A molecular signature for IL-10-producing Th1 cells in protozoan parasitic diseases.

Control of visceral leishmaniasis (VL) depends on proinflammatory Th1 cells that activate infected tissue macrophages to kill resident intracellular parasites. However, proinflammatory cytokines produced by Th1 cells can damage tissues and require tight regulation. Th1 cell IL-10 production is an important cell-autologous mechanism to prevent such damage. However, IL-10-producing Th1 (type 1 regulatory; Tr1) cells can also delay control of parasites and the generation of immunity following drug treatment or vaccination. To identify molecules to target in order to alter the balance between Th1 and Tr1 cells for improved antiparasitic immunity, we compared the molecular and phenotypic profiles of Th1 and Tr1 cells in experimental VL caused by Leishmania donovani infection of C57BL/6J mice. We also identified a shared Tr1 cell protozoan signature by comparing the transcriptional profiles of Tr1 cells from mice with experimental VL and malaria. We identified LAG3 as an important coinhibitory receptor in patients with VL and experimental VL, and we reveal tissue-specific heterogeneity of coinhibitory receptor expression by Tr1 cells. We also discovered a role for the transcription factor Pbx1 in suppressing CD4+ T cell cytokine production. This work provides insights into the development and function of CD4+ T cells during protozoan parasitic infections and identifies key immunoregulatory molecules.

STING activation promotes autologous type I interferon-dependent development of type 1 regulatory T cells during malaria.

The development of highly effective malaria vaccines and improvement of drug-treatment protocols to boost antiparasitic immunity are critical for malaria elimination. However, the rapid establishment of parasite-specific immune regulatory networks following exposure to malaria parasites hampers these efforts. Here, we identified stimulator of interferon genes (STING) as a critical mediator of type I interferon production by CD4+ T cells during blood-stage Plasmodium falciparum infection. The activation of STING in CD4+ T cells by cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) stimulated IFNB gene transcription, which promoted development of IL-10- and IFN-γ-coproducing CD4+ T (type I regulatory [Tr1]) cells. The critical role for type I IFN signaling for Tr1 cell development was confirmed in vivo using a preclinical malaria model. CD4+ T cell sensitivity to STING phosphorylation was increased in healthy volunteers following P. falciparum infection, particularly in Tr1 cells. These findings identified STING expressed by CD4+ T cells as an important mediator of type I IFN production and Tr1 cell development and activation during malaria.

Factores de riesgo ocupacional en profesionales de la salud de un hospital de Pucallpa-Perú / Occupational risk factors in health professionals of a hospital in Pucallpa-Peru / Fatores de risco ocupacional em profissionais de saúde em um hospital em Pucallpa-Peru

Los profesionales de la salud dentro del área de emergencia están expuestos a los diferentes riesgos ocupacionales, en donde pueden sufrir daños, lesiones, o contagios dentro del ámbito laboral mientras afrontan su jornada. Los peligros presentes pueden afectar de manera individual o colectiva, y tienen la posibilidad de desencadenar alguna modificación en la salud del trabajador, trayendo consigo alteraciones en el desarrollo ocasionando bajo rendimiento laboral o incumplimiento de los objetivos que tiene el hospital. Objetivo. Identificar el riesgo ocupacional en profesionales de la salud del servicio de emergencia del Hospital Regional de Pucallpa, 2022. Materiales y métodos. Se realizó un estudio de análisis descriptivo con diseño no experimental; de corte transversal -prospectivo; con una población muestral de 81 profesionales de la salud del servicio de emergencia del Hospital Regional de Pucallpa; como técnica se utilizó la encuesta y como instrumento un cuestionario con cuatro alternativas de escala de valor. Resultados. El 65.4% son del género femenino; el 64.2% tiene entre 31 a 40 años. El riesgo ocupacional en el 48.2% indica que es alto; el 33.3% indican que es medio, y el 18.5% indica que es bajo. Conclusiones. El riesgo ocupacional es alto; así mismo, en las dimensiones químico, físico, ergonómico, psicosocial es alto, mientras que en la dimensión biológico es bastante alto.

Health professionals in the emergency area are exposed to different occupational hazards, where they can suffer damages, injuries, or contagions within the work environment while facing their workday. The hazards present can affect individually or collectively, and have the possibility of triggering some modification in the worker's health, bringing with them alterations in the development causing low work performance or failure to meet the objectives of the hospital. Objective. To identify the occupational risk in health professionals of the emergency service of the Regional Hospital of Pucallpa, 2022. Materials and methods. A descriptive analysis study was carried out with a non-experimental design; cross-sectional -prospective; with a sample population of 81 health professionals of the emergency service of the Regional Hospital of Pucallpa; a survey was used as a technique and a questionnaire with four alternative value scales was used as an instrument. Results. The 65.4% were female; 64.2% were between 31 and 40 years old. The occupational risk in 48.2% indicated that it was high; 33.3% indicated that it was medium, and 18.5% indicated that it was low. Conclusions. The occupational risk is high; likewise, in the chemical, physical, ergonomic and psychosocial dimensions it is high, while in the biological dimension it is quite high.

Os profissionais de saúde da área de emergência estão expostos a diferentes riscos ocupacionais, nos quais podem sofrer danos, lesões ou contágio no local de trabalho durante o exercício da profissão. Os perigos presentes podem afetar de forma individual ou coletiva, e têm o potencial de desencadear alguma modificação na saúde do trabalhador, trazendo consigo alterações no desenvolvimento causando baixo desempenho no trabalho ou o não cumprimento dos objetivos do hospital. Objetivo. Identificar o risco ocupacional em profissionais de saúde do serviço de emergência do Hospital Regional de Pucallpa, 2022. Materiais e métodos. Foi realizado um estudo de análise descritiva com um desenho não experimental; transversal -prospectivo; com uma população amostral de 81 profissionais de saúde do serviço de emergência do Hospital Regional de Pucallpa; foi utilizada como técnica uma pesquisa e como instrumento um questionário com quatro escalas de valores alternativos. Resultados. 65,4% eram do sexo feminino; 64,2% tinham entre 31 e 40 anos de idade. O risco ocupacional foi alto em 48,2%, médio em 33,3% e baixo em 18,5%. Conclusões. O risco ocupacional é alto; da mesma forma, nas dimensões química, física, ergonômica e psicossocial ele é alto, enquanto na dimensão biológica ele é bastante alto.

Calidad de vida laboral y desempeño del personal en un Hospital Materno Infantil del Perú / Quality of work life and staff performance in a Maternal and Child Hospital of Perú / Qualidade de vida no trabalho e desempenho do pessoal em um Hospital Materno-Infantil do Perú

En los años 70, desarrollaron el término calidad de vida laboral, sin embargo, no se pudo reducir el riesgo de exposición a situaciones peligrosas en el trabajo, por lo que fue necesario perfeccionar el entorno laboral. El empleo es fundamental para la vida y la sociedad, porque la mayoría de nuestro tiempo es absorbido por las acciones laborales; la calidad de vida laboral es fundamental para la satisfacción y sobre todo para el desempeño en el trabajo. Objetivo. Determinar la relación entre calidad de vida laboral y desempeño del personal de salud en tiempos de pandemia en el Hospital Materno Infantil "Carlos Showing Ferrari, Amarilis - Huánuco, 2021. Materiales y método. Estudio de enfoque cuantitativo, tipo prospectivo, observacional, transversal y de nivel relacional. Con una población de 161 y una muestra de 114 elementos. La técnica fue la encuesta y los instrumentos fueron: cuestionario de calidad laboral GOHISALO modificado y un cuestionario de desempeño. Resultados. El 54.4% tienen regular calidad de vida laboral, el 38.6 % alta calidad de vida laboral y el 7% baja calidad de vida laboral. Respecto al desempeño, el 53.5% presentó regular desempeño, el 40.4% buen desempeño y el 6.1% deficiente desempeño. En cuanto a la relación entre calidad de vida laboral y desempeño, el 27.2% reportaron alta calidad de vida laboral y buen desempeño; 3.5% tuvieron deficiente calidad de vida y deficiente desempeño. Conclusiones. Existe relación entre calidad de vida laboral y desempeño (X2: 55,750, p =0.000), con un nivel asociación moderado (V de Cramer=0.494).

In the 1970s, they developed the term quality of work life, however, it was not possible to reduce the risk of exposure to hazardous situations at work, so it was necessary to improve the work environment. Employment is fundamental to life and society, because most of our time is absorbed by work actions; quality of work life is fundamental to satisfaction and specially to job performance. Objective. To determine the relationship between quality of work life and performance of health personnel in times of pandemic in the Maternal and Child Hospital "Carlos Showing Ferrari, Amarilis - Huánuco, 2021. Materials and Method. A quantitative, prospective, observational, cross-sectional and relational study. With a population of 161 and a sample of 114 elements. The technique was the survey and the instruments were: modified GOHISALO work quality questionnaire and a performance questionnaire. Results. 54.4% have a regular quality of work life, 38.6% have a high quality of work life and 7% have a low quality of work life. Regarding performance, 53.5% presented fair performance, 40.4% good performance and 6.1% poor performance. Regarding the relationship between quality of work life and performance, 27.2% reported high quality of work life and good performance; 3.5% had poor quality of life and poor performance. Conclusions. There is a relationship between quality of work life and performance (X2: 55.750, p =0.000), with a moderate level of association (Cramer's V=0.494).

Na década de 1970, o termo qualidade de vida no trabalho foi desenvolvido; no entanto, não era possível reduzir o risco de exposição a situações perigosas no trabalho, portanto, era necessário melhorar o ambiente de trabalho. O emprego é fundamental para a vida e a sociedade, pois a maior parte de nosso tempo é absorvida por ações de trabalho; a qualidade de vida no trabalho é fundamental para a satisfação no trabalho e, acima de tudo, para o desempenho no trabalho. Objetivo. Determinar a relação entre a qualidade de vida no trabalho e o desempenho do pessoal de saúde em tempos de pandemia no Hospital Materno-Infantil "Carlos Showing Ferrari, Amarilis - Huánuco, 2021. Materiais e método. Estudo quantitativo, prospectivo, observacional, transversal e relacional. Com uma população de 161 e uma amostra de 114 elementos. A técnica foi a pesquisa e os instrumentos foram: questionário de qualidade de trabalho GOHISALO modificado e um questionário de desempenho. Resultados. 54,4% têm uma qualidade de vida no trabalho razoável, 38,6% têm uma qualidade de vida no trabalho elevada e 7% têm uma qualidade de vida no trabalho baixa. Com relação ao desempenho, 53,5% apresentaram desempenho razoável, 40,4% bom desempenho e 6,1% desempenho ruim. Quanto à relação entre qualidade de vida no trabalho e desempenho, 27,2% relataram alta qualidade de vida no trabalho e bom desempenho; 3,5% apresentaram qualidade de vida ruim e desempenho ruim. Conclusões. Existe uma relação entre a qualidade de vida no trabalho e o desempenho (X2: 55,750, p = 0,000), com um nível moderado de associação (V de Cramer = 0,494).

IL-10-producing Th1 cells possess a distinct molecular signature in malaria

Control of intracellular parasites responsible for malaria requires host IFN-γ+T-bet+CD4+ T cells (Th1 cells) with IL-10 produced by Th1 cells to mitigate the pathology induced by this inflammatory response. However, these IL-10-producing Th1 (induced type I regulatory [Tr1]) cells can also promote parasite persistence or impair immunity to reinfection or vaccination. Here, we identified molecular and phenotypic signatures that distinguished IL-10-Th1 cells from IL-10+Tr1 cells in Plasmodium falciparum-infected people who participated in controlled human malaria infection studies, as well as C57BL/6 mice with experimental malaria caused by P. berghei ANKA. We also identified a conserved Tr1 cell molecular signature shared between patients with malaria, dengue, and graft-versus-host disease. Genetic manipulation of primary human CD4+ T cells showed that the transcription factor cMAF played an important role in the induction of IL-10, while BLIMP-1 promoted the development of human CD4+ T cells expressing multiple coinhibitory receptors. We also describe heterogeneity of Tr1 cell coinhibitory receptor expression that has implications for targeting these molecules for clinical advantage during infection. Overall, this work provides insights into CD4+ T cell development during malaria that offer opportunities for creation of strategies to modulate CD4+ T cell functions and improve antiparasitic immunity.

Increased amphiregulin expression by CD4+ T cells from individuals with asymptomatic Leishmania donovani infection.

Objectives: There is an urgent need to be able to identify individuals with asymptomatic Leishmania donovani infection, so their risk of progressing to VL and transmitting parasites can be managed. This study examined transcriptional markers expressed by CD4+ T cells that could distinguish asymptomatic individuals from endemic controls and visceral leishmaniasis (VL) patients. Methods: CD4+ T cells were isolated from individuals with asymptomatic L. donovani infection, endemic controls and VL patients. RNA was extracted and RNAseq employed to identify differentially expressed genes. The expression of one gene and its protein product during asymptomatic infection were evaluated. Results: Amphiregulin (AREG) was identified as a distinguishing gene product in CD4+ T cells from individuals with asymptomatic L. donovani infection, compared to VL patients and healthy endemic control individuals. AREG levels in plasma and antigen-stimulated whole-blood assay cell culture supernatants were significantly elevated in asymptomatic individuals, compared to endemic controls and VL patients. Regulatory T (Treg) cells were identified as an important source of AREG amongst CD4+ T-cell subsets in asymptomatic individuals. Conclusion: Increased Treg cell AREG expression was identified in individuals with asymptomatic L. donovani infection, suggesting the presence of an ongoing inflammatory response in these individuals required for controlling infection and that AREG may play an important role in preventing inflammation-induced tissue damage and subsequent disease in asymptomatic individuals.

Maximum Dose Food Challenges Reveal Transient Sustained Unresponsiveness in Peanut Oral Immunotherapy (POIMD Study).

BACKGROUND: The maximum tolerated dose of peanut protein following peanut oral immunotherapy (POIT) is unknown because most research studies have not examined very high thresholds. OBJECTIVE: To define the maximum dose tolerated by patients on POIT and severity of allergic reactions after a 1-month period of treatment discontinuation. METHODS: In a phase 2 3-year POIT open-label study, we enrolled participants age 5 to 13 years with a 1-year build-up period followed by a 2-year daily maintenance dose of 3900 mg with assessment of the maximum tolerated dose using double-blind placebo-controlled food challenges (DBPCFCs) of 26,225 mg cumulative dose of peanut protein. The DBPCFC was performed at baseline, after 12-month build-up, at 2 year of maintenance, and after a 1-month period of treatment discontinuation. Biomarkers were assessed every 6 weeks for the first 6 months of therapy. A general linear mixed model was used for analysis. RESULTS: The mean maximum cumulative tolerated dose after 12 months increased by 12,063 mg (P < .001) (n = 12), slightly decreased during maintenance (n = 11), and significantly decreased by 7593 mg after avoidance for 1 month (P = .03) (n = 6). Biomarker analysis revealed decreases in cytokine expression within the first 6 weeks of initiation of POIT and decreased peanut-IgG4 and increased cytokine expression after 1 month of discontinuation. The DBPCFC reaction severity, examined through a symptom score with 1 point for each defined symptom, decreased after 12 months, but did not significantly change after 1 month of POIT discontinuation. CONCLUSIONS: The evaluation of POIT and sustained unresponsiveness by maximum tolerated dose by DBPCFCs in this small phase 2 trial showed that desensitization is diminished, with 100% loss of tolerated dose after 1 month of avoidance following 3 years of treatment.

Liothyronine use in primary hypothyroidism - current concepts.

Hypothyroidism is an endocrine disorder whose management raises many challenges in clinical practice. Its standard treatment is levothyroxine (LT4). The goal of the treatment is to normalize signs and symptoms, as well as to achieve thyroid-stimulating hormone (TSH) concentrations within the reference range, on an individual basis. It is known that 5-10% of hypothyroid patients remain symptomatic, despite achieving the target TSH levels, which, in turn, affects their quality of life. After ruling out other causes of non-thyroid origin for this persistence, it is suggested that these patients could benefit from the use of liothyronine (LT3), added to LT4, especially if polymorphism of the deiodinase 2 (D2) genes is documented. There exist a variety of LT3 preparations, whose concentrations vary from 5 to 50 ug, with the recommended LT4/LT3 ratio of 13:1-20:1. The goals of combination therapy should be to achieve a physiological ratio of free triiodothyronine/free thyroxine (FT3/FT4) and non-suppression of TSH. Because there is currently no guide that makes evidence-based recommendations on the use of LT3 in primary hypothyroidism, more clinical studies are needed to be able to identify hypothyroid patients who may benefit from the use of LT3, by identifying new biomarkers.

Safety, infectivity and immunogenicity of a genetically attenuated blood-stage malaria vaccine.

BACKGROUND: There is a clear need for novel approaches to malaria vaccine development. We aimed to develop a genetically attenuated blood-stage vaccine and test its safety, infectivity, and immunogenicity in healthy volunteers. Our approach was to target the gene encoding the knob-associated histidine-rich protein (KAHRP), which is responsible for the assembly of knob structures at the infected erythrocyte surface. Knobs are required for correct display of the polymorphic adhesion ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1), a key virulence determinant encoded by a repertoire of var genes. METHODS: The gene encoding KAHRP was deleted from P. falciparum 3D7 and a master cell bank was produced in accordance with Good Manufacturing Practice. Eight malaria naïve males were intravenously inoculated (day 0) with 1800 (2 subjects), 1.8 × 105 (2 subjects), or 3 × 106 viable parasites (4 subjects). Parasitemia was measured using qPCR; immunogenicity was determined using standard assays. Parasites were rescued into culture for in vitro analyses (genome sequencing, cytoadhesion assays, scanning electron microscopy, var gene expression). RESULTS: None of the subjects who were administered with 1800 or 1.8 × 105 parasites developed parasitemia; 3/4 subjects administered 3× 106 parasites developed significant parasitemia, first detected on days 13, 18, and 22. One of these three subjects developed symptoms of malaria simultaneously with influenza B (day 17; 14,022 parasites/mL); one subject developed mild symptoms on day 28 (19,956 parasites/mL); and one subject remained asymptomatic up to day 35 (5046 parasites/mL). Parasitemia rapidly cleared with artemether/lumefantrine. Parasitemia induced a parasite-specific antibody and cell-mediated immune response. Parasites cultured ex vivo exhibited genotypic and phenotypic properties similar to inoculated parasites, although the var gene expression profile changed during growth in vivo. CONCLUSIONS: This study represents the first clinical investigation of a genetically attenuated blood-stage human malaria vaccine. A P. falciparum 3D7 kahrp- strain was tested in vivo and found to be immunogenic but can lead to patent parasitemia at high doses. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (number: ACTRN12617000824369 ; date: 06 June 2017).

Vaccination of human participants with attenuated Necator americanus hookworm larvae and human challenge in Australia: a dose-finding study and randomised, placebo-controlled, phase 1 trial.

BACKGROUND: Control of human hookworm infection would be greatly aided by the development of an effective vaccine. We aimed to develop a live attenuated human hookworm vaccine. METHODS: This was a two-part clinical trial done at Q-Pharm in Brisbane (QLD, Australia) using a live ultraviolet C (UVC)-attenuated Necator americanus larvae vaccine. Part one was an open-label, dose-finding study using 50 L3 larvae suspended in water to a volume of 200 µL, attenuated with UVC exposure of 700 µJ (L3-700) or 1000 µJ (L3-1000). Part two was a randomised, double-blind, placebo-controlled, challenge study, in which participants were randomly assigned 2:1 to the vaccine group or placebo group. Healthy hookworm-naive adults aged 18-65 years with body-mass index 18-35 kg/m2 received two doses of either placebo (Tabasco sauce) or vaccine (50 L3-700) on day 1 and day 42, followed by challenge with 30 unattenuated L3 larvae to both groups. All participants received a single oral dose of 400 mg albendazole 4 weeks after each inoculation and a 3-day course (400 mg orally daily) initiated on day 161 after the challenge phase, to eliminate any remaining infection. The primary outcome of part 1 was the level of larval attenuation the resulted in a grade 2 or 3 dermal adverse event. The primary outcome of part 2 was safety and tolerability, assessed by frequency and severity of adverse events in all randomly assigned participants. Prespecified exploratory outcomes in the challenge study were faecal N americanus DNA concentration, the number of N americanus larvae recovered per g of faeces cultured, hookworm antigen-specific serum IgG antibody responses, and hookworm antigen-specific peripheral blood cytokine responses. The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617001007325). FINDINGS: Between Sept 19, 2017, and Oct 24, 2018, seven participants were enrolled into three cohorts in part one (two participants in cohort 1, who received L3-700; two participants in cohort 2, who received L3-700; and three participants in cohort 3, who received L3-1000) and a further 15 were enrolled into part two. There were no serious adverse events in part one or part two. In part one, a greater number of skin penetration sites were observed after administration of L3-700 than L3-1000 (mean 15·75 [95% CI 11·18 to 20·32] with L3-700 vs 4·33 [-1·40 to 10·07] with L3-1000). Similarly, greater erythema (median 225 mm2 [IQR 150 to 325] vs 25 mm2 [12·5 to 80]) and a longer duration of the dermal reaction (median 8·0 days [IQR 3·5 to 11·5] vs 2·0 days [2·0 to 4·5]) were observed after L3-700 than L3-1000. The mean number of adverse events per participant did not differ between the groups (3·25 [95% CI 1·48 to 5·02] vs 3·00 [1·04 to 4·96]). Thus, L3-700 was used for vaccination in part two. In part two, ten participants were randomly assigned to receive L3-700 and five to placebo. Significantly more adverse events occurred after vaccination with attenuated larvae than with placebo (incident rate ratio [IRR] 2·13 [95% CI 2·09 to 5·51]; p=0·0030). There was no difference between groups in the frequency of adverse events after challenge (IRR 1·25 [0·78 to 2·01]; p=0·36). Most adverse events were mild in severity, with only one severe adverse event reported (erythematous and indurated pruritic rash >100 mm in a vaccine group participant after challenge). The eosinophil count increased in all participants after challenge, with a significantly greater increase among vaccinated participants than placebo participants (1·55 × 109 cells per L [IQR 0·92 to 1·81] in the vaccine group vs 0·49 × 109 cells per L [0·43 to 0·63] in the placebo group; p=0·014). Vaccinated participants had an IgG response to larval extract after challenge that was higher than that in placebo participants (increase in IgG titre 0·22 [IQR 0·10 to 0·41] vs 0·03 [-0·40 to 0·06]; p=0·020). Significantly fewer larvae per g of faeces were recovered in the vaccine group than in the placebo group after challenge (median larvae per g 0·8 [IQR 0·00 to 3·91] vs 10·2 [5·1 to 18·1]; p=0·014). The concentration of N americanus DNA in faeces was not significantly different between the vaccinated group and the placebo group (log10 DNA intensity 4·28 [95% CI 3·92 to 4·63] vs 4·88 [4·31 to 5·46]; p=0·14). Peripheral blood mononuclear cells from vaccinated participants exhibited significantly greater cytokine production at day 112 than placebo participants for IFNγ, TNFα, IL-2, IL-4, and IL-5 (p<0·05), but not IL-10. INTERPRETATION: Vaccination with UVC-attenuated N americanus larvae is well tolerated, induces humoral and cellular responses to hookworm antigens, and reduces larval output after challenge with unattenuated larvae. Larger studies are required to confirm protective efficacy. FUNDING: National Health and Medical Research Council of Australia.

Th2-like T Follicular Helper Cells Promote Functional Antibody Production during Plasmodium falciparum Infection.

CD4+ T follicular helper cells (Tfh) are key drivers of antibody development. During Plasmodium falciparum malaria in children, the activation of Tfh is restricted to the Th1 subset and not associated with antibody levels. To identify Tfh subsets that are associated with antibody development in malaria, we assess Tfh and antibodies longitudinally in human volunteers with experimental P. falciparum infection. Tfh cells activate during infection, with distinct dynamics in different Tfh subsets. Th2-Tfh cells activate early, during peak infection, while Th1-Tfh cells activate 1 week after peak infection and treatment. Th2-Tfh cell activation is associated with the functional breadth and magnitude of parasite antibodies. In contrast, Th1-Tfh activation is not associated with antibody development but instead with plasma cells, which have previously been shown to play a detrimental role in the development of long-lived immunity. Thus, our study identifies the contrasting roles of Th2 and Th1-Tfh cells during experimental P. falciparum malaria.

IL-27 signalling regulates glycolysis in Th1 cells to limit immunopathology during infection.

Inflammation is critical for controlling pathogens, but also responsible for symptoms of infectious diseases. IL-27 is an important regulator of inflammation and can limit development of IFNγ-producing Tbet+ CD4+ T (Th1) cells. IL-27 is thought to do this by stimulating IL-10 production by CD4+ T cells, but the underlying mechanisms of these immunoregulatory pathways are not clear. Here we studied the role of IL-27 signalling in experimental visceral leishmaniasis (VL) caused by infection of C57BL/6 mice with the human pathogen Leishmania donovani. We found IL-27 signalling was critical for the development of IL-10-producing Th1 (Tr1) cells during infection. Furthermore, in the absence of IL-27 signalling, there was improved control of parasite growth, but accelerated splenic pathology characterised by the loss of marginal zone macrophages. Critically, we discovered that IL-27 signalling limited glycolysis in Th1 cells during infection that in turn attenuated inflammation. Furthermore, the modulation of glycolysis in the absence of IL-27 signalling restricted tissue pathology without compromising anti-parasitic immunity. Together, these findings identify a novel mechanism by which IL-27 mediates immune regulation during disease by regulating cellular metabolism.

The NK cell granule protein NKG7 regulates cytotoxic granule exocytosis and inflammation.

Immune-modulating therapies have revolutionized the treatment of chronic diseases, particularly cancer. However, their success is restricted and there is a need to identify new therapeutic targets. Here, we show that natural killer cell granule protein 7 (NKG7) is a regulator of lymphocyte granule exocytosis and downstream inflammation in a broad range of diseases. NKG7 expressed by CD4+ and CD8+ T cells played key roles in promoting inflammation during visceral leishmaniasis and malaria-two important parasitic diseases. Additionally, NKG7 expressed by natural killer cells was critical for controlling cancer initiation, growth and metastasis. NKG7 function in natural killer and CD8+ T cells was linked with their ability to regulate the translocation of CD107a to the cell surface and kill cellular targets, while NKG7 also had a major impact on CD4+ T cell activation following infection. Thus, we report a novel therapeutic target expressed on a range of immune cells with functions in different immune responses.

Infection-induced plasmablasts are a nutrient sink that impairs humoral immunity to malaria.

Plasmodium parasite-specific antibodies are critical for protection against malaria, yet the development of long-lived and effective humoral immunity against Plasmodium takes many years and multiple rounds of infection and cure. Here, we report that the rapid development of short-lived plasmablasts during experimental malaria unexpectedly hindered parasite control by impeding germinal center responses. Metabolic hyperactivity of plasmablasts resulted in nutrient deprivation of the germinal center reaction, limiting the generation of memory B cell and long-lived plasma cell responses. Therapeutic administration of a single amino acid to experimentally infected mice was sufficient to overcome the metabolic constraints imposed by plasmablasts and enhanced parasite clearance and the formation of protective humoral immune memory responses. Thus, our studies not only challenge the current model describing the role and function of blood-stage Plasmodium-induced plasmablasts but they also reveal new targets and strategies to improve anti-Plasmodium humoral immunity.

Type I Interferons Suppress Anti-parasitic Immunity and Can Be Targeted to Improve Treatment of Visceral Leishmaniasis.

Type I interferons (IFNs) play critical roles in anti-viral and anti-tumor immunity. However, they also suppress protective immune responses in some infectious diseases. Here, we identify type I IFNs as major upstream regulators of CD4+ T cells from visceral leishmaniasis (VL) patients. Furthermore, we report that mice deficient in type I IFN signaling have significantly improved control of Leishmania donovani, a causative agent of human VL, associated with enhanced IFNγ but reduced IL-10 production by parasite-specific CD4+ T cells. Importantly, we identify a small-molecule inhibitor that can be used to block type I IFN signaling during established infection and acts synergistically with conventional anti-parasitic drugs to improve parasite clearance and enhance anti-parasitic CD4+ T cell responses in mice and humans. Thus, manipulation of type I IFN signaling is a promising strategy for improving disease outcome in VL patients.

Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis.

Differentiation and homeostasis of Foxp3+ regulatory T (Treg) cells are strictly controlled by T-cell receptor (TCR) signals; however, molecular mechanisms that govern these processes are incompletely understood. Here we show that Bach2 is an important regulator of Treg cell differentiation and homeostasis downstream of TCR signaling. Bach2 prevents premature differentiation of fully suppressive effector Treg (eTreg) cells, limits IL-10 production and is required for the development of peripherally induced Treg (pTreg) cells in the gastrointestinal tract. Bach2 attenuates TCR signaling-induced IRF4-dependent Treg cell differentiation. Deletion of IRF4 promotes inducible Treg cell differentiation and rescues pTreg cell differentiation in the absence of Bach2. In turn, loss of Bach2 normalizes eTreg cell differentiation of IRF4-deficient Treg cells. Mechanistically, Bach2 counteracts the DNA-binding activity of IRF4 and limits chromatin accessibility, thereby attenuating IRF4-dependent transcription. Thus, Bach2 balances TCR signaling induced transcriptional activity of IRF4 to maintain homeostasis of thymically-derived and peripherally-derived Treg cells.

HIV/AIDS stigma manifestations during clinical interactions with MSM in Puerto Rico.

HIV/AIDS stigma can have detrimental effects on physician/patient interactions when manifested by health professionals. Unfortunately, HIV/AIDS stigma is usually manifested in an intersectional manner with other pre-existing stigmas, including stigma towards men who have sex with men (MSM). Therefore, our study aimed to examine the behavioral manifestations of HIV/AIDS stigma among physicians in training during simulated clinical interactions with MSM, and explore the interrelation between HIV/AIDS stigma attitudes and behaviors. We implemented an experimental design using Standardized Patient simulations with a sample of 100 physicians in training in Puerto Rico. Results show a significant difference in the two groups' means (p<.001), with a higher number of stigma behaviors in the HIV MSM patient condition (M=6.39) than the common cold control condition (M=5.20). Results evidence that stigma manifestations towards MSM with HIV may continue to be an obstacle for public health in Puerto Rico, and that medical training to prevent stigma is still needed.