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Control of schistosomiasis japonica, endemic in Asia, including the Philippines, China, and Indonesia, is extremely challenging. Schistosoma japonicum is a highly pathogenic helminth parasite, with disease arising predominantly from an immune reaction to entrapped parasite eggs in tissues. Females of this species can generate 1000-2200 eggs per day, which is about 3- to 15-fold greater than the egg output of other schistosome species. Bovines (water buffalo and cattle) are the predominant definitive hosts and are estimated to generate up to 90% of parasite eggs released into the environment in rural endemic areas where these hosts and humans are present. Here, we highlight the necessity of developing veterinary transmission-blocking vaccines for bovines to better control the disease and review potential vaccine candidates. We also point out that the approach to producing efficacious transmission-blocking animal-based vaccines before moving on to human vaccines is crucial. This will result in effective and feasible public health outcomes in agreement with the One Health concept to achieve optimum health for people, animals, and the environment. Indeed, incorporating a veterinary-based transmission vaccine, coupled with interventions such as human mass drug administration, improved sanitation and hygiene, health education, and snail control, would be invaluable to eliminating zoonotic schistosomiasis.
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Schistosoma japonicum , Esquistosomiasis Japónica , Esquistosomiasis , Vacunas , Animales , Femenino , Bovinos , Humanos , Esquistosomiasis Japónica/prevención & control , Esquistosomiasis Japónica/veterinaria , Vacunación , China/epidemiología , BúfalosRESUMEN
With increasing rates of cesarean section worldwide and international guidelines advising pre-incision antibiotics, neonatal exposure to pre-birth antibiotics is higher than ever before. Emerging evidence has raised concern regarding the impact of such antibiotics on the neonatal intestinal microbiota, immune system development and health conditions later in life. This narrative review investigates current protocols for intrapartum prophylactic antibiotics in cesarean section, how this and other factors may affect the neonatal intestinal microbiota and whether intrapartum antibiotics used for cesarean section are linked to the development of allergic disease.
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Microbioma Gastrointestinal , Microbiota , Recién Nacido , Lactante , Humanos , Embarazo , Femenino , Antibacterianos/uso terapéutico , Cesárea , PartoRESUMEN
The prevalence of autoimmune diseases is on the rise globally. Currently, autoimmunity presents in over 100 different forms and affects around 9% of the world's population. Current treatments available for autoimmune diseases are inadequate, expensive, and tend to focus on symptom management rather than cure. Clinical trials have shown that live helminthic therapy can decrease chronic inflammation associated with inflammatory bowel disease and other gastrointestinal autoimmune inflammatory conditions. As an alternative and better controlled approach to live infection, we have identified and characterized two peptides, Acan1 and Nak1, from the excretory/secretory component of parasitic hookworms for their therapeutic activity on experimental colitis. We synthesized Acan1 and Nak1 peptides from the Ancylostoma caninum and Necator americanus hookworms and assessed their structures and protective properties in human cell-based assays and in a mouse model of acute colitis. Acan1 and Nak1 displayed anticolitic properties via significantly reducing weight loss and colon atrophy, edema, ulceration, and necrosis in 2,4,6-trinitrobenzene sulfonic acid-exposed mice. These hookworm peptides prevented mucosal loss of goblet cells and preserved intestinal architecture. Acan1 upregulated genes responsible for the repair and restitution of ulcerated epithelium, whereas Nak1 downregulated genes responsible for epithelial cell migration and apoptotic cell signaling within the colon. These peptides were nontoxic and displayed key immunomodulatory functions in human peripheral blood mononuclear cells by suppressing CD4+ T cell proliferation and inhibiting IL-2 and TNF production. We conclude that Acan1 and Nak1 warrant further development as therapeutics for the treatment of autoimmunity, particularly gastrointestinal inflammatory conditions.
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Ancylostomatoidea/química , Colitis/tratamiento farmacológico , Colitis/prevención & control , Leucocitos/inmunología , Péptidos/uso terapéutico , Secuencia de Aminoácidos , Ancylostoma , Animales , Proliferación Celular/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Mediadores de Inflamación/metabolismo , Intestinos/patología , Canal de Potasio Kv1.3/antagonistas & inhibidores , Canal de Potasio Kv1.3/metabolismo , Leucocitos/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Masculino , Ratones Endogámicos C57BL , Necator americanus , Péptidos/química , Péptidos/metabolismo , Péptidos/farmacología , Análisis de Componente Principal , Dominios Proteicos , Pliegue de Proteína , Linfocitos T/citología , Ácido Trinitrobencenosulfónico , Xenopus laevisRESUMEN
Inflammatory bowel diseases (IBDs) are a set of complex and debilitating diseases for which there is no satisfactory treatment. Recent studies have shown that small peptides show promise for reducing inflammation in models of IBD. However, these small peptides are likely to be unstable and rapidly cleared from the circulation, and therefore, if not modified for better stability, represent non-viable drug leads. We hypothesized that improving the stability of these peptides by grafting them into a stable cyclic peptide scaffold may enhance their therapeutic potential. Using this approach, we have designed a novel cyclic peptide that comprises a small bioactive peptide from the annexin A1 protein grafted into a sunflower trypsin inhibitor cyclic scaffold. We used native chemical ligation to synthesize the grafted cyclic peptide. This engineered cyclic peptide maintained the overall fold of the naturally occurring cyclic peptide, was more effective at reducing inflammation in a mouse model of acute colitis than the bioactive peptide alone, and showed enhanced stability in human serum. Our findings suggest that the use of cyclic peptides as structural backbones offers a promising approach for the treatment of IBD and potentially other chronic inflammatory conditions.
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Antiinflamatorios no Esteroideos/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Colon/efectos de los fármacos , Modelos Animales de Enfermedad , Fármacos Gastrointestinales/uso terapéutico , Modelos Moleculares , Péptidos Cíclicos/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/metabolismo , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/patología , Colon/inmunología , Colon/patología , Diseño de Fármacos , Estabilidad de Medicamentos , Fármacos Gastrointestinales/síntesis química , Fármacos Gastrointestinales/química , Humanos , Masculino , Ratones Endogámicos C57BL , Tamaño de los Órganos/efectos de los fármacos , Péptidos Cíclicos/química , Péptidos Cíclicos/metabolismo , Conformación Proteica , Ingeniería de Proteínas , Pliegue de Proteína , Estabilidad Proteica , Proteolisis , Distribución Aleatoria , Suero/enzimología , Organismos Libres de Patógenos EspecíficosRESUMEN
BACKGROUND: Celiac disease (CeD) is a common gluten-sensitive autoimmune enteropathy. A gluten-free diet is an effective treatment, but compliance is demanding; hence, new treatment strategies for CeD are required. OBJECTIVE: Parasitic helminths hold promise for treating inflammatory disorders, so we examined the influence of experimental hookworm infection on the predicted outcomes of escalating gluten challenges in CeD subjects. METHODS: A 52-week study was conducted involving 12 adults with diet-managed CeD. Subjects were inoculated with 20 Necator americanus larvae, and escalating gluten challenges consumed as pasta were subsequently administered: (1) 10 to 50 mg for 12 weeks (microchallenge); (2) 25 mg daily + 1 g twice weekly for 12 weeks (GC-1g); and (3) 3 g daily (60-75 straws of spaghetti) for 2 weeks (GC-3g). Symptomatic, serologic, and histological outcomes evaluated gluten toxicity. Regulatory and inflammatory T cell populations in blood and mucosa were examined. RESULTS: Two gluten-intolerant subjects were withdrawn after microchallenge. Ten completed GC-1g, 8 of whom enrolled in and completed GC-3g. PRIMARY OUTCOMES: median villous height-to-crypt depth ratios (2.60-2.63; P = .98) did not decrease as predicted after GC-1g, and the mean IgA-tissue transglutaminase titers declined, contrary to the predicted rise after GC-3g. SECONDARY OUTCOMES: quality of life scores improved (46.3-40.6; P = .05); celiac symptom indices (24.3-24.3; P = .53), intra-epithelial lymphocyte percentages (32.5-35.0; P = .47), and Marsh scores were unchanged by gluten challenge. Intestinal T cells expressing IFNγ were reduced following hookworm infection (23.9%-11.5%; P = .04), with corresponding increases in CD4(+) Foxp3(+) regulatory T cells (0.19%-1.12%; P = .001). CONCLUSIONS: Necator americanus and gluten microchallenge promoted tolerance and stabilized or improved all tested indices of gluten toxicity in CeD subjects.
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Ancylostomatoidea/inmunología , Enfermedad Celíaca/inmunología , Glútenes/inmunología , Infecciones por Uncinaria/inmunología , Tolerancia Inmunológica , Adulto , Anciano , Animales , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/terapia , Duodeno/inmunología , Duodeno/parasitología , Duodeno/patología , Femenino , Glútenes/administración & dosificación , Infecciones por Uncinaria/complicaciones , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Necator americanus/inmunología , Evaluación del Resultado de la Atención al Paciente , Encuestas y Cuestionarios , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
Na-ASP-2 is an efficacious hookworm vaccine antigen. However, despite elucidation of its crystal structure and studies addressing its immunobiology, the function of Na-ASP-2 has remained elusive. We probed a 9000-protein human proteome microarray with Na-ASP-2 and showed binding to CD79A, a component of the B-cell antigen receptor complex. Na-ASP-2 bound to human B lymphocytes ex vivo and downregulated the transcription of approximately 1000 B-cell messenger RNAs (mRNAs), while only approximately 100 mRNAs were upregulated, compared with control-treated cells. The expression of a range of molecules was affected by Na-ASP-2, including factors involved in leukocyte transendothelial migration pathways and the B-cell signaling receptor pathway. Of note was the downregulated transcription of lyn and pi3k, molecules that are known to interact with CD79A and control B-cell receptor signaling processes. Together, these results highlight a previously unknown interaction between a hookworm-secreted protein and B cells, which has implications for helminth-driven immunomodulation and vaccine development. Further, the novel use of human protein microarrays to identify host-pathogen interactions, coupled with ex vivo binding studies and subsequent analyses of global gene expression in human host cells, demonstrates a new pipeline by which to explore the molecular basis of infectious diseases.
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Ancylostomatoidea/inmunología , Linfocitos B/inmunología , Infecciones por Uncinaria/inmunología , Receptores de Células Precursoras de Linfocitos B/inmunología , Proteoma/inmunología , Proteínas Recombinantes/inmunología , Transducción de Señal/inmunología , Adulto , Animales , Antígenos Helmínticos/inmunología , Antígenos CD79/inmunología , Células Cultivadas , Regulación hacia Abajo/genética , Regulación hacia Abajo/inmunología , Proteínas del Helminto/inmunología , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Leucocitos Mononucleares/inmunología , Persona de Mediana Edad , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/inmunología , Análisis por Matrices de Proteínas/métodos , Proteoma/genética , ARN Mensajero/genética , ARN Mensajero/inmunología , Transducción de Señal/genética , Transcripción Genética/genética , Transcripción Genética/inmunología , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunología , Familia-src Quinasas/genética , Familia-src Quinasas/inmunologíaRESUMEN
Food allergy (FA) is considered the 'second wave' of the allergy epidemic in developed countries after asthma and allergic rhinitis with a steadily growing burden of 40%. The absence of early childhood pathogen stimulation embodied by the hygiene hypothesis is one explanation, and in particular, the eradication of parasitic helminths could be at play. Infections with parasites Schistosoma spp. have been found to have a negative correlation with allergic diseases. Schistosomes induce regulatory responses to evade immune detection and ensure their long-term survival. This is achieved via excretory/secretory (E/S) products, consisting of proteins, lipids, metabolites, nucleic acids and extracellular vesicles, representing an untapped therapeutic avenue for the treatment of FA without the unpleasant side-effects and risks associated with live infection. Schistosome-derived immunotherapeutic development is in its infancy and novel discoveries are heavily technology dependent; thus, it is essential to better understand how newly identified molecules interact with host immune systems to ensure safety and successful translation. This review will outline the identified Schistosoma-derived E/S products at all life cycle stages and discuss known mechanisms of action and their ability to suppress FA.
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Anterior cruciate ligament reconstructions are often performed with associated procedures, most commonly for associated meniscal tears. The lateral meniscal root tear is a commonly associated injury, which increases rotational instability and results in altered tibiofemoral biomechanics. Lateral meniscectomy results in poorer functional and long-term outcomes, making repair vital. The position of the lateral root tear makes its repair technique complicated. Because of the proximity to vessels posteriorly, the all-inside technique is considered potentially unsafe, and current transtibial repair techniques fail to appose the body with the root remnant. In the lineage of Laprade, who proclaimed the use of a transtibial suture for radial tears elsewhere in the knee in order to reduce the shear force, we describe a transtibial technique that optimizes meniscal apposition, theoretically improving the repair biomechanics and is technically easier to perform in comparison to suture hook techniques with one tunnel and one suture.
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Household food insecurity (HFI) and poorer prenatal diet quality are both associated with adverse perinatal outcomes. However, research assessing the relationship between HFI and diet quality in pregnancy is limited. A cross-sectional online survey was conducted to examine the relationship between HFI and diet quality among 1540 pregnant women in Australia. Multiple linear regression models were used to examine the associations between HFI severity (marginal, low, and very low food security compared to high food security) and diet quality and variety, adjusting for age, education, equivalised household income, and relationship status. Logistic regression models were used to assess the associations between HFI and the odds of meeting fruit and vegetable recommendations, adjusting for education. Marginal, low, and very low food security were associated with poorer prenatal diet quality (adj ß = -1.9, -3.6, and -5.3, respectively; p < 0.05), and very low food security was associated with a lower dietary variety (adj ß = -0.5, p < 0.001). An association was also observed between HFI and lower odds of meeting fruit (adjusted odds ratio [AOR]: 0.61, 95% CI: 0.49-0.76, p < 0.001) and vegetable (AOR: 0.40, 95% CI: 0.19-0.84, p = 0.016) recommendations. Future research should seek to understand what policy and service system changes are required to reduce diet-related disparities in pregnancy.
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Dieta , Inseguridad Alimentaria , Humanos , Femenino , Embarazo , Estudios Transversales , Adulto , Australia , Adulto Joven , Verduras , Frutas , Abastecimiento de Alimentos/estadística & datos numéricos , Seguridad Alimentaria , Fenómenos Fisiologicos Nutricionales MaternosRESUMEN
Evidence from human studies and mouse models shows that infection with parasitic helminths has a suppressive effect on the pathogenesis of some inflammatory diseases. Recently, we and others have shown that some of the suppressive effects of hookworms reside in their excretory/secretory (ES) products. Here, we demonstrate that ES products of the hookworm Ancylostoma caninum (AcES) suppress intestinal pathology in a model of chemically induced colitis. This suppression was associated with potent induction of a type 2 cytokine response characterized by coexpression of interleukin-4 (IL-4) and IL-10 by CD4(+) T cells, downregulation of proinflammatory cytokine expression in the draining lymph nodes and the colon, and recruitment of alternatively activated (M2) macrophages and eosinophils to the site of ES administration. Protease digestion and heat denaturation of AcES resulted in impaired induction of CD4(+) IL-4(+) IL-10(+) cell responses and diminished ability to suppress colitis, indicating that protein component(s) are responsible for some of the immunosuppressive effects of AcES. Identification of the specific parasite-derived molecules responsible for reducing pathology during chemically induced colitis could lead to the development of novel therapeutics for the treatment of human inflammatory bowel disease.
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Ancylostoma/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Colitis/patología , Proteínas del Helminto/farmacología , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Ancylostoma/inmunología , Animales , Linfocitos T CD4-Positivos/clasificación , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colon/inmunología , Colon/patología , Citocinas/metabolismo , Sulfato de Dextran/toxicidad , Eosinófilos/citología , Femenino , Proteínas del Helminto/uso terapéutico , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Macrófagos/citología , Ratones , Ratones Endogámicos C57BL , Cavidad Peritoneal/citologíaRESUMEN
A decline in the prevalence of parasites such as hookworms appears to be correlated with the rise in non-communicable inflammatory conditions in people from high- and middle-income countries. This correlation has led to studies that have identified proteins produced by hookworms that can suppress inflammatory bowel disease (IBD) and asthma in animal models. Hookworms secrete a family of abundant netrin-domain containing proteins referred to as AIPs (Anti-Inflammatory Proteins), but there is no information on the structure-function relationships. Here we have applied a downsizing approach to the hookworm AIPs to derive peptides of 20 residues or less, some of which display anti-inflammatory effects when co-cultured with human peripheral blood mononuclear cells and oral therapeutic activity in a chemically induced mouse model of acute colitis. Our results indicate that a conserved helical region is responsible, at least in part, for the anti-inflammatory effects. This helical region has potential in the design of improved leads for treating IBD and possibly other inflammatory conditions.
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Host immunity plays a central role in the regulation of anti-tumour responses during checkpoint inhibitor therapy (CIT). The mechanisms involved in long lasting remission remain unclear. Animal studies have revealed that the microbiome influences the host immune response. This is supported by human studies linking a higher microbial richness and diversity with enhanced responses to CIT. This review focuses on the role of diet, the microbiome and the microbiome-derived metabolome in enhancing responses to current CIT in solid tissue cancers. The Western diet has been associated with dysbiosis, inflammation and numerous metabolic disorders. There is preliminary evidence that lifestyle factors including a high fibre diet are associated with improved responses to CIT via a potential effect on the microbiota. The mechanisms through which the microbiota may regulate long-term immunotherapy responses have yet to be determined, although bacterial-metabolites including short chain fatty acids (SCFAs) are recognized to have an impact on T cell differentiation, and may affect T effector/regulatory T cell balance. SCFAs were also shown to enhance the memory potential of activated CD8 T cells. Many therapeutic approaches including dietary manipulation and fecal transplantation are currently being explored in order to enhance immunotherapy responses. The microbiome-derived metabolome may be one means through which bacterial metabolic products can be monitored from the start of treatment and could be used to identify patients at risk of poor immunotherapy responses. The current review will discuss recent advances and bring together literature from related fields in nutrition, oncology and immunology to discuss possible means of modulating immunity to improve responses to current CIT.
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Dieta/métodos , Microbioma Gastrointestinal/efectos de los fármacos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Metaboloma/inmunología , Neoplasias/tratamiento farmacológico , Animales , Bacterias/metabolismo , Dieta/efectos adversos , Disbiosis/complicaciones , Microbioma Gastrointestinal/inmunología , Humanos , Inmunomodulación , Estilo de Vida , Metaboloma/efectos de los fármacos , Ratones , Neoplasias/inmunologíaRESUMEN
Our understanding of chronic inflammation in obesity is evolving. Suggested mechanisms include hypoxia of adipose tissue and a subsequent increase in circulating cytokines. It is now known that adipose tissue, far from being an inert tissue, produces and secretes multiple peptides that influence inflammation and metabolism, including substrates of the renin-angiotensin-aldosterone system (RAAS). RAAS blocking antihypertensive medication and cholesterol-lowering agents are now being evaluated for their metabolic and inflammation-modulating effects. Surgery also has pro-inflammatory effects, which may be exacerbated in patients with obesity. This narrative review will summarise the recent literature surrounding obesity, metabolic syndrome, inflammation, and interplay with the RAAS, with evidence-based recommendations for the optimisation of patients with obesity, prior to surgery and anaesthesia.
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Síndrome Metabólico , Anestesistas , Humanos , Inflamación , Síndrome Metabólico/terapia , Obesidad/complicaciones , Obesidad/terapia , Atención al PacienteRESUMEN
Cancer immunotherapy with checkpoint blockade has become standard of care treatment for numerous cancer types. Despite this, robust predictive biomarkers are lacking. There is increasing evidence that the host microbiome is a predictor of immunotherapy response, although the optimal host microbiome has not been defined. Metabolomics is a new area of medicine that aims to analyze the metabolic profile of a biological system. The microbiome-derived metabolome (fecal and serum) represents the end products of microbial metabolism and these may be functionally more important than the distinct bacterial species that comprise a favorable microbiome. Short-chain fatty acids (SCFA) are metabolites produced by gut microbiota and have a role in T cell homeostasis, including differentiation of regulatory T cells. Recent studies have confirmed differential expression of SCFA for immunotherapy responders compared with non-responders. We propose that the microbiome metabolome, with a focus on SCFA may be a novel predictive biomarker for immunotherapy efficacy.
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Biomarcadores de Tumor/metabolismo , Inmunoterapia/métodos , Metaboloma/fisiología , Microbiota/fisiología , Neoplasias/inmunología , HumanosRESUMEN
The Pacific region, also referred to as Oceania, is a geographically widespread region populated by people of diverse cultures and ethnicities. Indigenous people in the region (Melanesians, Polynesians, Micronesians, Papuans, and Indigenous Australians) are over-represented on national, regional, and global scales for the burden of infectious and non-communicable diseases. Although social and environmental factors such as poverty, education, and access to health-care are assumed to be major drivers of this disease burden, there is also developing evidence that genetic and microbiotic factors should also be considered. To date, studies investigating genetic and/or microbiotic links with vulnerabilities to infectious and non-communicable diseases have mostly focused on populations in Europe, Asia, and USA, with uncertain associations for other populations such as indigenous communities in Oceania. Recent developments in personalized medicine have shown that identifying ethnicity-linked genetic vulnerabilities can be important for medical management. Although our understanding of the impacts of the gut microbiome on health is still in the early stages, it is likely that equivalent vulnerabilities will also be identified through the interaction between gut microbiome composition and function with pathogens and the host immune system. As rapid economic, dietary, and cultural changes occur throughout Oceania it becomes increasingly important that further research is conducted within indigenous populations to address the double burden of high rates of infectious diseases and rapidly rising non-communicable diseases so that comprehensive development goals can be planned. In this article, we review the current knowledge on the impact of nutrition, genetics, and the gut microbiome on infectious diseases in indigenous people of the Pacific region.
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Enfermedades Transmisibles/terapia , Microbiota , Enfermedades no Transmisibles/terapia , Salud Pública/estadística & datos numéricos , Determinantes Sociales de la Salud/estadística & datos numéricos , Enfermedades Transmisibles/etnología , Enfermedades Transmisibles/genética , Geografía , Servicios de Salud del Indígena/estadística & datos numéricos , Humanos , Pueblos Indígenas/estadística & datos numéricos , Enfermedades no Transmisibles/economía , Enfermedades no Transmisibles/etnología , OceaníaRESUMEN
Infection with helminths has been associated with lower rates of asthma and other allergic diseases. This has been attributed, in part, to the ability of helminths to induce regulatory T cells that suppress inappropriate immune responses to allergens. Recent compelling evidence suggests that helminths may promote regulatory T cell expansion or effector functions through either direct (secretion of excretory/secretory molecules) or indirect mechanisms (regulation of the microbiome). This review will discuss key findings from human immunoepidemiological observations, studies using animal models of disease, and clinical trials with live worm infections, discussing the therapeutic potential for worms and their secreted products for treating allergic inflammation.
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Helmintos/inmunología , Hipersensibilidad/inmunología , Hipersensibilidad/terapia , Linfocitos T Reguladores/inmunología , Animales , Humanos , Hipersensibilidad/prevención & controlRESUMEN
BACKGROUND: Resident memory T cells have emerged as key players in the immune response generated against a number of pathogens. Their ability to take residence in non-lymphoid peripheral tissues allows for the rapid deployment of secondary effector responses at the site of pathogen entry. This ability to provide enhanced regional immunity has gathered much attention, with the generation of resident memory T cells being the goal of many novel vaccines. OBJECTIVES: This review aimed to systematically analyze published literature investigating the role of resident memory T cells in human infectious diseases. Known effector responses mounted by these cells are summarized and key strategies that are potentially influential in the rational design of resident memory T cell inducing vaccines have also been highlighted. METHODS: A Boolean search was applied to Medline, SCOPUS, and Web of Science. Studies that investigated the effector response generated by resident memory T cells and/or evaluated strategies for inducing these cells were included irrespective of published date. Studies must have utilized an established technique for identifying resident memory T cells such as T cell phenotyping. RESULTS: While over 600 publications were revealed by the search, 147 articles were eligible for inclusion. The reference lists of included articles were also screened for other eligible publications. This resulted in the inclusion of publications that studied resident memory T cells in the context of over 25 human pathogens. The vast majority of studies were conducted in mouse models and demonstrated that resident memory T cells mount protective immune responses. CONCLUSION: Although the role resident memory T cells play in providing immunity varies depending on the pathogen and anatomical location they resided in, the evidence overall suggests that these cells are vital for the timely and optimal protection against a number of infectious diseases. The induction of resident memory T cells should be further investigated and seriously considered when designing new vaccines.
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ETHNOPHARMACOLOGICAL RELEVANCE: The traditional uses of Corydalis dubia, Ajania nubigena and Pleurospermum amabile in the Bhutanese traditional medicine for treating disorders related to inflammatory conditions and the in vitro anti-inflammatory activity of their crude extracts inspired the isolation and the investigation of anticolitic properties of four pure compounds. MATERIALS AND METHODS: Three medicinal plants were collected from Himalayan Mountains of Bhutan. Capnoidine and scoulerine were isolated from C. dubia, linalool oxide acetate from A. nubigena and isomyristicin from P. amabile using natural product isolation protocols. Four compounds were investigated for their anti-inflammatory activities against IBD-colitis using chemically induced (TNBS) mice model of colitis. Capnoidine conferred the best preliminary protection against TNBS-induced colitis in mice and we have conducted in-depth pharmacological investigation of this compound including clinical symptoms, pathological signs, cytokine profiles, histological structure and inflammasomes using relevant bioassay protocols. RESULTS: Capnoidine-treated mice had significantly: a) improved clinical symptoms (body weight loss, mobility, piloerection and faecal consistency); b) reduced colon pathology (adhesion, oedema, ulceration, and colon length); c) altered inflammatory cytokines profiles within the colons; d) reduced levels of p-IκB-α (Ser32) and p-NF-κB p65 (Ser536) and e) reduced histological inflammation in the colon when compared with mice administered TNBS only. CONCLUSION: Capnoidine presents as a potential new anti-inflammatory drug lead candidate for diseases where current standard-of-care often fails and is associated with major side effects. It also validates the traditional uses of C. dubia against inflammatory conditions and underlines the value of pursuing bioactive compounds derived from traditionally used ethnobotanical medicines.