Cutaneous leishmaniasis, leprosy, and tuberculosis are caused by intracellular pathogens whose development depends on impaired cell-mediated immunity. We report an exceptional triple association of ...American cutaneous leishmaniasis, lepromatous leprosy, and pulmonary tuberculosis in a man with no recognized immunodeficiency. Normal immunological assessment of the interferon-γ pathway does not support the hypothesis of a genetic defect in any of the genes involved in the T helper (Th)-1 cytokine cascade in this patient. Unresponsiveness to interleukin (IL)-12 of his T cells after stimulation with Leishmania guyanensis, Mycobacterium bovis bacille Calmette-Guérin, and Mycobacterium leprae antigens suggested the inability to mount an appropriate Th cell response to upregulate the IL-12 receptor expression.
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Mucocutaneous leishmaniasis is caused by infections with intracellular parasites of the Leishmania Viannia subgenus, including Leishmania guyanensis. The pathology develops after parasite ...dissemination to nasopharyngeal tissues, where destructive metastatic lesions form with chronic inflammation. Currently, the mechanisms involved in lesion development are poorly understood. Here we show that metastasizing parasites have a high Leishmania RNA virus-1 (LRV1) burden that is recognized by the host Toll-like receptor 3 (TLR3) to induce proinflammatory cytokines and chemokines. Paradoxically, these TLR3-mediated immune responses rendered mice more susceptible to infection, and the animals developed an increased footpad swelling and parasitemia. Thus, LRV1 in the metastasizing parasites subverted the host immune response to Leishmania and promoted parasite persistence.
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The murine model of Leishmania major infection has been an invaluable tool in understanding T helper differentiation in vivo. The initial evidence for a role of distinct CD4(+) T helper subsets in ...the outcome of infection was first obtained with this experimental model. The development of CD4(+) Th1 cells was associated with resolution of the lesion, control of parasite replication, and resistance to re-infection in most of the mouse strains investigated (i.e., C57BL/6). In contrast, differentiation of CD4(+) Th2 cells correlated with the development of unhealing lesions, and failure to control parasite load in a few strains (i.e., BALB/c). Since these first reports, an incredible amount of effort has been devoted to understanding the various parameters involved in the differentiation of these, and more recently discovered T helper subsets such as Th17 and T regulatory cells. The discovery of cross-talk between T helper subsets, as well as their plasticity force us to reevaluate the events driving a protective/deleterious T helper immune response following infection with L. major in mice. In this review, we describe the individual contributions of each of these CD4(+) T helper subsets following L. major inoculation, emphasizing recent advances in the field, such as the impact of different substrains of L. major on the pathogenesis of disease.
Recent evidence indicates that B cells are required for susceptibility to infection with Leishmania major in BALB/c mice. In this study, we analyzed the role of the IL-10 produced by B cells in this ...process. We showed that B cells purified from the spleen of BALB/c mice produced IL-10 in response to stimulation with L. major in vitro. In vivo, early IL-10 mRNA expression is detected after L. major infection in B cells from draining lymph nodes of susceptible BALB/c, but not of resistant C57BL/6 mice. Although adoptive transfer of naive wild-type B cells prior to infection in B cell-deficient BALB/c mice restored Th2 cell development and susceptibility to infection with L. major of these otherwise resistant mice, adoptive transfer of IL-10(-/-) B cells mice did not. B cells stimulated by L. major, following in vitro or in vivo encounter, express the CD1d and CD5 molecules and the IL-10 produced by these cells downregulate IL-12 production by L. major-stimulated dendritic cells. These observations indicate that IL-10 secreting B cells are phenotypically and functionally regulatory B cells. Altogether these results demonstrate that the IL-10 produced by regulatory CD1d+ CD5+ B cells in response to L. major is critical for Th2 cell development in BALB/c mice.
Implementation research (IR) is growing in recognition as an important generator of practical knowledge that can be translated into health policy. With its aim to answer questions about how to ...improve access to interventions that have been shown to work but have not reached many of the people who could benefit from them, IR involves a range of particular ethical considerations that have not yet been comprehensively covered in international guidelines on health research ethics. The fundamental ethical principles governing clinical research apply equally in IR, but the application of these principles may differ depending on the IR question, context, and the nature of the proposed intervention. IR questions cover a broad range of topics that focus on improving health system functioning and improving equitable and just access to effective health care interventions. As such, IR designs are flexible and often innovative, and ethical principles cannot simply be extrapolated from their applications in clinical research. Meaningful engagement with all stakeholders including communities and research participants is a fundamental ethical requirement that cuts across all study phases of IR and links most ethical concerns. Careful modification of the informed consent process may be required in IR to permit study of a needed intervention. The risks associated with IR may be difficult to anticipate and may be very context-specific. The benefits of IR may not accrue to the same groups who participate in the research, therefore justifying the risks versus benefits of IR may be ethically challenging. The expectation that knowledge generated through IR should be rapidly translated into health policy and practice necessitates up-front commitments from decision-makers to sustainability and scalability of effective interventions. Greater awareness of the particular ethical implications of the features of IR is urgently needed to facilitate optimal ethical conduct of IR and uniform ethical review.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Training and innovation in the field of medical entomology are essential to mitigate the burden of vector-borne diseases globally. However, there is a shortage of medical entomologists worldwide, and ...there are large discrepancies in capacity building in this field. In this article, we discuss the current situation, what is needed from the medical entomologist of today, and how we can bridge this gap.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Most health professionals lack the training and expertise to translate clinical innovations into actionable programs. Even though some public health expert communities understand that even widely ...proven solutions need to be adapted to the demands and characteristics of diverse health systems and societies to be successful, such knowledge has yet to inform routine public health approaches and practices. Therefore, it should not be a surprise that the “know-do” gap between clinical innovations and their on-the-ground application that implementation research seeks to bridge is pervasive and enduring, particularly in low- and middle-income countries. This article draws on a study of implementation research training courses to highlight the various competencies needed to translate different types of knowledge into action, many of which are not adequately addressed in existing curricula. We utilized a four-phase modified Delphi methodology that included a review of the academic and grey literature, one-on-one interviews with experts, virtual dialogue series with key stakeholders, and peer review of the synthesized results. The resulting areas in need of further development include the ability of learners to work as part of a multidisciplinary team, engage various stakeholders, and communicate research findings to decision-makers. Based on these insights, it is argued that knowledge translation in implementation research is a multi-faceted, multi-level sensemaking and communication activity that takes place throughout the research and research-to policy-processes.
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