Amphibian macrophage development and antiviral defenses
Introduction
It is becoming evident that akin to other vertebrate species, amphibians rely heavily on macrophage-lineage cells not only for immune defense, but also for homeostasis and tissue remodeling/resorption (Haislip et al., 2011, Nishikawa et al., 1998). Whereas committed macrophage precursors of other vertebrates reside within designated hematopoietic sites (Bartelmez et al., 1989, Garceau et al., 2010, Kriegler et al., 1994), amphibian species appear to vary in their respective hematopoietic strategies and do not always harbor macrophage precursors within designated sites used by other blood cells for development. This is particularly interesting when considering that many amphibians possess two distinct developmental stages: a typically aquatic tadpole stage and a more terrestrial adult one, each with distinct physiological and immunological requirements. Although metamorphosis is generally rudimentary, or even cryptic in urodelian species (e.g. salamanders, newts), in anuran species it is a major developmental transition between two distinct immune systems [reviewed in (Flajnik et al., 1987, Robert and Ohta, 2009)]. In addition, the different ecological niches occupied by tadpole and adult stages are presumably populated by different pathogens, thus representing unique immunological pressures. As such, metamorphosis is likely to have a profound influence on macrophage development and biology. Macrophage-lineage cells are of particular relevance when considering the alarming increase in the morbidity and mortality of amphibian populations worldwide caused by ranavirus infections [large DNA viruses of the family Iridoviridae (Chinchar, 2002, Chinchar et al., 2009, Williams et al., 2005)]. Indeed, there is increasing evidence implicating amphibian macrophages in persistence, evasion and dissemination of ranaviruses, and possibly differences in the interaction of these pathogens with tadpole and adult macrophages [discussed below and reviewed in (Chen et al., 2011, Grayfer et al., 2012)]. Thus, it is imperative that we garner greater insights into the ontogeny and functionality of these amphibian innate immune effectors.
The embryonic origins of amphibian hematopoietic precursors have been described in detail elsewhere (Ciau-Uitz et al., 2014, Ciau-Uitz et al., 2010a) and will be addressed in passing here. This review addresses the current understanding of amphibian hematopoiesis with a focus on myelopoiesis, and it highlights recent notable findings pertaining to the roles of amphibian macrophages during ranavirus infections.
Section snippets
Diversified sites of hematopoiesis in amphibians
Vertebrate blood cell precursors differentiate within designated sites of hematopoiesis. Typically, avian and mammalian committed myeloid-lineage progenitors arise from the bone marrow pluripotent populations (Bartelmez et al., 1989, Garceau et al., 2010, Kriegler et al., 1994), whereas teleost fish utilize the head kidney as their designate site of hematopoiesis (Belosevic et al., 2006, Neumann et al., 2000). In amphibians, the sub-cortical (peripheral) liver is generally considered to be the
The roles of anuran bone marrow
With respect to monopoiesis, or the development of macrophage lineage cells, it is noteworthy that in mammals, surface expression of the colony stimulating factor-1 receptor (CSF-1R) on progenitor cell populations is considered a hallmark of commitment to the macrophage lineage (Tagoh et al., 2002). The transcripts and protein levels of the CSF-1R increase to detectable levels from early precursor stages (detected as macrophage colony forming units) through macrophage development and maturation
Roles of amphibian macrophages during ranavirus infections
Ranaviruses (family Iridoviridae) are large double stranded DNA viruses that have become major amphibian pathogens (Chinchar, 2002, Chinchar et al., 2009, Williams et al., 2005). Extensive population die-offs caused by these infectious agents are thought to significantly contribute to the decline of amphibian species worldwide [reviewed in Chinchar, 2002, Grayfer et al., 2015a]. Increasing evidence suggests that amphibian macrophage-lineage cells are critical to anti-ranaviral immunity as well
Concluding remarks
It is evident from the literature described above that much remains to be elucidated regarding the monopoietic strategies of amphibian species and the roles of distinct macrophage populations during amphibian immune responses. In the face of the global amphibian decline, it is imperative to more fully examine the disparate hematopoietic/monopoietic strategies in phylogenetically and physiologically divergent amphibian species. We believe that this will bring us closer to understanding why there
Acknowledgments
L. Grayfer thanks the Howard Hughes Medical Institute—Life Sciences Research Foundation for postdoctoral research support. J. Robert research support: 2 R24 Al 059830-10 from the NIH, and IOS-0923772 from the NSF.
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