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Mansour, Michael

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Mansour

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Mansour, Michael
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Now showing 1 - 9 of 9
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    Fluorescent Tracking of Yeast Division Clarifies the Essential Role of Spleen Tyrosine Kinase in the Intracellular Control of Candida glabrata in Macrophages
    (Frontiers Media S.A., 2018) Dagher, Zeina; Xu, Shuying; Negoro, Paige E.; Khan, Nida S.; Feldman, Michael; Reedy, Jennifer; Tam, Jenny; Sykes, David; Mansour, Michael
    Macrophages play a critical role in the elimination of fungal pathogens. They are sensed via cell surface pattern-recognition receptors and are phagocytosed into newly formed organelles called phagosomes. Phagosomes mature through the recruitment of proteins and lysosomes, resulting in addition of proteolytic enzymes and acidification of the microenvironment. Our earlier studies demonstrated an essential role of Dectin-1-dependent activation of spleen tyrosine kinase (Syk) in the maturation of fungal containing phagosomes. The absence of Syk activity interrupted phago-lysosomal fusion resulting in arrest at an early phagosome stage. In this study, we sought to define the contribution of Syk to the control of phagocytosed live Candida glabrata in primary macrophages. To accurately measure intracellular yeast division, we designed a carboxyfluorescein succinimidyl ester (CFSE) yeast division assay in which bright fluorescent parent cells give rise to dim daughter cells. The CFSE-labeling of C. glabrata did not affect the growth rate of the yeast. Following incubation with macrophages, internalized CFSE-labeled C. glabrata were retrieved by cellular lysis, tagged using ConA-647, and the amount of residual CFSE fluorescence was assessed by flow cytometry. C. glabrata remained undivided (CFSE bright) for up to 18 h in co-culture with primary macrophages. Treatment of macrophages with R406, a specific Syk inhibitor, resulted in loss of intracellular control of C. glabrata with initiation of division within 4 h. Delayed Syk inhibition after 8 h was less effective indicating that Syk is critically required at early stages of macrophage–fungal interaction. In conclusion, we demonstrate a new method of tracking division of C. glabrata using CFSE labeling. Our results suggest that early Syk activation is essential for macrophage control of phagocytosed C. glabrata.
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    An unappreciated role for neutrophil-DC hybrids in immunity to invasive fungal infections
    (Public Library of Science, 2018) Fites, J. Scott; Gui, Michael; Kernien, John F.; Negoro, Paige; Dagher, Zeina; Sykes, David; Nett, Jeniel E.; Mansour, Michael; Klein, Bruce S.
    Neutrophils are classically defined as terminally differentiated, short-lived cells; however, neutrophils can be long-lived with phenotypic plasticity. During inflammation, a subset of neutrophils transdifferentiate into a population called neutrophil-DC hybrids (PMN-DCs) having properties of both neutrophils and dendritic cells. While these cells ubiquitously appear during inflammation, the role of PMN-DCs in disease remains poorly understood. We observed the differentiation of PMN-DCs in pre-clinical murine models of fungal infection: blastomycosis, aspergillosis and candidiasis. Using reporter strains of fungal viability, we found that PMN-DCs associate with fungal cells and kill them more efficiently than undifferentiated canonical neutrophils. During pulmonary blastomycosis, PMN-DCs comprised less than 1% of leukocytes yet contributed up to 15% of the fungal killing. PMN-DCs displayed higher expression of pattern recognition receptors, greater phagocytosis, and heightened production of reactive oxygen species compared to canonical neutrophils. PMN-DCs also displayed prominent NETosis. To further study PMN-DC function, we exploited a granulocyte/macrophage progenitor (GMP) cell line, generated PMN-DCs to over 90% purity, and used them for adoptive transfer and antigen presentation studies. Adoptively transferred PMN-DCs from the GMP line enhanced protection against systemic infection in vivo. PMN-DCs pulsed with antigen activated fungal calnexin-specific transgenic T cells in vitro and in vivo, promoting the production of interferon-γ and interleukin-17 in these CD4+ T cells. Through direct fungal killing and induction of adaptive immunity, PMN-DCs are potent effectors of antifungal immunity and thereby represent innovative cell therapeutic targets in treating life-threatening fungal infections.
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    The Role of Autophagy-Related Proteins in Candida albicans Infections
    (MDPI, 2016) Tam, Jenny; Mansour, Michael; Acharya, Mridu; Sokolovska, Anna; Timmons, Allison K.; Lacy-Hulbert, Adam; Vyas, Jatin
    Autophagy plays an important role in maintaining cell homeostasis by providing nutrients during periods of starvation and removing damaged organelles from the cytoplasm. A marker in the autophagic process is the reversible conjugation of LC3, a membrane scaffolding protein, to double membrane autophagosomes. Recently, a role for LC3 in the elimination of pathogenic bacteria and fungi, including Candida albicans (C. albicans), was demonstrated, but these organisms reside in single membrane phagosomes. This process is distinct from autophagy and is termed LC3-associated phagocytosis (LAP). This review will detail the hallmarks of LAP that distinguish it from classical autophagy and review the role of autophagy proteins in host response to C. albicans and other pathogenic fungi.
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    Erratum to: Modulatory role of vitamin A on the Candida albicans-induced immune response in human monocytes
    (Springer Berlin Heidelberg, 2014) Klassert, Tilman E.; Hanisch, Anja; Bräuer, Julia; Klaile, Esther; Heyl, Kerstin A.; Mansour, Michael; Tam, Jenny; Vyas, Jatin; Slevogt, Hortense
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    Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin
    (Springer Nature, 2016) Palchaudhuri, Rahul; Saez, Borja; Hoggatt, Jonathan; Schajnovitz, Amir; Sykes, David; Tate, Tiffany A; Czechowicz, Agnieszka; Kfoury, Youmna; Ruchika, FNU; Rossi, Derrick; Verdine, Gregory; Mansour, Michael; Scadden, David
    Hematopoietic stem cell transplantation (HSCT) offers curative therapy for patients with hemoglobinopathies, congenital immunodeficiencies, and other conditions, possibly including AIDS. Autologous HSCT using genetically corrected cells would avoid the risk of graft-versus-host disease (GVHD), but the genotoxicity of conditioning remains a substantial barrier to the development of this approach. Here we report an internalizing immunotoxin targeting the hematopoietic-cell-restricted CD45 receptor that effectively conditions immunocompetent mice. A single dose of the immunotoxin, CD45–saporin (SAP), enabled efficient (>90%) engraftment of donor cells and full correction of a sickle-cell anemia model. In contrast to irradiation, CD45–SAP completely avoided neutropenia and anemia, spared bone marrow and thymic niches, enabling rapid recovery of T and B cells, preserved anti-fungal immunity, and had minimal overall toxicity. This non-genotoxic conditioning method may provide an attractive alternative to current conditioning regimens for HSCT in the treatment of non-malignant blood diseases.
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    Dectin-1 Activation Controls Maturation of β-1,3-Glucan-containing Phagosomes
    (American Society for Biochemistry & Molecular Biology (ASBMB), 2013) Mansour, Michael; Tam, Jenny; Khan, Nida S.; Seward, Michael; Davids, Peter J.; Puranam, Sravanthi; Sokolovska, Anna; Sykes, David; Dagher, Zeina; Becker, Christine; Tanne, Antoine; Reedy, Jennifer; Stuart, Lynda M.; Vyas, Jatin
    Background: Dectin-1 is able to recognize and phagocytose the fungal carbohydrate, β-1,3-glucan, but its contribution to phagosomal maturation has not been explored. Results: Dectin-1-dependent Syk activation promotes phagolysosomal fusion and acidification. Conclusion: Dectin-1-dependent Syk-activation permits egress of early phagosomes to mature phagolysosomes. Significance: The surface recognition receptor, Dectin-1 shapes anti-fungal responses by controlling fungal phagosome maturation.
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    HIV-Care Outcome in Saudi Arabia; a Longitudinal Cohort
    (2014) Al-Mozaini, Maha A.; Mansour, Michael; Al-Hokail, Abdullah A.; Mohmed, Magid A.; Daham, Munirah A. Bin; Al-Abdely, Hail M.; Frayha, Husn H.; Al-Rabiah, Fahad A.; Alhajjar, Sami H.; Keshavjee, Salmaan; Adra, Chaker N.; Alrajhi, Abdulrahman A.
    Background: Clinical characteristics of HIV-1 infection in people inhabiting Western, Sub-Saharan African, and South-East Asian countries are well recognized. However, very little information is available with regard to HIV-1 infection and treatment outcome in MENA countries including the Gulf Cooperation Council (GCC) states. Methods: Clinical, demographic and epidemiologic characteristics of 602 HIV-1 infected patients followed in the adult Infectious Diseases Clinic of King Faisal Specialist Hospital and Research Centre, in Riyadh, Kingdom of Saudi Arabia a tertiary referral center were longitudinally collected from 1989 to 2010. Results: Of the 602 HIV-1 infected patients in this observation period, 70% were male. The major mode of HIV-1 transmission was heterosexual contact (55%). At diagnosis, opportunistic infections were found in 49% of patients, most commonly being pneumocysitis. AIDS associated neoplasia was also noted in 6% of patients. A hundred and forty-seven patients (24%) died from the cohort by the end of the observation period. The mortality rate peaked in 1992 at 90 deaths per 1000 person-year, whereas the mortality rate gradually decreased to <1% from 1993-2010. In 2010, 71% of the patients were receiving highly active retroviral therapy. Conclusions: These data describe the clinical characteristic of HIV-1-infected patients at a major tertiary referral hospital in KSA over a 20-year period. Initiation of antiretroviral therapy resulted in a significant reduction in both morbidity and mortality. Future studies are needed in the design and implementation of targeted treatment and prevention strategies for HIV-1 infection in KSA.
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    Serial Procalcitonin Levels Correlate with Microbial Etiology in Hospitalized Patients with Pneumonia
    (Oxford University Press, 2017) Ankomah, Pierre; McCluskey, Suzanne; Abers, Michael; Bearnot, Benjamin; Patel, Shreya; Schuetz, Philipp; Chiappa, Vic; Lewandrowski, Kent; Vyas, Jatin; Mansour, Michael
    Abstract Background: Procalcitonin (PCT) is a biomarker that is finding increasing diagnostic and prognostic utility in lower respiratory infections. It remains unclear, however, whether it can be helpful in predicting the bacterial etiology of pneumonia, with a view to informing antibiotic choice and duration. This study examines the relationship between serial PCT measurements and microbial etiology in patients hospitalized for pneumonia to determine whether changes in PCT levels provide discriminatory information on microbial etiology. Methods: We performed a subgroup analysis of data from a prospective cohort study of 505 patients admitted to a tertiary care center with findings concerning for pneumonia. Microbial etiology of pneumonia was determined from high quality respiratory samples, blood cultures or other relevant diagnostic tests according to standard protocols. Procalcitonin levels were measured serially during the first four days of hospitalization. We compared procalcitonin levels between different bacterial etiologies over the first four days of admission, using the Mann–Whitney-U test to assess for statistical significance. Results: Out of 505 patients, the diagnosis of pneumonia was adjudicated in 317, and bacterial etiology determined in 62 cases. The predominant pathogens were Staphylococcus aureus (N = 18), Streptococcus pneumoniae (N = 6), Pseudomonas aeruginosa (N = 11) and Haemophilus influenza (N = 5). Admission levels of PCT were lowest in Pseudomonas infections and highest in pneumococcal infections, though not reaching statistical significance. On hospital days two and three, pneumococcal procalcitonin levels were significantly higher than all other etiologies, but on day four, there was no statistically significant difference in PCT values for different microbial etiologies. Conclusion: Serial procalcitonin levels during the early course of bacterial pneumonia reveal a difference between pneumococcal and other bacterial etiologies, and may have an adjunct role in guiding antibiotic choice and duration. Disclosures All authors: No reported disclosures.
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    Personalized medicine: Is it time for infectious diseases?
    (Saudi Medical Journal, 2016) Al-Mozaini, Maha A.; Mansour, Michael