Over the last two decades it has become increasingly apparent that amphibian species are facing a serious threat of extinction [1
], where roughly one-third (32%) of the 6593 amphibian species are diminishing as a result of complex, as of yet poorly understood causes. A number of possible escalating factors have been attributed to these die-offs, including destruction of habitats, increased levels of pollution, changes in climate as well as increasing ultraviolet irradiation [2
]. While these may be underlining mechanisms, there is also a prevailing theory that the increasing amphibian declines stem from compromised immune systems of these animals coupled with elevated pathogenic threats [2
], undoubtedly resulting from one or a combination of the above.
Until recently, it was believed that viral infections were a secondary contributing factor in these die-offs. However, currently members of the family Iridoviridae
and particularly the genus Ranavirus
(RVs, family Iridoviridae
) have gained attention due to the dramatic rise in the prevalence of RV infections across pokilothermic species. In fact, ranaviruses are now considered the second most common infectious agent plaguing wild and cultured amphibian species [2
], with half of the amphibian deaths in United States between 1996 and 2001 attributed to ranaviral infections [4
Ranaviruses are icosahedral, double-stranded DNA viruses with large genomes, ranging between 105 and 140 kilobase pairs in size. Specifically, members of the family Iridoviridae
are known to infect three classes of ectothermic vertebrates: amphibians, bony fishes (teleosts) and reptiles [5
]. To date three RV species that infect amphibians have been identified and grouped according to genetic and ecological parameters [6
]. Amongst these, Bohle Iridovirus (BIV) infects Australian frogs and has so far remained confined to this region of the world. Ambystoma tiginum
virus (ATV) infects salamanders and is primarily localized to United States and Canada. In contrast, the Frog Virus 3 (FV3), initially isolated from the leopard frog, Rana
, has been recognized worldwide as an amphibian pathogen. With a rapid increases in the prevalence and spread to multiple amphibian species, FV3 is believed to be a potential global threat to amphibian populations [7
]. Although, FV3 is the greatest threat to pokilothermic vertebrates, information gained from studies dealing with the other two RV species and indeed from other members of the family Iridoviridae
(generically referred to as “iridovirids” to distinguish them from members of the genus Iridovirus
) should be recapitulated in order to better understand the mechanisms of infection and immunity within this family.
It is also becoming evident that RVs likely possess a plethora of immune evasion and host modulation mechanisms. A closer examination of the relationships between these viruses and their host immune systems is clearly warranted in light of increasing ranaviral prevalence and the potentially declining immune capacities of the ectothermic species that they infect. As compared to mammals, lower vertebrates such as those infected by iridovirids, possess functional but relatively less effective adaptive immune systems, with fewer antibody classes, poorer T lymphocyte expansion and generally less developed immunological memory responses (reviewed in reference [8
]). Accordingly these organisms likely rely more heavily on innate immune components for pathogen clearance. In turn, cells of the macrophage lineage are indispensable for innate immune responses. In mammals, macrophages are long-lived, terminally differentiated cells of myeloid origin that exhibit limited proliferation capabilities and a high level of heterogeneity [9
]. During certain viral infections, distinct macrophage subsets participate in anti-viral responses while in other instances mononuclear phagocytes may become productively infected and serve as long-term viral reservoirs and agents of viral dissemination. For example, during HIV infections macrophages are hijacked by the virus, store large numbers of virions and facilitate cell-to-cell spread of HIV [10
]. Conversely, as sentinels of the immune system, macrophages recognize viral infections through a repertoire of pattern recognition receptors [13
] and facilitate viral clearance by producing an array of bioactive molecules. Thus macrophages function in contrasting ways to either perpetuate virus replication or to eliminate it.
This review coalesces the current knowledge of the roles of innate immune components in ranaviral infections as well as recent advances in the understanding of ranavirus immune evasion strategies.