XB-ART-56392
Front Immunol
2018 Sep 12;9:2536. doi: 10.3389/fimmu.2018.02536.
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Review of the Amphibian Immune Response to Chytridiomycosis, and Future Directions.
Grogan LF
,
Robert J
,
Berger L
,
Skerratt LF
,
Scheele BC
,
Castley JG
,
Newell DA
,
McCallum HI
.
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The fungal skin disease, chytridiomycosis (caused by Batrachochytrium dendrobatidis and B. salamandrivorans), has caused amphibian declines and extinctions globally since its emergence. Characterizing the host immune response to chytridiomycosis has been a focus of study with the aim of disease mitigation. However, many aspects of the innate and adaptive arms of this response are still poorly understood, likely due to the wide range of species' responses to infection. In this paper we provide an overview of expected immunological responses (with inference based on amphibian and mammalian immunology), together with a synthesis of current knowledge about these responses for the amphibian-chytridiomycosis system. We structure our review around four key immune stages: (1) the naïve immunocompetent state, (2) immune defenses that are always present (constitutive defenses), (3) mechanisms for recognition of a pathogen threat and innate immune defenses, and (4) adaptive immune responses. We also evaluate the current hot topics of immunosuppression and immunopathology in chytridiomycosis, and discuss their respective roles in pathogenesis. Our synthesis reveals that susceptibility to chytridiomycosis is likely to be multifactorial. Susceptible amphibians appear to have ineffective constitutive and innate defenses, and a late-stage response characterized by immunopathology and Bd-induced suppression of lymphocyte responses. Overall, we identify substantial gaps in current knowledge, particularly concerning the entire innate immune response (mechanisms of initial pathogen detection and possible immunoevasion by Bd, degree of activation and efficacy of the innate immune response, the unexpected absence of innate leukocyte infiltration, and the cause and role of late-stage immunopathology in pathogenesis). There are also gaps concerning most of the adaptive immune system (the relative importance of B and T cell responses for pathogen clearance, the capacity and extent of immunological memory, and specific mechanisms of pathogen-induced immunosuppression). Improving our capacity for amphibian immunological research will require selection of an appropriate Bd-susceptible model species, the development of taxon-specific affinity reagents and cell lines for functional assays, and the application of a suite of conventional and emerging immunological methods. Despite current knowledge gaps, immunological research remains a promising avenue for amphibian conservation management.
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Figure 1. Amphibian host immunity schematic, depicting a histological section through the skin and progressive infection stages with Bd. The inference of the main cellular components is based on mammalian immunology and an expected ânormalâ immune response (including the expected response to vaccination). (A) Normal skin: Layers of uninfected frog skin epidermis including, from deepest to most superficial, the basal lamina, stratum germinativum, stratum spinosum, stratum granulosum, stratum corneum and the superficial mucus layer. Two immune surveillance cells are illustrated within the epidermis, an immune dendritic cell (homologous to Langerhans cell), and a dendritic epidermal T cell (dETC). Within the dermis is a capillary with the nucleated red blood cells of amphibians. An example complement of naïve B and T lymphocytes are depicted waiting quiescent in the spleen, illustrated schematically as the lower band on the figure (please note that the spleen is a separate organ and does not lie adjacent to the dermis in living amphibians). (B) Early infection: Expected immune mechanisms upon initial exposure to Bd, assuming constitutive defenses (such as AMPs and bacteria) are insufficient. Zoospores are illustrated penetrating the mucus layer, and early thalli with zoosporangia developing are illustrated inside deeper host cells. In a normal immune response, pathogen recognition should lead to the infiltration of innate immune cells, illustrated here to include macrophages and granulocytes (such as neutrophils). (C) Intermediate infection: Expected response at an intermediate stage of infection includes the recognition of antigens by dendritic cells that then differentiate into antigen presenting cells and migrate to the spleen enabling antigen-specific selection of lymphocytes. Simultaneously, membrane-bound immunoglobulin on naïve B lymphocytes is exposed to extracellular Bd antigens (transported via the blood circulatory and lymphatic systems). With the assistance of T helper cells, these B cells are activated to respond to infection. (D) Late infection: The late adaptive response involves lymphocyte clonal expansion, differentiation into plasma cells and activated T cells (including cytotoxic and helper T cells), as well as the production of antibodies by plasma cells. (E) Recovery: If the frog is cleared of infection (perhaps by topical antifungals or heat), the skin might be expected to return to normal, however, a cohort of selected memory lymphocytes should remain. (F) Re-exposure: If the frog is then later re-exposed to Bd, the memory lymphocytes (produced during the previous clonal expansion) are then activated and induced to replicate and differentiate, leading to a much more rapid and effective adaptive immune response on re-exposure. This is the concept of immunization (vaccination). | |
Figure 1. Amphibian host immunity schematic, depicting a histological section through the skin and progressive infection stages with Bd. The inference of the main cellular components is based on mammalian immunology and an expected ânormalâ immune response (including the expected response to vaccination). (A) Normal skin: Layers of uninfected frog skin epidermis including, from deepest to most superficial, the basal lamina, stratum germinativum, stratum spinosum, stratum granulosum, stratum corneum and the superficial mucus layer. Two immune surveillance cells are illustrated within the epidermis, an immune dendritic cell (homologous to Langerhans cell), and a dendritic epidermal T cell (dETC). Within the dermis is a capillary with the nucleated red blood cells of amphibians. An example complement of naïve B and T lymphocytes are depicted waiting quiescent in the spleen, illustrated schematically as the lower band on the figure (please note that the spleen is a separate organ and does not lie adjacent to the dermis in living amphibians). (B) Early infection: Expected immune mechanisms upon initial exposure to Bd, assuming constitutive defenses (such as AMPs and bacteria) are insufficient. Zoospores are illustrated penetrating the mucus layer, and early thalli with zoosporangia developing are illustrated inside deeper host cells. In a normal immune response, pathogen recognition should lead to the infiltration of innate immune cells, illustrated here to include macrophages and granulocytes (such as neutrophils). (C) Intermediate infection: Expected response at an intermediate stage of infection includes the recognition of antigens by dendritic cells that then differentiate into antigen presenting cells and migrate to the spleen enabling antigen-specific selection of lymphocytes. Simultaneously, membrane-bound immunoglobulin on naïve B lymphocytes is exposed to extracellular Bd antigens (transported via the blood circulatory and lymphatic systems). With the assistance of T helper cells, these B cells are activated to respond to infection. (D) Late infection: The late adaptive response involves lymphocyte clonal expansion, differentiation into plasma cells and activated T cells (including cytotoxic and helper T cells), as well as the production of antibodies by plasma cells. (E) Recovery: If the frog is cleared of infection (perhaps by topical antifungals or heat), the skin might be expected to return to normal, however, a cohort of selected memory lymphocytes should remain. (F) Re-exposure: If the frog is then later re-exposed to Bd, the memory lymphocytes (produced during the previous clonal expansion) are then activated and induced to replicate and differentiate, leading to a much more rapid and effective adaptive immune response on re-exposure. This is the concept of immunization (vaccination). |
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