In Focus Rift Valley fever: a review John Bingham Petrus Jansen van Vuren CSIRO Australian Animal Health Laboratory (AAHL) CSIRO Health and Biosecurity 5 Portarlington Road Australian Animal Health Geelong, Vic. 3220, Australia Laboratory (AAHL) Tel: + 61 3 52275000 5 Portarlington Road Email: [email protected] Geelong, Vic. 3220, Australia fi fi Rift Valley fever (RVF) is a mosquito-borne viral disease, Originally con ned to continental Africa since its rst isolation in principally of ruminants, that is endemic to Africa. The Kenya in 1930, RVFV has since spread to the Arabian Peninsula, 5,6 causative Phlebovirus, Rift Valley fever virus (RVFV), has a Madagascar and islands in the Indian Ocean . Molecular epide- broad host range and, as such, also infects humans to cause miological studies further highlight the ability of the virus to be primarily a self-limiting febrile illness. A small number of spread to distant geographical locations, with genetically related 4 human cases will also develop severe complications, includ- viruses found from distant regions of Africa . Serological evidence ing haemorrhagic fever, encephalitis and visual im- of RVFV circulation in Turkey is concerning and serves as a warning 7 pairment. In parts of Africa, it is a major disease of for possible incursion into Europe . However, serological surveys 8,9 domestic ruminants, causing epidemics of abortion and in Europe suggest absence of the virus and modelling indicates 10 mortality. It infects and can be transmitted by a broad range that the risk of introduction and large scale spread is low . Recent of mosquitos, with those of the genus Aedes and Culex importations of human RVF cases into Europe and Asia from thought to be the major vectors. Therefore, the virus has endemic African countries highlight the risk of intercontinental 11–13 the potential to become established beyond Africa, includ- spread via acutely infected travellers . Horizontal human-to- ing in Australia, where competent vector hosts are endemic. human transmission has never been documented, nevertheless, Vaccines for humans have not yet been developed to the experimental infection studies have demonstrated that non-vector 14 commercial stage. This review examines the threat of this transmission can occur between animals . virus, with particular reference to Australia, and assesses RVF affects mainly domestic ruminant livestock species and the gaps inour knowledge that maybenefitfrom research focus. disease is particularly prominent in sensitive species such as sheep. Camelids, including dromedaries and alpacas, also appear to be Epidemiology and ecology sensitive to infection15. Because Australia has large populations of Epizootics of RVF occur at irregular intervals, with inter-epizootic these species, the incursion of RVFV into the continent may be periods often spanning years or decades. The survival and re- highly visible and may adversely affect livestock industries. emergence of the virus after long periods of quiescence is thought to occur through transovarial transmission1, but likely also by low- level transmission between mosquitoes and a wildlife reservoir2. Vector competence Continuous low-level transmission also occurs within domestic RVFV has been isolated from a wide range of mosquito species but livestock populations without noticeable disease or abortions3. laboratory vector competence studies on African mosquitoes sup- RVF virus has been isolated from numerous mosquito species, but port the epidemiological importance of only a few specific Aedes certain Aedes species associated with freshly flooded temporary and Culex species4. Other species have been shown to be suscep- water bodies are regarded as maintenance vectors, while Culex tible to infection but poor at transmitting the virus. A single study species associated with permanent fresh water are regarded as evaluated vector competence of Australian Aedes and Culex mos- epidemic or amplifying vectors4. quitoes for RVFV, with high rates of infection noted, and the ability 28 10.1071/MA20008 MICROBIOLOGY AUSTRALIA * MARCH 2020 In Focus to transmit the virus efficiently after intrathoracic inoculation or depends on laboratory generated positive material. There is also oral exposure16. no well established internationally available external quality assurance or proficiency testing scheme for either serological or Genome and taxonomy molecular diagnosis of RVF, particularly in endemic African coun- Rift Valley fever virus is the only described member of the type tries, apart from some ad hoc studies that are mostly opportunistic 30,31 species of the Phlebovirus genus, Rift Valley fever phlebovirus, and dependent on funding availability . classified in the family Phenuiviridae, order Bunyavirales17. The ’ virus s relatively stable RNA genome, a result of alternating infec- Pathology and pathogenesis tion between arthropod and vertebrate hosts18, consists of two negative-strand segments and a third segment utilising an ambi- Human infections, which are usually acquired from contact with sense coding strategy. The negative sense large and medium infected animal tissues, and thus are an occupational risk for 32 segments encode the polymerase and precursor glycoproteins veterinarians, farm worker and abattoir workers , manifest as 33,34 respectively19,20, while the small segment encodes the nucleopro- sub-clinical infection or mild febrile illness . However, in a small tein in the negative sense and a non-structural protein in the number of cases the infection develops to cause severe disease, positive sense21. This non-structural protein (NSs) is the major which may take the form of a haemorrhagic fever syndrome, virulence factor of the virus due to its ability to counteract host encephalitis, retinal degeneration or other complications. The innate immune responses by acting as an interferon antagonist4. impact of these forms of the disease are usually severe with high Development of experimental live attenuated vaccines for RVF mortality or long-term impairment of neurological function and – exploits this knowledge, following the discovery of a naturally sight. In the initial phase of the disease, 1 4 days after infection, attenuated avirulent isolate, clone 13, that has a large deletion in there is a viraemia, which declines as antibody levels rise. Related to the NSs coding gene22. the viraemia is a vasculitis, which leads to thrombosis and other vascular complications, and these often manifest days to weeks Diagnostics after the initial infection. Infection of the liver is an important component of infection in highly susceptible species such as sheep Laboratory confirmation requires positive results from a combina- and mice; this develops during the acute infection stage and may tion of at least two different diagnostic test methods, which become the dominant pathological feature. includes virus detection and serological assays23. Laboratory con- firmatory testing is complicated by biocontainment requirements RVF haemorrhagic fever syndrome is characterised by haemor- and potential use as a bioweapon, thereby limiting testing to a small rhage and multi-organ failure and is caused by fulminant hepatic number of reference laboratories in the world. Technically, how- necrosis and vasculitis, two processes that lead to disseminated ever, laboratory testing is relatively simple due to the low genetic intravascular coagulopathy through non-renewal (hepatic variability of the virus4 and the existence of a single known serotype. necrosis) and depletion (vasculitis) of clotting factors. Clinical signs Virus isolation in suckling mice or cell culture and demonstration of include vomiting, bleeding from the gums, conjunctivae and other a neutralising antibody response by microneutralisation test or mucous membranes, haematemesis, subcutaneous haemorrhages plaque-reduction neutralisation test remain the gold standard and jaundice34,35. Severity of disease has a strong correlation with methods for virological and serological diagnosis respectively, but viral load, cytokine responses and coagulation pathways36,37. both require virus propagation, thus necessitating high biocon- Encephalitis may develop in a small proportion of cases some days tainment facilities. Safer alternatives have, however, been adapted or weeks after the initial febrile episode and its clinical presentation by most laboratories and are used as first line assays. Molecular may depend on the localisation of infection foci in the brain33,34.On assays such as real-time RT-PCR or loop-amplification mediated histopathological examination there is a focal necrosis with mono- PCR (LAMP) are mostly used for detecting acute infections24,25, nuclear cell perivascular cuffing35. Encephalitis usually occurs although antigen detection ELISAs have application for certain despite the presence of antibodies to RVFV, implying that the sample types26. Various ELISA platforms have been developed and condition is due to immunologically mediated damage in response shown to be sensitive and specific for detection of antibodies to the to residual infection. Recovery, like many viral encephalitides, can virus in various species27,28, including some based on recombinant be long and of variable outcome. viral proteins that do not require biocontainment facilities for production29. Proper validation of assays using clinically relevant Retinal degeneration is probably a sequel to local ocular vascular material in sufficient numbers remains a challenge and often thrombosis, appearing during