Interplay between innate immunity and the viral oncoproteins Tax and HBZ in the pathogenesis and therapeutic response of HTLV-1 associated adult T cell leukemia

The Human T-cell Leukemia virus type 1 (HTLV-1) causes an array of pathologies, the most aggressive of which is adult T-cell leukemia (ATL), a fatal blood malignancy with dismal prognosis. The progression of these diseases is partly ascribed to the failure of the immune system in controlling the spread of virally infected cells. HTLV-1 infected subjects, whether asymptomatic carriers or symptomatic patients are prone to opportunistic infections. An increasing body of literature emphasizes the interplay between HTLV-1, its associated pathologies, and the pivotal role of the host innate and adoptive immune system, in shaping the progression of HTLV-1 associated diseases and their response to therapy. In this review, we will describe the modalities adopted by the malignant ATL cells to subvert the host innate immune response with emphasis on the role of the two viral oncoproteins Tax and HBZ in this process. We will also provide a comprehensive overview on the function of innate immunity in the therapeutic response to chemotherapy, anti-viral or targeted therapies in the pre-clinical and clinical settings

Controversies in Targeted Therapy of Adult T Cell Leukemia/Lymphoma: ON Target or OFF Target Effects?

Adult T cell leukemia/lymphoma (ATL) represents an ideal model for targeted therapy because of intrinsic chemo-resistance of ATL cells and the presence of two well identified targets: the HTLV-I retrovirus and the viral oncoprotein Tax. The combination of zidovudine (AZT) and interferon-alpha (IFN) has a dramatic impact on survival of ATL patients. Although the mechanism of action remains unclear, arguments in favor or against a direct antiviral effect will be discussed. Yet, most patients relapse and alternative therapies are mandatory. IFN and arsenic trioxide induce Tax proteolysis, synergize to induce apoptosis in ATL cells and cure Tax-driven ATL in mice through specific targeting of leukemia initiating cell activity. These results provide a biological basis for the clinical success of arsenic/IFN/AZT therapy in ATL patients and suggest that both extinction of viral replication (AZT) and Tax degradation (arsenic/IFN) are needed to cure ATL

Use of the job demands-resource model to understand community pharmacists’ burnout during the COVID-19 pandemic

BackgroundCommunity pharmacists are one of the most accessible healthcare providers during the COVID-19 pandemic. Whilst playing a vital role in medication supply and patient education, exposure to the pandemic demands and prolonged stressors increase their risk of burnout. ObjectivesUsing the Job Demands-Resources model, this study aims to understand the factors that led to community pharmacists’ burnout and to identify their coping strategies and perceived recommendations on interventions to mitigate burnout during the COVID-19 pandemic. MethodsA qualitative phenomenological approach was used with focus groups and interviews of community pharmacists in Qatar who were recruited using purposeful, convenience, and snowballing sampling methods. Interviews were conducted between February and April 2021, were audio-recorded and transcribed verbatim. Using thematic analysis methodology, manual inductive and deductive (based on the model) codes from the interviews were used for synthesis of themes. 11 themes emerged from six focus groups, six dyadic interviews and mini focus groups, and four individual interviews with community pharmacists. ResultsThe contributing factors to community pharmacists’ burnout have been identified as practical job demands, and emotional demands including fear of infection. On the other hand, government and workplace-specific resources, personal characteristics such as resiliency and optimism, as well as the implementation of coping strategies, have reduced their stress and burnout. ConclusionsThe use of the Job Demands-Resources model was appropriate to identify the contributing factors to community pharmacists’ burnout during the COVID-19 pandemic. Based on these factors, individual, organizational, and national strategies can be implemented to mitigate burnout in community pharmacists during the pandemic and future emergencies.This work was supported by a student grant (grant number QUST-1-CPH-2021-14) from Qatar University Office of Research and Graduate Studies. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of Qatar University

ROP18 Is a Rhoptry Kinase Controlling the Intracellular Proliferation of Toxoplasma gondii

Toxoplasma gondii is an obligate intracellular parasite for which the discharge of apical organelles named rhoptries is a key event in host cell invasion. Among rhoptry proteins, ROP2, which is the prototype of a large protein family, is translocated in the parasitophorous vacuole membrane during invasion. The ROP2 family members are related to protein-kinases, but only some of them are predicted to be catalytically active, and none of the latter has been characterized so far. We show here that ROP18, a member of the ROP2 family, is located in the rhoptries and re-localises at the parasitophorous vacuole membrane during invasion. We demonstrate that a recombinant ROP18 catalytic domain (amino acids 243–539) possesses a protein-kinase activity and phosphorylate parasitic substrates, especially a 70-kDa protein of tachyzoites. Furthermore, we show that overexpression of ROP18 in transgenic parasites causes a dramatic increase in intra-vacuolar parasite multiplication rate, which is correlated with kinase activity. Therefore, we demonstrate, to our knowledge for the first time, that rhoptries can discharge active protein-kinases upon host cell invasion, which can exert a long-lasting effect on intracellular parasite development and virulence

Tax ubiquitylation and SUMOylation control the dynamic shuttling of Tax and NEMO between Ubc9 nuclear bodies and the centrosome

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A proteomic analysis unravels novel CORVET and HOPS proteins involved in Toxoplasma gondii secretory organelles biogenesis

Apicomplexans use the endolysosomal system for the biogenesis of their secretory organelles, namely, micronemes, rhoptries, and dense granules. In Toxoplasma gondii, our previous in silico search identified the HOPS tethering but not the CORVET complex and demonstrated a role of Vps11 (a common component for both complexes) in its secretory organelle biogenesis. Herein, we performed Vps11‐GFP‐Trap pull‐down assays and identified by proteomic analysis, not only the CORVET‐specific subunit Vps8 but also a BEACH domain‐containing protein (BDCP) conserved in eukaryotes. We show that knocking‐down Vps8 affects targeting of dense granule proteins, transport of rhoptry proteins, and the localization of the cathepsin L protease vacuolar compartment marker. Only a subset of micronemal proteins are affected by the absence of Vps8, shedding light on at least two trafficking pathways involved in microneme maturation. Knocking‐down BDCP revealed a restricted and particular role of this protein in rhoptry and vacuolar compartment biogenesis. Moreover, depletion of BDCP or Vps8 abolishes parasite virulence in vivo. This study identified BDCP as a novel CORVET/HOPS‐associated protein, playing specific roles and acting in concert during secretory organelle biogenesis, an essential process for host cell infection. Our results open the hypothesis for a role of BDCP in the vesicular trafficking towards lysosome‐related organelles in mammals and yeast

The combination of arsenic, interferon-alpha, and zidovudine restores an “immunocompetent-like” cytokine expression profile in patients with adult T-cell leukemia lymphoma

BACKGROUND: HTLV-I associated adult T-cell leukemia/lymphoma (ATL) carries a dismal prognosis due to chemo-resistance and immuno-compromised micro-environment. The combination of zidovudine and interferon-alpha (IFN) significantly improved survival in ATL. Promising results were reported by adding arsenic trioxide to zidovudine and IFN. RESULTS: Here we assessed Th1/Th2/T(reg) cytokine gene expression profiles in 16 ATL patients before and 30 days after treatment with arsenic/IFN/zidovudine, in comparison with HTLV-I healthy carriers and sero-negative blood donors. ATL patients at diagnosis displayed a T(reg)/Th2 cytokine profile with significantly elevated transcript levels of Foxp3, interleukin-10 (IL-10), and IL-4 and had a reduced Th1 profile evidenced by decreased transcript levels of interferon-γ (IFN-γ) and IL-2. Most patients (15/16) responded, with CD4(+)CD25(+) cells significantly decreasing after therapy, paralleled by decreases in Foxp3 transcript. Importantly, arsenic/IFN/zidovudine therapy sharply diminished IL-10 transcript and serum levels concomittant with decrease in IL-4 and increases in IFN-γ and IL-2 mRNA, whether or not values were adjusted to the percentage of CD4(+)CD25(+) cells. Finally, IL-10 transcript level negatively correlated with clinical response at Day 30. CONCLUSIONS: The observed shift from a T(reg)/Th2 phenotype before treatment toward a Th1 phenotype after treatment with arsenic/IFN/zidovudine may play an important role in restoring an immuno-competent micro-environment, which enhances the eradication of ATL cells and the prevention of opportunistic infections

Fatal Visceral Leishmaniasis Caused by Leishmania infantum, Lebanon

Visceral leishmaniasis, a fatal disease if not treated, is caused by Leishmania parasites. This disease might be overlooked in the Middle East because of limited awareness and low incidence. We report 5 patients who died of visceral leishmaniasis in Lebanon and make recommendations to improve faster diagnosis and treatment

Rethinking Education: An In-Depth Examination of Modern Technologies and Pedagogic Recommendations

Educational technology has changed the teaching and learning process in many ways. As teachers needed new strategies to adapt to emerging technology tools and to interact with students, immediate feedback and digital instructional resources had become the norm. Teaching and learning expectations are growing because of technological improvements. Many digital libraries and online resources are now easily accessible to teachers and students. Therefore, a qualified teacher must be aware of the new teaching requirements and the adjustments related to educational technology trends. Additionally, it is important to adopt a Technological Pedagogical Content Knowledge (TPCK) framework and to clarify how teachers and students can collaborate to achieve learning outcomes through updated educational practices. This collaborative education can occur because technology makes it easier for students and teachers to interact together, despite the physical distance that could separate them. This paper emphasizes the optimum use of educational technologies and the potential of new digital tools that have already been exploited in an unprecedented way. It aims to provide a comprehensive review of current technologies with pedagogic recommendations, to highlight the importance of educational technologies in teaching, and to reconsider strategies for acquiring digital skills in the Artificial Intelligence era. The discussion revolves around identifying and depicting various advanced educational technologies that can be integrated with engaging pedagogical approaches. Furthermore, it explains how each technology can enhance the learning experience, emphasizing the teacher’s role in the technology-based educational process