objetivo de prevenir enfermedades bucales, como caries y enfermedad periodontal. Actualmente, con los cambios en los patrones dietéticos de la sociedad, se ha utilizado con mayor valor el uso de aceites naturales, ya que los estudios demuestran su importancia para la salud. Objetivo: Esta revisión integradora tuvo como objetivo seleccionar evidencias que mostraran el uso de aceites vegetales, con acción antimicrobiana, en el control del biofilm dental.Metodología: El relevamiento bibliográfico se realizó en julio y agosto de 2020, mediante investigación electrónica, consultando la base de datos Pubmed y SciELO (Scientific Electronic Library Online). Se utilizaron los descriptores: Aceites vegetales, agentes antimicrobianos, placa dental, odontología preventiva y odontología, los descriptores se utilizaron por separado y en corte transversal con el operador booleano AND. Se utilizaron los siguientes criterios de inclusión: Estudios clínicos, artículos completos y de libre acceso, publicados entre 2010 y 2020 en portugués y / o inglés, e indexados en las bases de datos ya citadas. Se excluyeron trabajos de finalización de curso, disertaciones, tesis, libros y capítulosde libros, así como artículos duplicados que no abordaran el tema de estudio. Resultados: Cuatro estudios de tipo clínico aleatorizado cumplieron con los criterios de investigación, los cuales mostraron la eficiencia de los aceites vegetales utilizados enel control del biofilm dental. Realizar investigaciones que involucren y motiven la industrialización de productos naturales contribuye a la Política Nacional de Prácticas Integrativas y Complementarias.Conclusiones: Los artículos analizados mostraron eficacia en el uso de aceites vegetales en el control del biofilm dental, los cuales fueron aplicados clínicamente sin mostrar daño a los participantes e indicados como coadyuvante en el mantenimiento de la salud bucal (AU).

An overview of chitosan and its application in infectious diseases.

Infectious diseases, such as the coronavirus disease-19, SARS virus, Ebola virus, and AIDS, threaten the health of human beings globally. New viruses, drug-resistant bacteria, and fungi continue to challenge the human efficacious drug bank. Researchers have developed a variety of new antiviral and antibacterial drugs in response to the infectious disease crisis. Meanwhile, the development of functional materials has also improved therapeutic outcomes. As a natural material, chitosan possesses good biocompatibility, bioactivity, and biosafety. It has been proven that the cooperation between chitosan and traditional medicine greatly improves the ability of anti-infection. This review summarized the application and design considerations of chitosan-composed systems for the treatment of infectious diseases, looking forward to providing the idea of infectious disease therapy.

Toposome: Source of antimicrobial molecules in the gonads of the sea urchin Lytechinus variegatus (Lamarck, 1816).

Sea urchins live in a challenging environment that requires rapid and efficient responses against pathogens and invaders. This response may be also important in reproductive processes once males and females release their gametes into water. In addition, the gonads are organs with dual function: reproductive organ and nutrient reserve, therefore it needs efficient protective mechanisms to preserve the nutrients as well as the reproductive cells. The aim of this study was to evaluate the presence and characterize antimicrobial molecules in the male and female gonads of the sea urchin Lytechinus variegatus. Through HPLC purification, antimicrobial activity test and mass spectrometry several antimicrobial molecules were found in the gonads of both gender. Computational in silico analyses showed that they are fragments of a glycoprotein called toposome, also known as major yolk protein (MYP) which is one of the major proteins found in the gonads. Although different functions have been reported for this protein, this is the first description of a direct antimicrobial activity in Lytechinus variegatus. The results indicate that when undergoing proteolysis the toposome generates different fragments with antimicrobial activity which may indicate the importance of a rapid defense response strategy against invading microorganisms in the gonads used by both males and females sea urchins.

IgIT-Mediated Signaling Inhibits the Antimicrobial Immune Response in Oyster Hemocytes.

The long-term evolutionary interaction between the host and symbiotic microbes determines their cooperative relationship. It is well known that the symbiotic microbes have evolved various mechanisms to either benefit or exploit the mammalian host immune system to maintain homeostasis. However, the strategies employed by the symbiotic microbes to overcome host immune responses in invertebrates are still not clear. In the current study, the hemolymph microbes in oyster Crassostrea gigas were found to be able to directly bind an oyster Ig superfamily member (IgSF) (designated as CgIgIT) to inhibit the immune responses of hemocytes. The mRNA transcripts of CgIgIT in hemocytes increased significantly after the stimulation with hemolymph microbes. CgIgIT was found to be located on the hemocyte membrane and it was able to directly bind the hemolymph microbes and polysaccharides via its three Ig domains and recruited the protein tyrosine phosphatase CgSHP2 through its ITIM. The recruited CgSHP2 inhibited the activities of CgERK, CgP38 and CgJNK proteins to reduce the productions of dual oxidase 2 (CgDuox2) and defensin 2 (CgDef2), which eventually protected the hemolymph microbes from CgDuox2/CgDef2-mediated elimination. Collectively, the results suggest that the oyster IgIT-SHP2 signaling pathway can recognize bacteria capable of residing in oyster hemolymph and inhibit innate immune responses, which contributes to the maintenance, colonization, and survival of hemolymph microbes.

IKKγ/NEMO Is Required to Confer Antimicrobial Innate Immune Responses in the Yellow Mealworm, Tenebrio Molitor.

IKKγ/NEMO is the regulatory subunit of the IκB kinase (IKK) complex, which regulates the NF-κB signaling pathway. Within the IKK complex, IKKγ/NEMO is the non-catalytic subunit, whereas IKKα and IKKß are the structurally related catalytic subunits. In this study, TmIKKγ was screened from the Tenebrio molitor RNA-Seq database and functionally characterized using RNAi screening for its role in regulating T. molitor antimicrobial peptide (AMP) genes after microbial challenges. The TmIKKγ transcript is 1521 bp that putatively encodes a polypeptide of 506 amino acid residues. TmIKKγ contains a NF-κB essential modulator (NEMO) and a leucine zipper domain of coiled coil region 2 (LZCC2). A phylogenetic analysis confirmed its homology to the red flour beetle, Tribolium castaneum IKKγ (TcIKKγ). The expression of TmIKKγ mRNA showed that it might function in diverse tissues of the insect, with a higher expression in the hemocytes and the fat body of the late-instar larvae. TmIKKγ mRNA expression was induced by Escherichia coli, Staphylococcus aureus, and Candida albicans challenges in the whole larvae and in tissues such as the hemocytes, gut and fat body. The knockdown of TmIKKγ mRNA significantly reduced the survival of the larvae after microbial challenges. Furthermore, we investigated the tissue-specific induction patterns of fourteen T. molitor AMP genes in TmIKKγ mRNA-silenced individuals after microbial challenges. In general, the mRNA expression of TmTenecin1, -2, and -4; TmDefensin1 and -2; TmColeoptericin1 and 2; and TmAttacin1a, 1b, and 2 were found to be downregulated in the hemocytes, gut, and fat body tissues in the TmIKKγ-silenced individuals after microbial challenges. Under similar conditions, TmRelish (NF-κB transcription factor) mRNA was also found to be downregulated. Thus, TmIKKγ is an important factor in the antimicrobial innate immune response of T. molitor.

Immunological regulatory effect of flavonoid baicalin on innate immune toll-like receptors.

As an essential component of the innate immune system, Toll-like receptors (TLRs) are a family of well-recognized ligand-binding receptors found in various organisms and initiate host immune responses. Activation of TLRs signaling pathways lead to the induction of numerous genes that function in host defense. Baicalin is a natural compound from the dry raw root of Scutellaria baicalensis (S. baicalensis) and it has been found to exhibit several pharmaceutical actions, such as anti-inflammation, anti-tumor and antivirus. These biological activities are mainly related to the regulatory effect of baicalin on the host immune response. In this review, we provide an overview of the regulation of baicalin on TLRs signaling pathways in various pathological conditions, and highlight potential targets for the development of the regulatory effect of natural compound from traditional Chinese medicine on innate immune system.

Galectin-3 as a modifier of anti-microbial immunity: Unraveling the unknowns.

Galectins play diverse roles in pathophysiology of infectious diseases and cancers. Galectin-3 is one of the most studied family member and the only chimeric type lectin. Many aspects of its biogenesis, range of activities, and the disease-modifying potential particularly during microbial infections are yet to be known. We review our current understanding of these issues and also highlight gaps in better defining the immune modulatory potential of galectin-3 during different stages of host responsiveness when an infection sets in. Additionally, we discuss commonly used strategies to disrupt galectin-3 functions both extracellulalry and intracellularly. Existing and improved novel strategies could help fine-tune immune responses to achieve better prognosis of infectious diseases.

Recombinant expression and functional analysis of antimicrobial Siganus oraminl-amino acid oxidase using the Bac-to-Bac baculovirus expression system.

Siganus oraminl-amino acid oxidase (SR-LAAO), isolated from the serum of Siganus oramin, is an innate immune protein with significant antibacterial activity. The aim of this study was to express SR-LAAO in insect cells using a baculovirus expression system and evaluate the function of the recombinant SR-LAAO. To this end, an optimized sequence of the SR-LAAO gene was designed and synthesized, based on the codon bias of insect cells. Bacmid shuttle vectors and recombinant baculovirus were successfully constructed, and the recombinant baculovirus was transfected into Sf9 insect cells. The antibacterial activity and enzymatic characteristics of the recombinant SR-LAAO were investigated. The results showed that the pFastBac-optiSR-LAAO shuttle vectors and Bacmid-optiSR-LAAO were correctly constructed. The Sf9 insect cells exhibited significant cytopathic effects following infection with Bacmid-optiSR-LAAO and Bacmid; the specific PCR analysis proved that the recombinant baculovirus was successfully constructed. The immunofluorescence assay revealed that the recombinant baculovirus rSR-LAAO was abundantly expressed in infected Sf9 insect cells; the results of SDS/PAGE and Western blot analyses showed that a specific band appeared at about 60 kDa. Moreover, the crude rSR-LAAO enzyme displayed strong antibacterial activity against aquatic pathogens, particularly Streptococcus agalactiae and Streptococcus iniae. In addition, the results of catalase interference test implied that the antibacterial activity of rSR-LAAO was directly associated with (H2O2 production). The results of the rSR-LAAO enzymatic characteristics test indicated that the Km value with l-Lysine as a substrate was 16.61 mM when the temperature was under 37 °C, and the optimum pH was 7. The antibacterial activity of rSR-LAAO could be completely inhibited by 10 mg/mL of pepsin, trypsin, and proteinase K compared with both methanol and acetone. Adding an equal volume of ethanol had a minimal impact on the antibacterial activity of rSR-LAAO. The crude enzyme could maintain a high level of antibacterial activity against both Gram-positive and -negative bacteria from 4 °C to 30 °C. In the present study, SR-LAAO was successfully expressed in Sf9 cells using the baculovirus expression system, and provides basic references for further research into the role of LAAO in marine animals and the development of new antimicrobial drugs.

The Antimicrobial and Immunomodulatory Function of RNase 7 in Skin.

The human ribonuclease RNase 7 has been originally isolated from human skin and is a member of the human RNase A superfamily. RNase 7 is constantly released by keratinocytes and accumulates on the skin surface. The expression of RNase 7 in keratinocytes can be induced by diverse stimuli such as cytokines, growth factors, and microbial factors. RNase 7 exhibits a potent broad spectrum of antimicrobial activity against various microorganisms and contributes to control bacterial growth on the skin surface. The ribonuclease and antimicrobial activity of RNase 7 can be blocked by the endogenous ribonuclease inhibitor. There is also increasing evidence that RNase 7 exerts immunomodulatory activities and may participate in antiviral defense. In this review, we discuss how these characteristics of RNase 7 contribute to innate cutaneous defense and highlight its role in skin infection and inflammation. We also speculate how a potential dysregulation of RNase 7 promotes inflammatory skin diseases and if RNase 7 may have therapeutic potential.

Antimicrobial activity and mechanisms of multiple antimicrobial peptides isolated from rockfish Sebastiscus marmoratus.

Pathogenic disease is a major factor affecting the aquaculture of the rockfish Sebastiscus marmoratus, an important commercial species inhabiting the nearshore waters of the Western Pacific Ocean. Antimicrobial peptides (AMPs), as critical components of innate immunity, have been considered as promising antibiotic substitutes. The aims of this study were 1) to identify major AMPs in the rockfish, 2) to assess their antimicrobial activity and 3) to evaluate their potential therapeutic application. Six AMPs were identified, Hepcidin 1, liver-expressed antimicrobial peptide 2 (LEAP-2), Piscidin, Moronecidin, NK-lysin and ß-defensin through analysis of the liver transcriptome of S. marmoratus. The transcriptional expression profiles of these AMPs were investigated by real-time quantitative PCR (RT-qPCR). These AMPs showed tissue-specific distribution patterns, and S. marmoratus displays a time-, dose- and tissue-dependent expression of AMPs in response to lipopolysaccharide (LPS) challenge. While the synthetic peptides of LEAP-2 and Moronecidin exerted broad-spectrum antimicrobial activity against important aquatic pathogens in vitro by directly disrupting microbial membrane, and no cytotoxicity against murine hepatic cells was observed at the effective concentrations from 5 µM to 40 µM. The existence of multiple AMPs and their distinct tissue distribution patterns and inducible expression patterns suggests a sophisticated, highly redundant, and multilevel network of antimicrobial defensive mechanisms of S. marmoratus. Therefore, S. marmoratus-derived AMPs appear to be potential therapeutic applications against pathogen infections in aquaculture.

Drug hypersensitivity in HIV infection.

PURPOSE OF REVIEW: Immune-mediated adverse drug reactions (IM-ADRs) are many times more common in HIV-infected patients. Usual offending drugs include antiretroviral and antiinfectives, but the burden of specific drug IM-ADRs is population-specific; changing as new and fixed dose combinations enter the market, and drug-resistance patterns demand. This review considers recent literature on epidemiology, mechanisms, clinical management and prevention of IM-ADRs amongst persons living with HIV/AIDS. RECENT FINDINGS: Epidemiological studies continue to describe high rates of delayed hypersensitivity to known offenders, as well as similar reactions in preexposure prophylaxis. IM-ADRs to oral and injectable integrase strand transfer inhibitors are reported with expanding use. The clinical spectrum and management of IM-ADRs occurring in HIV-infected populations is similar to uninfected; with exceptions such as a recently described severe delayed efavirenz DILI with high mortality. Furthermore, the context can be unique, such as the lower than expected mortality in a Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) cohort from a HIV/TB high burden setting. Programmatic data showing the near complete elimination of Abacavir drug hypersensitivity syndrome following implementation of HLA-B57:01 screening is a stellar example of how prevention is possible with mechanistic insight. SUMMARY: IM-ADRs remain a challenge in persons living with HIV. The complexities posed by polypharmacy, overlapping drug toxicities, drug interactions, overlap of IM-ADRs with other diseases, limited alternative drugs, and vulnerable patients with advanced immunosuppression with high mortality, necessitate increased use of drug provocation testing, treat-through and desensitization strategies. There is an urgent need for improved diagnostics and predictive biomarkers for prevention, or to guide treat-through, rechallenge and desensitization approaches.

Diversity, immunoregulatory action and structure-activity relationship of green sea turtle cathelicidins.

Cathelicidins are a family of gene-encoded immune effectors in vertebrate innate immunity. Here, we reported the diversity and biological activity of cathelicidins in green sea turtle, a marine reptile species known for long lifespan and disease resistance. Four novel cathelicidins (Cm-CATH1-4) were identified from green sea turtle. All of them, especially Cm-CATH2, exhibited potent, broad-spectrum and rapid bactericidal and anti-biofilm activities by inducing the disruption of cell membrane integrity. Additionally, Cm-CATH2 effectively induced the macrophages/monocytes and neutrophils trafficking to the infection site, and inhibited the LPS-induced production of inflammatory cytokines, by blocking TLR4/MD2 complex and the downstream signaling pathway activation. In mouse peritonitis and pneumonia models, Cm-CATH2 exhibited evident protection against drug-resistant bacterial infections. Taken together, the diverse structures and functions of Cm-CATHs indicated their pleiotropic role in innate immunity of green sea turtle, and the potent antimicrobial, anti-biofilm and immunomodulatory properties make them ideal candidates for the development of novel anti-infective drugs.

Molecular characterization, expression and antimicrobial activities of a c-type lysozyme from the mud crab, Scylla paramamosain.

Lysozyme is an important immune protein involved in the first line of defense for crustaceans. In the present study, a c-type lysozyme gene (SpLyzC) was cloned and characterized from the mud crab, Scylla paramamosain. The full-length cDNA was 849 bp with an open reading frame of 669 bp, and encoded a polypeptide of 223 amino acids with a calculated molecular mass of 23.7 kDa and an isoelectric point of 8.90. SpLyzC shared conserved active sites with c-type lysozymes from other species, detected in all tested tissues and had higher expression levels in hepatopancreas and gill tissues. The expression of SpLyzC was up-regulated in hepatopancreas and gill after infection with Vibrio parahaemolyticus and Staphylococcus aureus. The density of bacteria in the hemolymph and the mortality of crabs increased following infection with V. parahaemolyticus after SpLyzC expression was silenced by injecting double-strand RNA of SpLyzC. The recombinant protein of the S. paramamosain c-type lysozyme (rSpLyzC) exhibited antibacterial activities against Micrococcus lysodeikticus, S. aureus, Vibrio harveyi and V. parahaemolyticus. These results indicate that SpLyzC could help eliminate bacteria in S. paramamosain and may play an important role in resistance to bacterial infection.