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1.
Antimicrob Agents Chemother ; : AAC0158421, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34694880

RESUMO

Despite repeated malaria infection, individuals living in malaria endemic areas remain vulnerable to re-infection. The Janus kinase (JAK1/2) inhibitor ruxolitinib could potentially disrupt the parasite-induced dysfunctional immune response when administered with anti-malarial therapy. This randomized, single-blind, placebo-controlled, single center phase 1 trial investigated the safety, tolerability, pharmacokinetic and pharmacodynamic profile of ruxolitinib and the approved antimalarial artemether-lumefantrine in combination. Ruxolitinib pharmacodynamics were assessed by inhibition of phosphorylation of signal transducer and activator of transcription 3 (pSTAT3). Eight healthy male and female participants aged 18-55 years were randomized to either ruxolitinib (20 mg) (n = 6) or placebo (n = 2) administered 2 h after artemether-lumefantrine (80/480 mg) twice daily for three days. Mild adverse events occurred in six participants (four ruxolitinib; two placebo). The combination of artemether-lumefantrine and ruxolitinib was well tolerated, with adverse events and pharmacokinetics consistent with the known profiles of both drugs. The incidence of adverse events and artemether, dihydroartemisinin (the major active metabolite of artemether) and lumefantrine exposure were not affected by ruxolitinib co-administration. Ruxolitinib co-administration resulted in a 3-fold greater pSTAT3 inhibition compared to placebo (geometric mean ratio: 3.01 [90%CI 2.14, 4.24]), with a direct and predictable relationship between ruxolitinib plasma concentrations and %pSTAT3 inhibition. This study supports the investigation of the combination of artemether-lumefantrine and ruxolitinib in healthy volunteers infected with Plasmodium falciparum malaria. (This study has been registered at ClinicalTrials.gov under registration no. NCT04456634).

2.
J Cell Physiol ; 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34698381

RESUMO

Amphiregulin (AREG), which acts as one of the ligands for epidermal receptor growth factor receptor (EGFR), plays a crucial role in tissue repair, inflammation, and immunity. AREG is synthesized as membrane-anchored pre-protein, and is excreted after proteolytic cleavage, and serves as an autocrine or paracrine factor. After engagement with the EGFR, AREG triggers a cascade of signaling events required for many cellular physiological processes including metabolism, cell cycle, and proliferation. Under different inflammatory and pathogenic conditions, AREG is expressed by various activated immune cells that orchestrate both tolerance and host resistance mechanisms. Several factors including xenobiotics, cytokines, and inflammatory lipids have been shown to trigger AREG gene expression and release. In this review, we discuss the structure, function, and regulation of AREG, its role in tissue repair, inflammation, and homeostasis as well as the potential of AREG as a biomarker and therapeutic target.

3.
Lancet Infect Dis ; 21(12): 1725-1736, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34419209

RESUMO

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.

4.
Nat Metab ; 3(7): 892-893, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34113020
5.
Cell ; 184(8): 2167-2182.e22, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33811809

RESUMO

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1ß, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.


Assuntos
COVID-19/complicações , Cardiotônicos/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Cardiopatias/tratamento farmacológico , Quinazolinonas/uso terapêutico , Fatores de Transcrição/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/tratamento farmacológico , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Citocinas/metabolismo , Feminino , Cardiopatias/etiologia , Células-Tronco Embrionárias Humanas , Humanos , Inflamação/complicações , Inflamação/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição/metabolismo
6.
Malar J ; 20(1): 97, 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33593383

RESUMO

BACKGROUND: Plasmodium falciparum malaria increases plasma levels of the cytokine Fms-like tyrosine kinase 3 ligand (Flt3L), a haematopoietic factor associated with dendritic cell (DC) expansion. It is unknown if the zoonotic parasite Plasmodium knowlesi impacts Flt3L or DC in human malaria. This study investigated circulating DC and Flt3L associations in adult malaria and in submicroscopic experimental infection. METHODS: Plasma Flt3L concentration and blood CD141+ DC, CD1c+ DC and plasmacytoid DC (pDC) numbers were assessed in (i) volunteers experimentally infected with P. falciparum and in Malaysian patients with uncomplicated (ii) P. falciparum or (iii) P. knowlesi malaria. RESULTS: Plasmodium knowlesi caused a decline in all circulating DC subsets in adults with malaria. Plasma Flt3L was elevated in acute P. falciparum and P. knowlesi malaria with no increase in a subclinical experimental infection. Circulating CD141+ DCs, CD1c+ DCs and pDCs declined in all adults tested, for the first time extending the finding of DC subset decline in acute malaria to the zoonotic parasite P. knowlesi. CONCLUSIONS: In adults, submicroscopic Plasmodium infection causes no change in plasma Flt3L but does reduce circulating DCs. Plasma Flt3L concentrations increase in acute malaria, yet this increase is insufficient to restore or expand circulating CD141+ DCs, CD1c+ DCs or pDCs. These data imply that haematopoietic factors, yet to be identified and not Flt3L, involved in the sensing/maintenance of circulating DC are impacted by malaria and a submicroscopic infection. The zoonotic P. knowlesi is similar to other Plasmodium spp in compromising DC in adult malaria.


Assuntos
Células Dendríticas/metabolismo , Malária/parasitologia , Proteínas de Membrana/sangue , Doença Aguda , Adulto , Feminino , Humanos , Malária Falciparum/parasitologia , Masculino , Pessoa de Meia-Idade , Plasma/química , Plasmodium falciparum/fisiologia , Plasmodium knowlesi/fisiologia , Adulto Jovem
7.
Cell Rep Med ; 1(9): 100157, 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33377128

RESUMO

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.

8.
Nat Immunol ; 21(12): 1597-1610, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046889

RESUMO

The dynamics of CD4+ T cell memory development remain to be examined at genome scale. In malaria-endemic regions, antimalarial chemoprevention protects long after its cessation and associates with effects on CD4+ T cells. We applied single-cell RNA sequencing and computational modelling to track memory development during Plasmodium infection and treatment. In the absence of central memory precursors, two trajectories developed as T helper 1 (TH1) and follicular helper T (TFH) transcriptomes contracted and partially coalesced over three weeks. Progeny of single clones populated TH1 and TFH trajectories, and fate-mapping suggested that there was minimal lineage plasticity. Relationships between TFH and central memory were revealed, with antimalarials modulating these responses and boosting TH1 recall. Finally, single-cell epigenomics confirmed that heterogeneity among effectors was partially reset in memory. Thus, the effector-to-memory transition in CD4+ T cells is gradual during malaria and is modulated by antiparasitic drugs. Graphical user interfaces are presented for examining gene-expression dynamics and gene-gene correlations ( http://haquelab.mdhs.unimelb.edu.au/cd4_memory/ ).


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Memória Imunológica , Malária/imunologia , Plasmodium/imunologia , Transcriptoma , Transferência Adotiva , Animais , Antimaláricos/farmacologia , Biomarcadores , Cromatina/genética , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Malária/parasitologia , Malária/terapia , Camundongos , Plasmodium/efeitos dos fármacos
9.
PLoS Pathog ; 16(10): e1008994, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33049000

RESUMO

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.


Assuntos
Interleucinas/metabolismo , Leishmaniose Visceral/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Feminino , Glicólise , Interferon gama/imunologia , Interleucinas/imunologia , Leishmania donovani/imunologia , Leishmaniose Visceral/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/imunologia , Baço/imunologia
10.
Immunol Cell Biol ; 98(8): 620-622, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32895977

RESUMO

Holz et al. report a glycolipid-conjugate vaccine that provides sterile immunity in mice against Plasmodium berghei ANKA sporozoite challenge by inducing long-lasting tissue-resident memory (TRM) CD8+ T cells in the liver.


Assuntos
Vacinas Anticâncer , Vacinas Antimaláricas , Malária , Animais , Linfócitos T CD8-Positivos/imunologia , Glicolipídeos , Memória Imunológica , Fígado/imunologia , Malária/prevenção & controle , Camundongos , Peptídeos , Roedores , Vacinação , Vacinas de Subunidades
11.
Nat Immunol ; 21(10): 1205-1218, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32839608

RESUMO

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.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Inflamação/imunologia , Células Matadoras Naturais/imunologia , Leishmania donovani/fisiologia , Leishmaniose Visceral/imunologia , Malária/imunologia , Proteínas de Membrana/metabolismo , Plasmodium/fisiologia , Animais , Células Cultivadas , Citotoxicidade Imunológica , Modelos Animais de Doenças , Exocitose , Humanos , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Vesículas Secretórias/metabolismo
12.
Clin Transl Immunology ; 9(6): e1144, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32566226

RESUMO

Objectives: Malaria, caused by Plasmodium infection, remains a major global health problem. Monocytes are integral to the immune response, yet their transcriptional and functional responses in primary Plasmodium falciparum infection and in clinical malaria are poorly understood. Methods: The transcriptional and functional profiles of monocytes were examined in controlled human malaria infection with P. falciparum blood stages and in children and adults with acute malaria. Monocyte gene expression and functional phenotypes were examined by RNA sequencing and flow cytometry at peak infection and compared to pre-infection or at convalescence in acute malaria. Results: In subpatent primary infection, the monocyte transcriptional profile was dominated by an interferon (IFN) molecular signature. Pathways enriched included type I IFN signalling, innate immune response and cytokine-mediated signalling. Monocytes increased TNF and IL-12 production upon in vitro toll-like receptor stimulation and increased IL-10 production upon in vitro parasite restimulation. Longitudinal phenotypic analyses revealed sustained significant changes in the composition of monocytes following infection, with increased CD14+CD16- and decreased CD14-CD16+ subsets. In acute malaria, monocyte CD64/FcγRI expression was significantly increased in children and adults, while HLA-DR remained stable. Although children and adults showed a similar pattern of differentially expressed genes, the number and magnitude of gene expression change were greater in children. Conclusions: Monocyte activation during subpatent malaria is driven by an IFN molecular signature with robust activation of genes enriched in pathogen detection, phagocytosis, antimicrobial activity and antigen presentation. The greater magnitude of transcriptional changes in children with acute malaria suggests monocyte phenotypes may change with age or exposure.

13.
Nat Immunol ; 21(7): 790-801, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32424361

RESUMO

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.


Assuntos
Imunidade Humoral , Malária/imunologia , Plasmócitos/metabolismo , Plasmodium falciparum/imunologia , Adolescente , Adulto , Aminoácidos/administração & dosagem , Aminoácidos/metabolismo , Animais , Anticorpos Antiprotozoários/sangue , Anticorpos Antiprotozoários/imunologia , Anticorpos Antiprotozoários/metabolismo , Antimaláricos/administração & dosagem , DNA de Protozoário/isolamento & purificação , Modelos Animais de Doenças , Centro Germinativo/citologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Interações Hospedeiro-Parasita/imunologia , Humanos , Malária/sangue , Malária/tratamento farmacológico , Malária/parasitologia , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Nutrientes/metabolismo , Plasmócitos/imunologia , Plasmócitos/parasitologia , Plasmodium falciparum/genética , Plasmodium falciparum/isolamento & purificação , Estudo de Prova de Conceito , Adulto Jovem
14.
Cancer Immunol Res ; 8(8): 1085-1098, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32444423

RESUMO

The adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) is known to facilitate caspase-1 activation, which is essential for innate host immunity via the formation of the inflammasome complex, a multiprotein structure responsible for processing IL1ß and IL18 into their active moieties. Here, we demonstrated that ASC-deficient CD8+ T cells failed to induce severe graft-versus-host disease (GVHD) and had impaired capacity for graft rejection and graft-versus-leukemia (GVL) activity. These effects were inflammasome independent because GVHD lethality was not altered in recipients of caspase-1/11-deficient T cells. We also demonstrated that ASC deficiency resulted in a decrease in cytolytic function, with a reduction in granzyme B secretion and CD107a expression by CD8+ T cells. Altogether, our findings highlight that ASC represents an attractive therapeutic target for improving outcomes of clinical transplantation.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Linfócitos T CD8-Positivos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Inflamassomos/imunologia , Leucemia/terapia , Linfócitos T Citotóxicos/imunologia , Animais , Apoptose , Caspase 1/metabolismo , Modelos Animais de Doenças , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/metabolismo , Inflamassomos/metabolismo , Leucemia/imunologia , Leucemia/patologia , Camundongos , Camundongos Endogâmicos BALB C
15.
Cell Rep ; 30(8): 2512-2525.e9, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32101732

RESUMO

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.


Assuntos
Imunidade/efeitos dos fármacos , Interferon Tipo I/farmacologia , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/parasitologia , Parasitos/imunologia , Anfotericina B/farmacologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Epitopos , Humanos , Inflamação/imunologia , Inflamação/patologia , Interferon gama/farmacologia , Camundongos Endogâmicos C57BL , Parasitos/efeitos dos fármacos , Pirazóis/farmacologia , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
Nat Commun ; 11(1): 252, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937752

RESUMO

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.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica/deficiência , Diferenciação Celular/imunologia , Cromatina/metabolismo , Colite/imunologia , Modelos Animais de Doenças , Epigênese Genética/imunologia , Fatores de Transcrição Forkhead/metabolismo , Trato Gastrointestinal/imunologia , Regulação da Expressão Gênica/imunologia , Homeostase/imunologia , Fatores Reguladores de Interferon/deficiência , Fatores Reguladores de Interferon/metabolismo , Interleucina-10/biossíntese , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo
17.
Immunol Rev ; 293(1): 70-87, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31674682

RESUMO

Malaria is a major global health problem. Despite decades of research, there is still no effective vaccine to prevent disease in the majority of people living in malaria-endemic regions. Additionally, drug treatment options are continually threatened by the emergence of drug-resistant parasites. Immune responses generated against Plasmodium parasites that cause malaria are generally not sufficient to prevent the establishment of infection and can even contribute to the development of disease, unless individuals have survived multiple infections. Research conducted in experimental models, controlled human malaria infection studies, and with malaria patients from disease-endemic areas indicate the rapid development of immunoregulatory pathways in response to Plasmodium infection. These "imprinted" immune responses limit inflammation, and likely prevent progression to severe disease manifestations. However, they also cause slow acquisition of immunity and possibly hamper the development of vaccine-mediated protection against disease. A major target for and mediator of the immunoregulatory pathways established during malaria are CD4+ T cells that play critical roles in priming phagocytic cells to capture and kill malaria parasites, as well as helping B cells produce functional anti-parasitic antibodies. In this review, we describe mechanisms of CD4+ T cell activation during malaria and discuss the immunoregulatory mechanisms that develop to dampen their anti-parasitic and pathological functions. We also offer some ideas about how host-directed approaches might be applied to modulate CD4+ T cell functions to improve vaccine responses and enhance development of natural immunity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interações Hospedeiro-Parasita/imunologia , Imunomodulação , Malária/imunologia , Plasmodium/imunologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Comunicação Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Ativação Linfocitária/imunologia , Malária/tratamento farmacológico , Malária/metabolismo , Malária/parasitologia , Camundongos , Terapia de Alvo Molecular , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Receptores Toll-Like/metabolismo
18.
Cytokine X ; 2(4): 100036, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33604560

RESUMO

Visceral leishmaniasis (VL) causes extensive splenic pathology that contributes to dysfunctional immune responses, in part through displacement and destruction of cell populations involved in maintaining splenic structural integrity. The expression of pro and anti-inflammatory cytokines and chemokines is crucial in orchestrating the delicate balance that exists between host resistance and tissue pathology. In an effort to restore homeostatic balance to the local microenvironment, remodelling of the splenic architecture occurs in a compartmentalised manner to retain some level of functionality, despite persistent inflammatory pressures. Animal models of VL as well as human studies have significantly contributed to our understanding of the architectural changes that occur in the spleen during VL. Here, we review the role of cytokines in mediating microarchitectural changes associated with the development of splenomegaly during VL.

19.
Malar J ; 18(1): 312, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31533836

RESUMO

BACKGROUND: Anaemia is a major consequence of malaria, caused by the removal of both infected and uninfected red blood cells (RBCs) from the circulation. Complement activation and reduced expression of complement regulatory proteins (CRPs) on RBCs are an important pathogenic mechanism in severe malarial anaemia in both Plasmodium falciparum and Plasmodium vivax infection. However, little is known about loss of CRPs on RBCs during mild malarial anaemia and in low-density infection. METHODS: The expression of CRP CR1, CD55, CD59, and the phagocytic regulator CD47, on uninfected normocytes and reticulocytes were assessed in individuals from two study populations: (1) P. falciparum and P. vivax-infected patients from a low transmission setting in Sabah, Malaysia; and, (2) malaria-naïve volunteers undergoing P. falciparum induced blood-stage malaria (IBSM). For clinical infections, individuals were categorized into anaemia severity categories based on haemoglobin levels. For IBSM, associations between CRPs and haemoglobin level were investigated. RESULTS: CRP expression on RBC was lower in Malaysian individuals with P. falciparum and P. vivax mild malarial anaemia compared to healthy controls. CRP expression was also reduced on RBCs from volunteers during IBSM. Reduction occurred on normocytes and reticulocytes. However, there was no significant association between reduced CRPs and haemoglobin during IBSM. CONCLUSIONS: Removal of CRPs occurs on both RBCs and reticulocytes during Plasmodium infection even in mild malarial anaemia and at low levels of parasitaemia.


Assuntos
Anemia/parasitologia , Proteínas do Sistema Complemento/genética , Eritrócitos/metabolismo , Malária Falciparum/complicações , Malária Vivax/complicações , Adulto , Proteínas do Sistema Complemento/metabolismo , Eritrócitos/parasitologia , Feminino , Humanos , Malária Falciparum/parasitologia , Malária Vivax/parasitologia , Malásia , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/fisiologia , Plasmodium vivax/fisiologia , Adulto Jovem
20.
Trends Parasitol ; 35(2): 154-162, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30579700

RESUMO

Malaria remains an important global disease. Despite significant advances over the past decade in reducing disease morbidity and mortality, new measures are needed if malaria is to be eliminated. Significant advances in our understanding about host immune responses during malaria have been made, opening up opportunities to generate long-lasting antiparasitic immunity through vaccination or immune therapy. However, there is still much debate over which immune cell populations contribute to immunity to malaria, including innate lymphocytes that comprise recently identified innate lymphoid cells (ILCs) and better known innate-like T cell subsets. Here, we review research on these immune cell subsets and discuss whether they have any important roles in immunity to malaria or if they are redundant.


Assuntos
Imunidade Inata/imunologia , Linfócitos/imunologia , Malária/imunologia , Humanos
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