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      Translating Observations From Leishmanization Into Non-Living Vaccines: The Potential of Dendritic Cell-Based Vaccination Strategies Against Leishmania

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          Abstract

          Leishmaniasis is a health-threatening vector-borne disease in almost 90 different countries. While a prophylactic human vaccine is not yet available, the fact that recovery from leishmaniasis establishes lifelong immunity against secondary infection suggests that a vaccine is attainable. In the past, deliberate infection with virulent parasites, termed Leishmanization, was used as a live-vaccine against cutaneous leishmaniasis and effectively protected against vector-transmitted disease in endemic areas. However, the practice was discontinued due to major complications including non-healing skin lesions, exacerbation of skin diseases, and the potential impact of immunosuppression. Instead, tremendous effort has been made to develop killed, live attenuated, and non-living subunit formulations. Many of these formulations produce promising experimental results but have failed in field trials or against experimental challenge with infected sand flies. Recently, experimental models of leishmanization have unraveled the critical role of parasite persistence in maintaining the circulating CD4 + effector T cells responsible for mitigating the inflammatory response early after sand fly challenge and mediating protective immunity. Here, we put forward the notion that for effective vaccine design (especially non-living vaccines), the role of antigen persistence and pre-existing effector CD4 + T cells should be taken into consideration. We propose that dendritic cell-based vaccination strategies warrant greater attention because of their potential to act as long-term antigen depots, thereby emulating this critical requirement of naturally acquired protective immunity against infected sand fly challenge.

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          Most cited references85

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          CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity.

          The long-term persistence of pathogens in a host that is also able to maintain strong resistance to reinfection, referred to as concomitant immunity, is a hallmark of certain infectious diseases, including tuberculosis and leishmaniasis. The ability of pathogens to establish latency in immune individuals often has severe consequences for disease reactivation. Here we show that the persistence of Leishmania major in the skin after healing in resistant C57BL/6 mice is controlled by an endogenous population of CD4+CD25+ regulatory T cells. These cells constitute 5-10% of peripheral CD4+ T cells in naive mice and humans, and suppress several potentially pathogenic responses in vivo, particularly T-cell responses directed against self-antigens. During infection by L. major, CD4+CD25+ T cells accumulate in the dermis, where they suppress-by both interleukin-10-dependent and interleukin-10-independent mechanisms-the ability of CD4+CD25- effector T cells to eliminate the parasite from the site. The sterilizing immunity achieved in mice with impaired IL-10 activity is followed by the loss of immunity to reinfection, indicating that the equilibrium established between effector and regulatory T cells in sites of chronic infection might reflect both parasite and host survival strategies.
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            Leishmania RNA virus controls the severity of mucocutaneous leishmaniasis.

            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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              Cutting edge: neutrophil granulocyte serves as a vector for Leishmania entry into macrophages.

              Macrophages (MF) are the final host cells for multiplication of the intracellular parasite Leishmania major (L. major). However, polymorphonuclear neutrophil granulocytes (PMN), not MF, are the first leukocytes that migrate to the site of infection and encounter the parasites. Our previous studies indicated that PMN phagocytose but do not kill L. major. Upon infection with Leishmania, apoptosis of human PMN is delayed and takes 2 days to occur. Infected PMN were found to secrete high levels of the chemokine MIP-1beta, which attracts MF. In this study, we investigated whether MF can ingest parasite-infected PMN. We observed that MF readily phagocytosed infected apoptotic PMN. Leishmania internalized by this indirect way survived and multiplied in MF. Moreover, ingestion of apoptotic infected PMN resulted in release of the anti-inflammatory cytokine TGF-beta by MF. These data indicate that Leishmania can misuse granulocytes as a "Trojan horse" to enter their final host cells "silently" and unrecognized.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                04 June 2018
                2018
                : 9
                : 1227
                Affiliations
                [1] 1Department of Immunotherapy and Leishmania Vaccine Research, Pasteur Institute of Iran , Tehran, Iran
                [2] 2Cumming School of Medicine, Snyder Institute for Chronic Diseases of Canada, University of Calgary , Calgary, Canada
                Author notes

                Edited by: Alexandre Barbosa Reis, Universidade Federal de Ouro Preto, Brazil

                Reviewed by: Paula Mello De Luca, Fundação Oswaldo Cruz (Fiocruz), Brazil; Bruno Mendes Roatt, Universidade Federal de Minas Gerais – UFMG, Brazil; Ricardo Fujiwara, Universidade Federal de Minas Gerais, Brazil

                *Correspondence: Negar Seyed, negarse@ 123456gmail.com

                Specialty section: This article was submitted to Vaccines and Molecular Therapeutics, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2018.01227
                5996938
                29403488
                1573301e-60b8-4400-a9ad-ca2e5038655f
                Copyright © 2018 Seyed, Peters and Rafati.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 12 January 2018
                : 16 May 2018
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 96, Pages: 10, Words: 8160
                Categories
                Immunology
                Review

                Immunology
                leishmania,vaccine design,antigen persistence,effector t cells,long-term protection
                Immunology
                leishmania, vaccine design, antigen persistence, effector t cells, long-term protection

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