The ongoing SARS-CoV-2 pandemic has seen an unprecedented amount of rapidly generated genome data. These data have revealed the emergence of lineages with mutations associated to transmissibility and antigenicity, known as variants of concern (VOCs). A striking aspect of VOCs is that many of them involve an unusually large number of defining mutations. Current phylogenetic estimates of the substitution rate of SARS-CoV-2 suggest that its genome accrues around 2 mutations per month. However, VOCs can have 15 or more defining mutations and it is hypothesized that they emerged over the course of a few months, implying that they must have evolved faster for a period of time. We analysed genome sequence data from the GISAID database to assess whether the emergence of VOCs can be attributed to changes in the substitution rate of the virus and whether this pattern can be detected at a phylogenetic level using genome data. We fit a range of molecular clock models and assessed their statistical performance. Our analyses indicate that the emergence of VOCs is driven by an episodic increase in the substitution rate of around 4-fold the background phylogenetic rate estimate that may have lasted several weeks or months. These results underscore the importance of monitoring the molecular evolution of the virus as a means of understanding the circumstances under which VOCs may emerge.
School of Veterinary and Biomedical Sciences, James Cook University, Townsville, Australia Amphibian populations suffer massive mortalities from infection with frog virus 3 (FV3, genus Ranavirus, family Iridoviridae), a pathogen also involved in mortalities of fish and reptiles. Experimental oral infection with FV3 in captive-raised adult wood frogs, Rana sylvatica (Lithobates sylvaticus), was performed as the first step in establishing a native North American animal model of ranaviral disease to study pathogenesis and host response. Oral dosing was successful; LD 50 was 10 2.93 (2.42-3.44) p.f.u. for frogs averaging 35 mm in length. Onset of clinical signs occurred 6-14 days post-infection (p.i.) (median 11 days p.i.) and time to death was 10-14 days p.i. (median 12 days p.i.). Each tenfold increase in virus dose increased the odds of dying by 23-fold and accelerated onset of clinical signs and death by approximately 15 %. Ranavirus DNA was demonstrated in skin and liver of all frogs that died or were euthanized because of severe clinical signs. Shedding of virus occurred in faeces (7-10 days p.i.; 3-4.5 days before death) and skin sheds (10 days p.i.; 0-1.5 days before death) of some frogs dead from infection. Most common lesions were dermal erosion and haemorrhages; haematopoietic necrosis in bone marrow, kidney, spleen and liver; and necrosis in renal glomeruli, tongue, gastrointestinal tract and urinary bladder mucosa. Presence of ranavirus in lesions was confirmed by immunohistochemistry. Intracytoplasmic inclusion bodies (probably viral) were present in the bone marrow and the epithelia of the oral cavity, gastrointestinal tract, renal tubules and urinary bladder. Our work describes a ranavirus-wood frog model and provides estimates that can be incorporated into ranavirus disease ecology models.
Ranaviruses are able to infect multiple species of fish, amphibian and reptile, and some strains are capable of interclass transmission. These numerous potential carriers and reservoir species compound efforts to control and contain infections in cultured and wild populations, and a comprehensive knowledge of susceptible species and life stage is necessary to inform such processes. Here we report on the challenge of 6 water-associated reptiles with Bohle iridovirus (BIV) to investigate its potential pathogenicity in common native reptiles of the aquatic and riparian fauna of northern Queensland, Australia. Adult tortoises Elseya latisternum and Emydura krefftii, snakes Boiga irregularis, Dendrelaphis punctulatus and Amphiesma mairii, and yearling crocodiles Crocodylus johnstoni were exposed via intracoelomic inoculation or co-habitation with infected con-specifics, but none were adversely affected by the challenge conditions applied here. Bohle iridovirus was found to be extremely virulent in hatchling tortoises E. latisternum and E. krefftii via intracoelomic challenge, as demonstrated by distinct lesions in multiple organs associated with specific immunohistochemistry staining and a lethal outcome (10/17) of the challenge. Virus was re-isolated from 2/5 E. latisternum, 4/12 E. krefftii and 1/3 brown tree snakes B. irregularis. Focal necrosis, haemorrhage and infiltration of granulocytes were frequently observed histologically in the pancreas, liver and sub-mucosa of the intestine of challenged tortoise hatchlings. Immunohistochemistry demonstrated the presence of ranavirus antigens in the necrotic lesions and in individual cells of the vascular endothelium, the connective tissue and in granulocytes associated with necrosis or present along serosal surfaces. The outcome of this study confirms hatchling tortoises are susceptible to BIV, thereby adding Australian reptiles to the host range of ranaviruses. Additionally, given that BIV was originally isolated from an amphibian, our study provides additional evidence that interclass transmission of ranavirus may occur in the wild.
Ranaviruses can infect many vertebrate classes including fish, amphibians and reptiles, but for the most part, research has been focused on non-reptilian hosts, amphibians in particular. More recently, reports of ranaviral infections of reptiles are increasing with over 12 families of reptiles currently susceptible to ranaviral infection. Reptiles are infected by ranaviruses that are genetically similar to, or the same as, the viruses that infect amphibians and fish; however, physiological and ecological differences result in differences in study designs. Although ranaviral disease in reptiles is often influenced by host species, viral strain and environmental differences, general trends in pathogenesis are emerging. More experimental studies using a variety of reptile species, life stages and routes of transmission are required to unravel the complexity of wild ranavirus transmission. Further, our understanding of the reptilian immune response to ranaviral infection is still lacking, although the considerable amount of work conducted in amphibians will serve as a useful guide for future studies in reptiles.
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