Fig 9 - uploaded by Brian J Sheahan
Content may be subject to copyright.
Olfactory bulb; mouse no. 1, LI/I, 9 days p.i. (i.n.). LIV antigen in mitral cells and cell processes. Avidin– biotin–peroxidase complex method, haematoxylin counterstain. Bar, 33 m. Fig. 10. Olfactory bulb; mouse no. 3, LI/I, 9 days p.i. (i.n.). Strong positive labelling for apoptosis in periglomerular areas. TUNEL method, haematoxylin counterstain. Bar, 33 m. Fig. 11. Thalamus; mouse no. 1, LI/I, 9 days p.i. (i.n.). Mac-3 antigen-positive histiocytes in perivascular spaces and in the neuropil. Avidin–biotin–peroxidase complex method, haematoxylin counterstain. Bar, 33 m. Fig. 12. Pons; mouse no. 2, MA54, 5 days p.i. (i.p.). CD45RA-reactive lymphocytes in perivascular cuffs. Avidin– biotin–peroxidase complex method, haematoxylin counterstain. Bar, 33 m.
Source publication
Mice and lambs were infected with the LI/I, LI/31 or MA54 strain of louping ill virus (LIV) to provide information relevant to testing the efficacy and biosafety of a new generation of flavivirus vaccines based on a Semliki Forest virus (SFV) vector. Whereas clinical signs and neuropathological lesions were consistently severe in mice, the majority...
Similar publications
Louping ill virus (LIV) infection of mice was used as a model to evaluate the protective efficacy of Semliki Forest virus (SFV)-based vaccines in comparison to a standard DNA vaccine and a commercial chemically inactivated vaccine. The recombinant SFV-based vaccines consisted of suicidal particles and a naked layered DNA/RNA construct. The nucleic...
Citations
... However, whilst sheep showed more severe lesions in the ventral horns of the spinal cord [21], these goats presented with diffuse lesions affecting both the ventral and dorsal horns. Despite lesions having been reported in the hippocampus in lambs experimentally infected with LIV [22], the goats in this study (and those infected experimentally in a previous study [10]) were devoid of any lesion in this area and the mechanism and relevance of this difference is unknown. However, the high dose of LIV used for experimental infections and the longer post-infection survival time (21 days) may explain the presence of lesions in the hippocampus of lambs [22]. ...
... Despite lesions having been reported in the hippocampus in lambs experimentally infected with LIV [22], the goats in this study (and those infected experimentally in a previous study [10]) were devoid of any lesion in this area and the mechanism and relevance of this difference is unknown. However, the high dose of LIV used for experimental infections and the longer post-infection survival time (21 days) may explain the presence of lesions in the hippocampus of lambs [22]. ...
... Severity and presentation of clinical signs in LI disease are related directly to the extent of damage to neurons [22,23], with neuropathological changes in moribund sheep most marked in the Purkinje cells, neurons of the dorsal motor nucleus of the vagus nerve and vestibular nuclei, and the ventral horns of the spinal cord [23]. This is in agreement with most of the areas affected in the three goats examined in this study, all of which developed severe neurological clinical signs. ...
In autumn 2011, a disease outbreak caused by Spanish goat encephalitis virus (SGEV) was reported in a herd of goats from Asturias (north-western Spain), expanding the known geographic distribution of tick-borne encephalitis in Europe. The virus was classified as a new subtype (subspecies) within the Louping-ill virus species of the mammalian tick-borne flavivirus group. The aims of the present study were to describe the pathology in goats naturally infected with SGEV, as well as discuss the pathogenesis of the disease in that outbreak. A total of 22/85 (25.88%) goats (20 adults and 2 kids) died between October 2011 and June 2012, showing neurological clinical signs. Over three years, the mortality rate in the herd reached 100%. Neuropathological lesions caused by SGEV were severe and widespread throughout the central nervous system but were more severe and numerous in the proximal cervical spinal cord, medulla oblongata, pons and cerebellar cortex. They consisted of neuron necrosis, neuronophagia, mononuclear inflammatory cell perivascular cuffs (lymphocytes, plasma cells and macrophages) and gliosis. The distribution of viral antigens was restricted to the cytoplasm of neurons in several brain areas but not associated with inflammatory foci nor inflammatory cells. SGEV should be considered a significant pathogen of goats that results in severe neurological clinical disease and high mortality.
... The response to SGEV in goat CNS has been shown to comprise microglia, T lymphocytes, and, a to lesser extent, B lymphocytes [6]. This is similar to the responses to LIV in mice and lambs [7], to West Nile virus in humans and horses [8,9], to Japanese encephalitis virus in humans [10], and to tick-borne encephalitis virus in humans and non-human primates [11,12]. ...
... The inflammatory cells were predominantly microglia, with a moderate number of T lymphocytes and a smaller number of B lymphocytes. These findings are similar to those of previous studies on SGEV in goats [6] and on LIV and other flaviviruses in horses, humans, and non-human primates [7][8][9][10][11][12]14,15]. Microglia, which are of mesodermal origin, play a key role in the innate and adaptive immune responses in the CNS [10]; in fact, they are the first cells that respond to CNS infection [12,16]. ...
... T lymphocytes were the second most abundant cell population, as reported in flavivirus infections in goats, lambs, humans, non-human primates, horses, and mice [6,7,9,11,15,17,19]. T lymphocytes control viral infections in the CNS by destroying infected cells, producing cytokines, stimulating phagocytic activity of microglia, and stimulating local antibody production by B lymphocytes [12,20]. ...
Spanish goat encephalitis virus (SGEV), a novel subtype of tick-borne flavivirus closely related to louping ill virus, causes a neurological disease in experimentally infected goats and lambs. Here, the distribution of microglia, T and B lymphocytes, and astrocytes was determined in the encephalon and spinal cord of eight Assaf lambs subcutaneously infected with SGEV. Cells were identified based on immunohistochemical staining against Iba1 (microglia), CD3 (T lymphocytes), CD20 (B lymphocytes), and glial fibrillary acidic protein (astrocytes). In glial foci and perivascular cuffing areas, microglia were the most abundant cell type (45.4% of immunostained cells), followed by T lymphocytes (18.6%) and B lymphocytes (4.4%). Thalamus, hypothalamus, corpus callosum, and medulla oblongata contained the largest areas occupied by glial foci. Reactive astrogliosis occurred to a greater extent in the lumbosacral spinal cord than in other regions of the central nervous system. Lesions were more frequent on the side of the animal experimentally infected with the virus. Lesions were more severe in lambs than in goats, suggesting that lambs may be more susceptible to SGEV, which may be due to species differences or to interindividual differences in the immune response, rather than to differences in the relative proportions of immune cells. Larger studies that monitor natural or experimental infections may help clarify local immune responses to this flavivirus subtype in the central nervous system.
... Sheep can be reservoirs of LIV without the need for any other transmission hosts of tick or LIV (14-16) since sheep are competent transmission hosts (17) and also feed all active stages (larvae, nymphs and adults) of the I. ricinus vector (18). Therefore, it may seem reasonable to predict that higher prevalences of LIV occur in areas with higher densities of sheep. ...
Identifying the risk factors for disease is crucial for developing policy and strategies for controlling exposure to pathogens. However, this is often challenging, especially in complex disease systems, such as vector-borne diseases with multiple hosts and other environmental drivers. Here we combine seroprevalence data with GIS-based environmental variables to identify the environmental risk factors associated with an endemic tick-borne pathogen—louping ill virus—in sheep in Scotland. Higher seroprevalences were associated with (i) upland/moorland habitats, in accordance with what we predicted from the habitat preferences of alternative LIV transmission hosts (such as red grouse), (ii) areas of higher deer density, which supports predictions from previous theoretical models, since deer are the key Ixodes ricinus tick reproduction host in this system, and (iii) a warmer climate, concurring with our current knowledge of how temperature affects tick activity and development rates. The implications for policy include adopting increased disease management and awareness in high risk habitats and in the presence of alternative LIV hosts (e.g., grouse) and tick hosts (especially deer). These results can also inform deer management policy, especially where there may be conflict between contrasting upland management objectives, for example, revenue from deer hunting vs. sheep farmers.
... 57 Louping ill virus, an agriculturally important flavivirus of sheep, can be modeled in BALB/c mice and (albeit less reliably) in lambs. 60 As the natural host, adult laboratory sheep show promise for pathogenesis studies. ...
Arthropod-borne viruses (arboviruses) have continued to emerge in recent years, posing a significant health threat to millions of people worldwide. The majority of arboviruses that are pathogenic to humans are transmitted by mosquitoes and ticks, but other types of arthropod vectors can also be involved in the transmission of these viruses. To alleviate the health burdens associated with arbovirus infections, it is necessary to focus today's research on disease control and therapeutic strategies. Animal models for arboviruses are valuable experimental tools that can shed light on the pathophysiology of infection and will enable the evaluation of future treatments and vaccine candidates. Ideally an animal model will closely mimic the disease manifestations observed in humans. In this review, we outline the currently available animal models for several viruses vectored by mosquitoes, ticks, and midges, for which there are no standardly available vaccines or therapeutics. Copyright 2017 by the American Association for Laboratory Animal Science.
... 57 Louping ill virus, an agriculturally important flavivirus of sheep, can be modeled in BALB/c mice and (albeit less reliably) in lambs. 60 As the natural host, adult laboratory sheep show promise for pathogenesis studies. ...
Arthropod-borne viruses (arboviruses) have continued to emerge in recent years, posing a significant health threat to millions ofpeople worldwide. The majority of arboviruses that are pathogenic to humans are transmitted by mosquitoes and ticks, but othertypes of arthropod vectors can also be involved in the transmission of these viruses. To alleviate the health burdens associated with arbovirus infections, it is necessary to focus today's research on disease control and therapeutic strategies. Animal models for arboviruses are valuable experimental tools that can shed light on the pathophysiology of infection and will enable the evaluation of future treatments and vaccine candidates. Ideally an animal model will closely mimic the disease manifestations observed in humans. In this review, we outline the currently available animal models for several viruses vectored by mosquitoes, ticks, and midges, for which there are no standardly available vaccines or therapeutics.
... Naturally acquired SGEV infection caused a 100% mortality rate in clinically affected goats (Balseiro et al., 2012) and although the challenge isolate used for this study was derived from that original natural outbreak, no fatalities occurred in this study. This was despite the induction of histological lesions in the CNS in all animals in the positive control group and 5/9 of these animals developing neurological clinical signs, all of which is similar to experimental infection of sheep with LIV (Doherty and Reid, 1971a;Reid et al., 1984;Sheahan et al., 2002). This difference in mortality rate between the naturally acquired and experimentally induced disease may be due to a number of factors. ...
... Furthermore, if the Bermeya goats had not been exposed to ticks previously, they may have had a combined infection of SGEV and anaplasmosis (Anaplasma phagocytophilum), which has been shown to increase dramatically the mortality rate of flavivirus infection (Reid et al., 1986). Additionally, the differences in mortality rate may be due to the challenge dose, the route of inoculation, the individual immunocompetence and general condition of the animals and/or the loss of virulence of the original viral strain after culture in tick and mammalian cell lines, plus laboratory manipulation (Reid et al., 1984;Sheahan et al., 2002). However, considering the severity of the lesions in the brain, which were similar to those in naturally infected goats (Balseiro et al., 2012), it is unlikely that the virus had become significantly less pathogenic. ...
... bluetongue; Maclachlan et al., 2009) and differences in the individual immune response of each species should be taken into account. Experimental infection of lambs with LIV results in neurological clinical signs 8e13 dpc (Reid and Doherty, 1971;Sheahan et al., 2002), but in goats, pyrexia, which correlates with viraemia, occurs at 3e10 dpc, followed by the appearance of neurological clinical signs, such as tremors, at 12 and 13 dpc (Reid et al., 1984). Our findings showed initial clinical signs, such as pyrexia and depression, began at 3 dpc, coinciding with the initial peak of RNA load (also at 3 dpc), but with onset of neurological clinical signs later (i.e. at 10 dpc), which suggests that goats have a shorter incubation period when challenged with SGEV compared with LIV (Reid et al., 1984). ...
Spanish goat encephalitis virus (SGEV) is a recently described member of the genus Flavivirus belonging to the tick-borne encephalitis group of viruses, and is closely related to louping ill virus (LIV). Naturally acquired disease in goats results in severe, acute encephalitis and 100% mortality. Eighteen goats were challenged subcutaneously with SGEV; nine were vaccinated previously against LIV and nine were not. None of the vaccinated goats showed any clinical signs of disease or histological lesions, but all of the non-vaccinated goats developed pyrexia and 5/9 developed neurological clinical signs, primarily tremors in the neck and ataxia. All non-vaccinated animals developed histological lesions restricted to the central nervous system and consistent with a lymphocytic meningomyeloencephalitis. Vaccinated goats had significantly (P <0.003) greater concentrations of serum IgG and lower levels of IgM (P <0.0001) compared with unvaccinated animals. SGEV RNA levels were below detectable limits in the vaccinated goats throughout the experiment, but increased rapidly and were significantly (P <0.0001) greater 2–10 days post challenge in the non-vaccinated group. In conclusion, vaccination of goats against LIV confers highly effective protection against SGEV; this is probably mediated by IgG and prevents an increase in viral RNA load in serum such that vaccinated animals would not be an effective reservoir of the virus.
... An extensive series of studies into LIV infection in sheep demonstrated relationships between viraemia, neutralising antibodies and the pathology of disease in the infected brain Reid and Doherty, 1971). Later studies confirmed the presence of perivascular cuffing and mononuclear infiltration of the brain parenchyma (Sheahan et al., 2002). TBEV causes similar lesions in the brains of infected humans, typical of viral encephalitis (Gelpy et al., 2005), but there is no evidence to suggest that this virus can cause neuroinvasion in other mammalian species. ...
... In Borna disease, lesions mainly involve the frontal and olfactory cortex, basal ganglia and hippocampus. Descriptions of the histopathology and other aspects of these diseases can be found in Maxie and Youssef (2007) and in Vandevelde et al. (2012), as well as specifically for louping ill in (Doherty and Reid, 1971;González et al., 1987;Sheahan et al., 2002), for rabies in Perl and Good (1991) and Suja et al. (2011), for Aujeszky's disease in Dow andMcFerran (1964, 1966;Schmidt et al., 1992) and Henderson et al. (1995) and for Borna disease in Richt et al. (1997), Stitz et al. (1995) and Wahlenkamp et al. (2002). ...
... Reid (1984) similarly reported only very low levels of viraemia in bank voles, wood mice and brown rats (Rattus norvegicus), whereas only 8 % of field voles produced a viraemia. House mice (Mus musculus) were not tested in these studies, although LIV has been recorded to be pathogenic in experimentally infected laboratory mice (Gao et al. 1994;Sheahan et al. 2002). Note that this does not necessarily mean mice would act as competent transmission hosts. ...
... Sheep produce a post-infection viraemia sufficient for vector-host-vector transmission and they suffer variable levels of disease, including mortality, as a result (Reid and Doherty 1971;Reid 1978;Sheahan et al. 2002). Again, this is in stark contrast to LIV's closest genetic and geographic neighbour, Western TBEV, which does not cause disease in sheep (Gritsun et al. 2003). ...
Louping ill virus (LIV) is a tick-borne flavivirus that is part of the tick-borne encephalitis complex of viruses (TBEV) and has economic and welfare importance by causing illness and death in livestock, especially sheep, Ovies aries, and red grouse, Lagopus lagopus scoticus, an economically valuable gamebird. Unlike Western TBEV which is found primarily in woodlands and is reservoired by small rodents, LIV is not generally transmitted by small rodents but instead by sheep, red grouse and mountain hares and, therefore, is associated with upland heather moorland and rough grazing land. Red grouse are a particularly interesting transmission host because they may acquire most of their LIV infections through eating ticks rather than being bitten by ticks. Furthermore, the main incentive for the application of LIV control methods is not to protect sheep, but to protect red grouse, which is an economically important gamebird. The widespread intensive culling of mountain hares which has been adopted in several areas of Scotland to try to control ticks and LIV has become an important issue in Scotland in recent years. This review outlines the reservoir hosts and transmission cycles of LIV in the UK, then describes the various control methods that have been tried or modelled, with far-reaching implications for conservation and public opinion.
... Experimentally infected lambs exposed to LIV directly by intracranial inoculation invariably develop neurological disease and die within 6 days (Reid & Doherty, 1971). Inoculations by peripheral routes such as subcutaneous infection show a range of outcomes, from mild fever, recumbency, panting and depression to the full spectrum of neurological disease (Doherty & Reid, 1971a;Sheahan et al., 2002). Disease usually results after an incubation period of between 8 and 13 days. ...
... Laboratory mice are also particularly susceptible to louping ill infection. Subcutaneous inoculation leads to disease, which develops within 6 days as ruffled fur, reduced movement and depression associated with viraemia (Sheahan et al., 2002;unpublished data). This then develops into more severe neurological disease and results ultimately in death. ...
... In British field cases, viral antigen can be observed in the cytoplasm of morphologically normal and degenerated neurons and neuronal processes throughout the brain (Fig. 3b). In protracted cases, immunoreactivity can also be observed in phagocytes in areas of neuronophagia (Sheahan et al., 2002). In a detailed analysis of field cases (Simpson et al., 2003), labelling with mouse monoclonal antibody LM3.3 was observed in a wide range of neurones throughout the brain. ...
In Europe and Asia, Ixodid ticks transmit tick-borne encephalitis virus (TBEV), a flavivirus that causes severe encephalitis in humans but appears to show no virulence for livestock and wildlife. In the British Isles, where TBEV is absent, a closely related tick-borne flavivirus, named Louping ill virus (LIV), is present. However, unlike TBEV, LIV causes a febrile illness in sheep, cattle, grouse and some other species, that can progress to fatal encephalitis. The disease is detected predominantly in animals from upland areas of the United Kingdom and Ireland. This distribution is closely associated with the presence of its arthropod vector, the hard tick Ixodes ricinus. The virus is a positive-strand RNA virus belonging to the Flavivirus genus, exhibiting a high degree of genetic homology to TBEV and other mammalian tick-borne viruses. In addition to causing acute encephalomyelitis in sheep, other mammals and some avian species, the virus is recognised as a zoonotic agent with occasional reports of seropositive individuals, particularly those whose occupation involves contact with sheep. Preventative vaccination in sheep is effective although there is no treatment for disease. Surveillance for LIV in Great Britain (GB) is limited despite an increased awareness of emerging arthropod-borne diseases and potential changes in distribution and epidemiology. This review provides an overview of LIV and highlights areas where further effort is needed to control this disease.
