Imperial College London

DrIngridMuller

Faculty of MedicineDepartment of Infectious Disease

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120Wright Fleming WingSt Mary's Campus

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Publications

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115 results found

Takele Y, Adem E, Franssen SU, Womersley RL, Kaforou MC, Levin ML, Mueller IC, Cotton JAL, Kropf PCet al., 2022, Impaired in vitro Interferon-gamma production in patients with visceral leishmaniasis is improved by inhibition of PD1/PDL-1 ligation, PLOS NEGLECTED TROPICAL DISEASES, Vol: 16, ISSN: 1935-2735

Journal article

Takele Y, Mulaw, Adem, Shaw E, Franssen, Womersley R, Kaforou M, Taylor G, Levin M, Muller I, Cotton, Kropf Pet al., 2022, Immunological factors, but not clinical features, predict visceral leishmaniasis relapse in patients co-infected with HIV, Cell Reports Medicine, Vol: 3, ISSN: 2666-3791

Visceral leishmaniasis (VL) has emerged as a clinically important opportunistic infection in HIV patients, as VL/HIV co-infected patients suffer from frequent VL relapse. Here, we follow cohorts of VL patients with or without HIV in Ethiopia. By the end of the study 78.1% of VL/HIV, but none of the VL patients, experience VL relapse. Despite clinically defined cure, VL/HIV patients maintain higher parasite loads, lower BMI, hepatosplenomegaly and pancytopenia. We identify three immunological markers associated with VL relapse in VL/HIV patients: i) failure to restore antigen-specific production of IFNg, ii) persistently lower CD4+ T cell counts, and iii) higher expression of PD1 on CD4+ and CD8+ T cells. We show that these three markers, that can be measured in primary hospital settings in Ethiopia, combine well in predicting VL relapse. The use of our prediction model has the potential to improve disease management and patient care.

Journal article

Franssen SU, Takele Y, Adem E, Sanders MJ, Müller I, Kropf P, Cotton JAet al., 2021, Diversity and within-host evolution of Leishmania donovani from visceral Leishmaniasis patients with and without HIV coinfection in northern Ethiopia., mBio, Vol: 12, Pages: 1-19, ISSN: 2150-7511

Visceral leishmaniasis (VL) is a fatal disease and a growing public health problem in East Africa, where Ethiopia has one of the highest VL burdens. The largest focus of VL in Ethiopia is driven by high prevalence in migrant agricultural workers and associated with a high rate of coinfection with HIV. This coinfection makes VL more difficult to treat successfully and is associated with a high rate of relapse, with VL/HIV patients frequently experiencing many relapses of VL before succumbing to this infection. We present genome-wide data on Leishmania donovani isolates from a longitudinal study of cohorts of VL and VL/HIV patients reporting to a single clinic in Ethiopia. Extensive clinical data allow us to investigate the influence of coinfection and relapse on the populations of parasites infecting these patients. We find that the same parasite population is responsible for both VL and VL/HIV infections and that, in most cases, disease relapse is caused by recrudescence of the population of parasites that caused primary VL. Complex, multiclonal infections are present in both primary and relapse cases, but the infrapopulation of parasites within a patient loses genetic diversity between primary disease presentation and subsequent relapses, presumably due to a population bottleneck induced by treatment. These data suggest that VL/HIV relapses are not caused by genetically distinct parasite infections or by reinfection. Treatment of VL does not lead to sterile cure, and in VL/HIV, the infecting parasites are able to reestablish after clinically successful treatment, leading to repeated relapse of VL. IMPORTANCE Visceral leishmaniasis (VL) is the second largest cause of deaths due to parasite infections and a growing problem in East Africa. In Ethiopia, it is particularly associated with migrant workers moving from regions of nonendemicity for seasonal agricultural work and is frequently found as a coinfection with HIV, which leads to frequent VL relapse following trea

Journal article

Giraud E, Svobodova M, Mueller I, Volf P, Rogers MEet al., 2019, Promastigote secretory gel from natural and unnatural sand fly vectors exacerbate Leishmania major and Leishmania tropica cutaneous leishmaniasis in mice, PARASITOLOGY, Vol: 146, Pages: 1796-1802, ISSN: 0031-1820

Journal article

Abera EA, Tajebe F, Getahun M, Kiflie A, Hailu A, Diro E, Takele Y, Shkedy Z, Deressa T, Modolell M, Munder M, Mueller I, Kropf Pet al., 2019, Successful treatment of human visceral leishmaniasis restores antigen-specific IFN-gamma, but not IL-10 production, 17th International Congress of Immunology of the International-Union-of-Immunological-Societies (IUIS), Publisher: WILEY, Pages: 1186-1187, ISSN: 0014-2980

Conference paper

Giraud E, Lestinova T, Derrick T, Martin O, Dillon RJ, Volf P, Muller I, Bates PA, Rogers MEet al., 2018, Leishmania proteophosphoglycans regurgitated from infected sand flies accelerate dermal wound repair and exacerbate leishmaniasis via insulin-like growth factor 1-dependent signalling, PLOS PATHOGENS, Vol: 14, ISSN: 1553-7366

Journal article

Villa-Pulgarin JA, Gajate C, Botet J, Jimenez A, Justies N, Varela-M RE, Cuesta-Marban A, Muller I, Modolell M, Revuelta JL, Mollinedo Fet al., 2017, Mitochondria and lipid raft-located FOF1-ATP synthase as major therapeutic targets in the antileishmanial and anticancer activities of ether lipid edelfosine, PLOS NEGLECTED TROPICAL DISEASES, Vol: 11, ISSN: 1935-2735

Journal article

Tajebe F, Getahun M, Adem E, Hailu A, Lemma M, Fikre H, Raynes J, Tamiru A, Mulugeta Z, Diro E, Toulza F, Shkedy Z, Ayele T, Modolell M, Munder M, Mueller I, Takele Y, Kropf Pet al., 2017, Disease severity in patients with visceral leishmaniasis is not altered by co-infection with intestinal parasites, PLoS Neglected Tropical Diseases, Vol: 11, ISSN: 1935-2727

Visceral leishmaniasis (VL) is a neglected tropical disease that affects the poorest communities and can cause substantial morbidity and mortality. Visceral leishmaniasis is characterized by the presence of Leishmania parasites in the spleen, liver and bone marrow, hepatosplenomegaly, pancytopenia, prolonged fever, systemic inflammation and low body mass index (BMI). The factors impacting on the severity of VL are poorly characterized. Here we performed a cross-sectional study to assess whether co-infection of VL patients with intestinal parasites influences disease severity, assessed with clinical and haematological data, inflammation, cytokine profiles and BMI. Data from VL patients was similar to VL patients co-infected with intestinal parasites, suggesting that co-infection of VL patients with intestinal parasites does not alter disease severity.

Journal article

Taslimi Y, Sadeghipour P, Habibzadeh S, Mashayekhi V, Mortazavi H, Muller I, Lane ME, Kropf P, Rafati Set al., 2017, A novel non-invasive diagnostic sampling technique for cutaneous leishmaniasis, PLoS Neglected Tropical Diseases, Vol: 11, ISSN: 1935-2727

Accurate diagnosis of cutaneous leishmaniasis (CL) is important for chemotherapy and epidemiological studies. Common approaches for Leishmania detection involve the invasive collection of specimens for direct identification of amastigotes by microscopy and the culturing of promastigotes from infected tissues. Although these techniques are highly specific, they require highly skilled health workers and have the inherent risks of all invasive procedures, such as pain and risk of bacterial and fungal super-infection. Therefore, it is essential to reduce discomfort, potential infection and scarring caused by invasive diagnostic approaches especially for children. In this report, we present a novel non-invasive method, that is painless, rapid and user-friendly, using sequential tape strips for sampling and isolation of DNA from the surface of active and healed skin lesions of CL patients. A total of 119 patients suspected of suffering from cutaneous leishmaniasis with different clinical manifestations were recruited and samples were collected both from their lesions and from uninfected areas. In addition, 15 fungal-infected lesions and 54 areas of healthy skin were examined. The duration of sampling is short (less than one minute) and species identification by PCR is highly specific and sensitive. The sequential tape stripping sampling method is a sensitive, non-invasive and cost-effective alternative to traditional diagnostic assays and it is suitable for field studies as well as for use in health care centers.

Journal article

Mortazavi H, Sadeghipour P, Taslimi Y, Habibzadeh S, Zali F, Zahedifard F, Rahmati J, Kamyab K, Ghandi N, Zamanian A, Reza Tohidinik H, Muller I, Kropf P, Rafati Set al., 2016, Comparing acute and chronic human cutaneous leishmaniasis caused by Leishmania major and Leishmania tropica focusing on arginase activity., Journal of the European Academy of Dermatology and Venereology, Vol: 30, Pages: 2118-2121, ISSN: 1468-3083

BACKGROUND: Cutaneous leishmaniasis (CL) in Iran is mainly caused by Leishmania major (L. major) and L. tropica. Arginase mediated L-arginine metabolism is an important issue in Leishmania parasite propagation. Arginase activity in human CL due to L. major and L. tropica have not been studied up to now. OBJECTIVES: We aimed to compare the clinical and laboratory aspects of acute and chronic CL, focussing on arginase activity. METHODS: In this case-control study, 30 patients with acute CL (duration ≤ 1 year), 13 patients with chronic CL (duration ≥ 2 year) and 11 healthy controls were recruited. Arginase activity was measured in skin biopsies of lesions, peripheral blood polymorphonuclear cells (PMNs), peripheral blood mononuclear cells (PBMCs) and plasma by standard methods. RESULTS: The median of arginase activity in the acute lesions was higher than in chronic samples and significantly higher than in healthy controls (P = 0.008). PMNs of both acute and chronic patients showed higher levels of arginase activity as compared to the levels in PBMCs and plasma. The median of arginase activity in the PMNs of patients with chronic CL was higher than that of patients with acute CL and significantly higher than that of the healthy controls (P = 0.010). CONCLUSION: The level of arginase activity in lesions of patients with acute and chronic CL was higher than the skin of healthy controls. The highest level of arginase activity was observed in PMNs from patients with chronic CL. This suggests that the high level of arginase activity in PMNs of patients with chronic CL may contribute to the chronicity.

Journal article

Yizengaw E, Getahun M, Tajebe F, Cruz Cervera E, Adem E, Mesfin G, Hailu A, Van der Auwera G, Yardley V, Lemma M, Skhedy Z, Diro E, Yeshanew A, Melkamu R, Mengesha B, Modolell M, Munder M, Muller I, Takele Y, Kropf Pet al., 2016, Visceral leishmaniasis patients display altered composition and maturity of neutrophils as well as impaired neutrophil effector functions, Frontiers in Immunology, Vol: 7, ISSN: 1664-3224

Immunologically, active visceral leishmaniasis (VL) is characterised by profound immunosuppression, severe systemic inflammatoryresponses and an impaired capacity to control parasite replication. Neutrophils are highly versatile cells, which play a crucial rolein the induction as well as the resolution of inflammation, the control of pathogen replication and the regulation of immuneresponses. Neutrophil functions have been investigated in human cutaneous leishmaniasis, however, their role in human visceralleishmaniasis is poorly understood.In the present study we evaluated the activation status and effector functions of neutrophils in patients with active VL and aftersuccessful anti-leishmanial treatment. Our results show that neutrophils are highly activated and have degranulated; high levels ofarginase, myeloperoxidase and elastase, all contained in neutrophils’ granules, were found in the plasma of VL patients. Inaddition, we show that a large proportion of these cells are immature. We also analysed effector functions of neutrophils that areessential for pathogen clearance and show that neutrophils have an impaired capacity to release neutrophil extracellular traps,produce reactive oxygen species and phagocytose bacterial particles, but not Leishmania parasites.Our results suggest that impaired effector functions, increased activation and immaturity of neutrophils play a key role in thepathogenesis of VL.

Journal article

Takele Y, Adem E, Getahun M, Tajebe F, Kiflie A, Hailu A, Raynes J, Mengesha B, Ayele TA, Shkedy Z, Lemma M, Diro E, Toulza F, Modolell M, Munder M, Müller I, Kropf Pet al., 2016, Malnutrition in Healthy Individuals Results in Increased Mixed Cytokine Profiles, Altered Neutrophil Subsets and Function, PLOS One, Vol: 11, ISSN: 1932-6203

Malnutrition is commonly associated with increased infectious disease susceptibility and severity. Whereas malnutrition might enhance the incidence of disease as well as its severity, active infection can in turn exacerbate malnutrition. Therefore, in a malnourished individual suffering from a severe infection, it is not possible to determine the contribution of the pre-existing malnutrition and/or the infection itself to increased disease severity. In the current study we focussed on two groups of malnourished, but otherwise healthy individuals: moderately malnourished (BMI: 18.4-16.5) and severely malnourished (BMI <16.5) and compared several immune parameters with those of individuals with a normal BMI (≥18.5). Our results show a similar haematological profile in all three groups, as well as a similar ratio of CD4+ and CD8+ T cells. We found significant correlations between low BMI and increased levels of T helper (Th) 1 (Interferon (IFN)-γ, (interleukin (IL)-2, IL-12), Th2 (IL-4, IL-5, IL-13), as well as IL-10, IL-33 and tumor necrosis factor-α, but not IL-8 or C reactive protein. The activities of arginase, an enzyme associated with immunosuppression, were similar in plasma, peripheral blood mononuclear cells (PBMC) and neutrophils from all groups and no differences in the expression levels of CD3ζ, a marker of T cell activation, were observed in CD4+ and CD8+T cells. Furthermore, whereas the capacity of neutrophils from the malnourished groups to phagocytose particles was not impaired, their capacity to produce reactive oxygen species was impaired. Finally we evaluated the frequency of a subpopulation of low-density neutrophils and show that they are significantly increased in the malnourished individuals. These differences were more pronounced in the severely malnourished group. In summary, our results show that even in the absence of apparent infections, healthy malnourished individuals display dysfunctional immune responses that might

Journal article

Adem E, Tajebe F, Getahun M, Kiflie A, Diro E, Hailu A, Shkedy Z, Mengesha B, Mulaw T, Atnafu S, Deressa T, Mathewos B, Abate E, Modolell M, Munder M, Müller I, Takele Y, Kropf Pet al., 2016, Successful treatment of human visceral leishmaniasis restores antigen-specific IFN-γ, but not IL-10 production, PLOS Neglected Tropical Diseases, Vol: 10, Pages: e0004468-e0004468, ISSN: 1935-2735

One of the key immunological characteristics of active visceral leishmaniasis (VL) is a profound immunosuppression and impaired production of Interferon-γ (IFN-γ). However, recent studies from Bihar in India showed using a whole blood assay, that whole blood cells have maintained the capacity to produce IFN-γ. Here we tested the hypothesis that a population of low-density granulocytes (LDG) might contribute to T cell responses hyporesponsiveness via the release of arginase. Our results show that this population is affected by the anticoagulant used to collect blood: the frequency of LDGs is significantly lower when the blood is collected with heparin as compared to EDTA; however, the anticoagulant does not impact on the levels of arginase released. Next, we assessed the capacity of whole blood cells from patients with active VL to produce IFN-γ and IL-10 in response to antigen-specific and polyclonal activation. Our results show that whole blood cells produce low or levels below detection limit of IFN-γ and IL-10, however, after successful treatment of VL patients, these cells gradually regain their capacity to produce IFN-γ, but not IL-10, in response to activation. These results suggest that in contrast to VL patients from Bihar, India, whole blood cells from VL patients from Gondar, Ethiopia, have lost their ability to produce IFN-γ during active VL and that active disease is not associated with sustained levels of IL-10 production following stimulation.

Journal article

Kapp K, Pruefer S, Michel CS, Habermeier A, Luckner-Minden C, Giese T, Bomalaski J, Langhans C-D, Kropf P, Mueller I, Closs EI, Radsak MP, Munder Met al., 2014, Granulocyte functions are independent of arginine availability, JOURNAL OF LEUKOCYTE BIOLOGY, Vol: 96, Pages: 1047-1053, ISSN: 0741-5400

Journal article

Rath M, Mueller I, Kropf P, Closs EI, Munder Met al., 2014, Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages, Frontiers in Immunology, Vol: 5, ISSN: 1664-3224

Macrophages play a major role in the immune system, both as antimicrobial effector cellsand as immunoregulatory cells, which induce, suppress or modulate adaptive immuneresponses. These key aspects of macrophage biology are fundamentally driven by thephenotype of macrophage arginine metabolism that is prevalent in an evolving or ongoingimmune response. M1 macrophages express the enzyme nitric oxide synthase, whichmetabolizes arginine to nitric oxide (NO) and citrulline. NO can be metabolized to furtherdownstream reactive nitrogen species, while citrulline might be reused for efficient NOsynthesis via the citrulline–NO cycle. M2 macrophages are characterized by expression ofthe enzyme arginase, which hydrolyzes arginine to ornithine and urea. The arginase pathwaylimits arginine availability for NO synthesis and ornithine itself can further feed into theimportant downstream pathways of polyamine and proline syntheses, which are importantfor cellular proliferation and tissue repair. M1 versus M2 polarization leads to opposing outcomesof inflammatory reactions, but depending on the context, M1 and M2 macrophagescan be both pro- and anti-inflammatory. Notably, M1/M2 macrophage polarization can bedriven by microbial infection or innate danger signals without any influence of adaptiveimmune cells, secondarily driving the T helper (Th)1/Th2 polarization of the evolving adaptiveimmune response. Since both arginine metabolic pathways cross-inhibit each other onthe level of the respective arginine break-down products andTh1 andTh2 lymphocytes candrive or amplify macrophage M1/M2 dichotomy via cytokine activation, this forms the basisof a self-sustaining M1/M2 polarization of the whole immune response. Understanding thearginine metabolism of M1/M2 macrophage phenotypes is therefore central to find newpossibilities to manipulate immune responses in infection, autoimmune diseases, chronicinflammatory conditions, and cancer.

Journal article

Corware K, Yardley V, Mack C, Schuster S, Al-Hassi H, Herath S, Bergin P, Modolell M, Munder M, Mueller I, Kropf Pet al., 2014, Protein energy malnutrition increases arginase activity in monocytes and macrophages, Nutrition & Metabolism, Vol: 11, ISSN: 1743-7075

Background: Protein energy malnutrition is commonly associated with immune dysfunctions and is a major factorin susceptibility to infectious diseases.Methods: In this study, we evaluated the impact of protein energy malnutrition on the capacity of monocytes andmacrophages to upregulate arginase, an enzyme associated with immunosuppression and increased pathogenreplication.Results: Our results show that monocytes and macrophages are significantly increased in the bone marrow andblood of mice fed on a protein low diet. No alteration in the capacity of bone marrow derived macrophagesisolated from malnourished mice to phagocytose particles, to produce the microbicidal molecule nitric oxide andto kill intracellular Leishmania parasites was detected. However, macrophages and monocytes from malnourished miceexpress significantly more arginase both in vitro and in vivo. Using an experimental model of visceral leishmaniasis, weshow that following protein energy malnutrition, the increased parasite burden measured in the spleen of these micecoincided with increased arginase activity and that macrophages provide a more permissive environment for parasitegrowth.Conclusions: Taken together, these results identify a novel mechanism in protein energy malnutrition that mightcontributes to increased susceptibility to infectious diseases by upregulating arginase activity in myeloid cells.

Journal article

Ssemaganda A, Kindinger L, Bergin P, Nielsen L, Mpendo J, Ssetaala A, Kiwanuka N, Munder M, Teoh TG, Kropf P, Mueller Iet al., 2014, Characterization of neutrophil subsets in healthy human pregnancies, PLOS One, Vol: 9, ISSN: 1932-6203

We have previously shown that in successful pregnancies increased arginase activity is a mechanism that contributes to the suppression of the maternal immune system. We identified the main type of arginase-expressing cells as a population of activated low-density granulocytes (LDGs) in peripheral blood mononuclear cells and in term placentae. In the present study, we analyzed the phenotype of LDGs and compared it to the phenotype of normal density granulocytes (NDGs) in maternal peripheral blood, placental biopsies and cord blood. Our data reveal that only LDGs but no NDGs could be detected in placental biopsies. Phenotypically, NDGs and LDGs from both maternal and cord blood expressed different levels of maturation, activation and degranulation markers. NDGs from the maternal and cord blood were phenotypically similar, while maternal, cord and placental LDGs showed different expression levels of CD66b. LDGs present in cord blood expressed higher levels of arginase compared to maternal and placental LDGs. In summary, our results show that in maternal and cord blood, two phenotypically different populations of neutrophils can be identified, whereas in term placentae, only activated neutrophils are present.

Journal article

Conceicao-Silva F, Morgado FN, Fernandes Pimentel MI, Ferreira e Vasconcellos EDC, Schubach AO, Valete-Rosalino CM, Kropf P, Mueller Iet al., 2013, Two women presenting worsening cutaneous ulcers during pregnancy: diagnosis, immune response, and follow-up, PLOS Neglected Tropical Diseases, Vol: 7, ISSN: 1935-2735

Journal article

Cloke T, Munder M, Bergin P, Herath S, Modolell M, Taylor G, Mueller I, Kropf Pet al., 2013, Phenotypic Alteration of Neutrophils in the Blood of HIV Seropositive Patients, PLOS ONE, Vol: 8, ISSN: 1932-6203

Journal article

Munder M, Engelhardt M, Knies D, Medenhoff S, Wabnitz G, Luckner-Minden C, Feldmeyer N, Voss R-H, Kropf P, Mueller I, Conradi R, Samstag Y, Theobald M, Ho AD, Goldschmidt H, Hundemer Met al., 2013, Cytotoxicity of tumor antigen specific human T cells is unimpaired by arginine depletion, PLOS One, Vol: 8, ISSN: 1932-6203

Tumor-growth is often associated with the expansion of myeloid derived suppressor cells that lead to local or systemic arginine depletion via the enzyme arginase. It is generally assumed that this arginine deficiency induces a global shut-down of T cell activation with ensuing tumor immune escape. While the impact of arginine depletion on polyclonal T cell proliferation and cytokine secretion is well documented, its influence on chemotaxis, cytotoxicity and antigen specific activation of human T cells has not been demonstrated so far. We show here that chemotaxis and early calcium signaling of human T cells are unimpaired in the absence of arginine. We then analyzed CD8+ T cell activation in a tumor peptide as well as a viral peptide antigen specific system: (i) CD8+ T cells with specificity against the MART-1aa26–35*A27L tumor antigen expanded with in vitro generated dendritic cells, and (ii) clonal CMV pp65aa495–503 specific T cells and T cells retrovirally transduced with a CMV pp65aa495–503 specific T cell receptor were analyzed. Our data demonstrate that human CD8+ T cell antigen specific cytotoxicity and perforin secretion are completely preserved in the absence of arginine, while antigen specific proliferation as well as IFN-γ and granzyme B secretion are severely compromised. These novel results highlight the complexity of antigen specific T cell activation and demonstrate that human T cells can preserve important activation-induced effector functions in the context of arginine deficiency.

Journal article

Abebe T, Takele Y, Weldegebreal T, Cloke T, Closs E, Corset C, Hailu A, Hailu W, Sisay Y, Corware K, Corset M, Modolell M, Munder M, Tacchini-Cottier F, Mueller I, Kropf Pet al., 2013, Arginase activity - a marker of disease status in patients with visceral leishmaniasis in Ethiopia, PLOS Neglected Tropical Diseases, Vol: 7, ISSN: 1935-2735

The underlying mechanisms resulting in the profound immune suppression characteristic of human visceral leishmaniasis (VL) are not fully understood.Here, we tested the hypothesis that arginase, an enzyme associated with immunosuppression, is higher in patients with VL and contributes to impaired T cell responses. We recruited patients with VL before and after treatment and healthy controls and measured the arginase metabolism in the blood of these individuals. Our results show that arginase activity is significantly higher in the blood of patients with active VL as compared to controls. These high levels of arginase decline considerably once the patients are successfully treated. We identified the phenotype of arginase-expressing cells among PBMCs as neutrophils and show that their frequency was increased in PBMCs of patients before treatment; this coincides with reduced levels of L-arginine in the plasma and decreased expression levels of CD3ζ in T cells.

Journal article

Takele Y, Abebe T, Weldegebreal T, Hailu A, Hailu W, Hurissa Z, Ali J, Diro E, Sisay Y, Cloke T, Modolell M, Munder M, Tacchini-Cottier F, Mueller I, Kropf Pet al., 2013, Arginase activity in the blood of patients with visceral leishmaniasis and HIV infection, PLOS Neglected Tropical Diseases, Vol: 7, ISSN: 1935-2735

BackgroundVisceral leishmaniasis is a parasitic disease associated with high mortality. The most important foci of visceral leishmaniasis in Ethiopia are in the Northwest and are predominantly associated with high rates of HIV co-infection. Co-infection of visceral leishmaniasis patients with HIV results in higher mortality, treatment failure and relapse. We have previously shown that arginase, an enzyme associated with immunosuppression, was increased in patients with visceral leishmaniasis and in HIV seropositive patients; further our results showed that high arginase activity is a marker of disease severity. Here, we tested the hypothesis that increased arginase activities associated with visceral leishmaniasis and HIV infections synergize in patients co-infected with both pathogens.Methodology/Principal FindingsWe recruited a cohort of patients with visceral leishmaniasis and a cohort of patients with visceral leishmaniasis and HIV infection from Gondar, Northwest Ethiopia, and recorded and compared their clinical data. Further, we measured the levels of arginase activity in the blood of these patients and identified the phenotype of arginase-expressing cells. Our results show that CD4+ T cell counts were significantly lower and the parasite load in the spleen was significantly higher in co-infected patients. Moreover, our results demonstrate that arginase activity was significantly higher in peripheral blood mononuclear cells and plasma of co-infected patients. Finally, we identified the cells-expressing arginase in the PBMCs as low-density granulocytes.ConclusionOur results suggest that increased arginase might contribute to the poor disease outcome characteristic of patients with visceral leishmaniasis and HIV co-infection.

Journal article

Cloke T, Munder M, Taylor G, Mueller I, Kropf Pet al., 2012, Characterization of a novel population of low-density granulocytes associated with disease severity in HIV-1 infection, PLOS One, Vol: 7, ISSN: 1932-6203

The mechanisms resulting in progressive immune dysfunction during the chronic phase of HIV infection are not fully understood. We have previously shown that arginase, an enzyme with potent immunosuppressive properties, is increased in HIV seropositive (HIV+) patients with low CD4+ T cell counts. Here we show that the cells expressing arginase in peripheral blood mononuclear cells of HIV+ patients are low-density granulocytes (LDGs) and that whereas these cells have a similar morphology to normal-density granulocyte, they are phenotypically different. Importantly, our results reveal that increased frequencies of LDGs correlate with disease severity in HIV+ patients.

Journal article

Baker BS, Harrington JE, Choi B-S, Kropf P, Muller I, Hoffman CJet al., 2012, A randomised controlled pilot feasibility study of the physical and psychological effects of an integrated support programme in breast cancer, Complementary Therapies in Clinical Practice, Vol: 18, Pages: 182-189, ISSN: 1744-3881

Journal article

Lamour SD, Choi B, Keun HC, Müller I, Saric Jet al., 2012, Metabolic characterization of leishmania major infection in activated and nonactivated macrophages., Journal of Proteome Research, Vol: 11, Pages: 4211-4222, ISSN: 1535-3907

Infection with Leishmania spp. can lead to a range of symptoms in the affected individual, depending on underlying immune-metabolic processes. The macrophage activation state hereby plays a key role. Whereas the l-arginine pathway has been described in detail as the main biochemical process responsible for either nitric oxide mediated parasite killing (classical activation) or amplification of parasite replication (alternative activation), we were interested in a wider characterization of metabolic events in vitro. We therefore assessed cell growth medium, parasite extract, and intra- and extracellular metabolome of activated and nonactivated macrophages, in presence and absence of Leishmania major. A metabolic profiling approach was applied combining (1)H NMR spectroscopy with multi- and univariate data treatment. Metabolic changes were observed along both conditional axes, that is, infection state and macrophage activation, whereby significantly higher levels of potential parasite end products were found in parasite exposed samples including succinate, acetate, and alanine, compared to uninfected macrophages. The different macrophage activation states were mainly discriminated by varying glucose consumption. The presented profiling approach allowed us to obtain a metabolic snapshot of the individual biological compartments in the assessed macrophage culture experiments and represents a valuable read out system for further multiple compartment in vitro studies.

Journal article

Abebe T, Hailu A, Woldeyes M, Mekonen W, Bilcha K, Cloke T, Fry L, al Basatena N-KS, Corware K, Modolell M, Munder M, Tacchini-Cottier F, Mueller I, Kropf Pet al., 2012, Local increase of arginase activity in lesions of patients with cutaneous leishmaniasis in Ethiopia, PLOS Neglected Tropical Diseases, Vol: 6, ISSN: 1935-2735

BackgroundCutaneous leishmaniasis is a vector-borne disease that is in Ethiopia mainly caused by the parasite Leishmania aethiopica. This neglected tropical disease is common in rural areas and causes serious morbidity. Persistent nonhealing cutaneous leishmaniasis has been associated with poor T cell mediated responses; however, the underlying mechanisms are not well understood.Methodology/Principal FindingsWe have recently shown in an experimental model of cutaneous leishmaniasis that arginase-induced L-arginine metabolism suppresses antigen-specific T cell responses at the site of pathology, but not in the periphery. To test whether these results translate to human disease, we recruited patients presenting with localized lesions of cutaneous leishmaniasis and assessed the levels of arginase activity in cells isolated from peripheral blood and from skin biopsies. Arginase activity was similar in peripheral blood mononuclear cells (PBMCs) from patients and healthy controls. In sharp contrast, arginase activity was significantly increased in lesion biopsies of patients with localized cutaneous leishmaniasis as compared with controls. Furthermore, we found that the expression levels of CD3ζ, CD4 and CD8 molecules were considerably lower at the site of pathology as compared to those observed in paired PBMCs.ConclusionOur results suggest that increased arginase in lesions of patients with cutaneous leishmaniasis might play a role in the pathogenesis of the disease by impairing T cell effector functions.

Journal article

Varela-M RE, Villa-Pulgarin JA, Yepes E, Mueller I, Modolell M, Munoz DL, Robledo SM, Muskus CE, Lopez-Aban J, Muro A, Velez ID, Mollinedo Fet al., 2012, In Vitro and In Vivo Efficacy of Ether Lipid Edelfosine against Leishmania spp. and SbV-Resistant Parasites, PLOS NEGLECTED TROPICAL DISEASES, Vol: 6, ISSN: 1935-2735

Journal article

Feldmeyer N, Wabnitz G, Leicht S, Luckner-Minden C, Schiller M, Franz T, Conradi R, Kropf P, Mueller I, Ho AD, Samstag Y, Munder Met al., 2012, Arginine deficiency leads to impaired cofilin dephosphorylation in activated human T lymphocytes, International Immunology, Vol: 24, Pages: 303-313, ISSN: 1460-2377

Journal article

Corware K, Harris D, Teo I, Rogers M, Naresh K, Mueller I, Shaunak Set al., 2011, Accelerated healing of cutaneous leishmaniasis in non-healing BALB/c mice using water soluble amphotericin B-polymethacrylic acid, BIOMATERIALS, Vol: 32, Pages: 8029-8039, ISSN: 0142-9612

Journal article

Fu H, Khan A, Coe D, Zaher S, Chai J-G, Kropf P, Mueller I, Larkin DFP, George AJTet al., 2011, Arginine depletion as a mechanism for the immune privilege of corneal allografts, European Journal of Immunology, Vol: 41, Pages: 2997-3005, ISSN: 1521-4141

The cornea is an immune privileged tissue. Since arginase has been found to modulate T-cell function by depleting arginine, we investigated the expression of arginase in the cornea and its possible role in immune privilege using a murine transplant model. We found that both the endothelium and epithelium of murine corneas express functional arginase I, capable of down-regulating T-cell proliferation in an in vitro culture system. The administration of the specific arginase inhibitor N-hydroxy-nor-l-Arg to recipient mice resulted in an accelerated rejection of allogeneic C57BL/6 (B6) corneal grafts. In contrast, in vivo blockade of arginase activity had no effect in altering the course of rejection of primary skin grafts that express little, if any, arginase. In addition, the inhibition of arginase did not alter systemic T-cell proliferation. These data show that arginase is functional in the cornea and contributes to the immune privilege of the eye, and that modulation of arginase contributes to graft survival.

Journal article

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