Louping ill

R SWANEPOEL AND M K LAURENSON

GENERAL INTRODUCTION: FLAVIVIRIDAE

Introduction

Louping ill (louping in Scottish dialect = leaping) is an acute encephalomyelitis caused by a tick-borne flavivirus. It occurs in hill farming and certain other areas of Scotland, England, Wales and Ireland, and affects mainly sheep, less frequently cattle and rarely other livestock. Closely related or identical viruses are thought to cause encephalomyelitis of sheep in Norway, Spain, Turkey and Bulgaria, and the disease may be more widespread in Eurasia than is realized at present.^{72, 76} Louping ill (LI) is a zoonosis associated with occasional infections in laboratory workers or persons engaged in the livestock industry who are exposed to tick bites or to infected animal tissues.

A disease fitting the description of LI has been known in Scotland for at least two centuries, but the causative agent was not isolated until 1929. Shortly thereafter it was demonstrated that the virus is transmitted by ticks.^{64, 73, 76}

Aetiology

Louping ill virus (LIV) is a member of the Russian springsummer encephalitis (RSSE) antigenic complex of flaviviruses, also referred to as the tick-borne encephalitis (TBE) complex. Despite marked variation in pathogenicity, members of the complex are very closely related antigenically. In the past they could only be separated with difficulty in tests involving polyclonal antisera,^{16, 17} but can now be differentiated by use of monoclonal antibodies.¹⁰³ Members of the complex, which occur in temperate latitudes throughout the northern hemisphere,^{13, 14, 69} include:

• LIV, which is present in Great Britain, Ireland and possibly elsewhere in Eurasia;
• Central European TBE in Europe;
• RSSE (also known as Far Eastern TBE) in eastern Europe and the former USSR;
• Omsk haemorrhagic fever in Siberia;
• Kyasanur Forest disease in the Indian subcontinent;
• Langat in Malaysia;
• Negishi in Japan;
• Powassan in North America and parts of the former USSR; and
• four viruses in Asia that have no known veterinary or medical significance: Karshi, Royal Farm, Phnom-Penh bat and Carey Island.

Viruses that have been isolated in association with encephalomyelitis of sheep in continental Eurasia are as yet incompletely characterized, but they are considered to be either identical or similar to LIV. No strain diversity of LIV has been established in Great Britain and Ireland.⁷⁶ It is curious that no member of the RSSE complex has been isolated in the southern hemisphere.

Phylogenetic analysis of nucleotide and deduced amino acid sequences of either the entire envelope gene of LIV or a portion of the gene that spans a hypervariable region of LIV isolates, collected from representative regions of the British Isles and Norway, revealed the presence of three major geographical populations of LIV in the British Isles.⁶⁷ ‘British’ LIV occurs throughout Scotland, England, Ireland and Norway, whereas ‘Irish’ and ‘Welsh’ LI viruses occur only in Ireland and Wales, respectively. Phylogenetic analysis also suggests that LIV initially emerged in Ireland and that a descendant was then introduced into Great Britain via Wales, being subsequently transported to the borders of Scotland. From there it may have dispersed throughout Scotland, northern England and Norway. More recently, the British LIV was reintroduced into Ireland and also into south-west England. Dates of lineage divergence, calculated from the synonymous substitution rate, indicate that LIV emerged in the British Isles less than 800 years ago and most LIV dispersal occurred during the last 300 years.⁶⁷

Biological differences in the virulence of viruses from different regions are also apparent as manifested by differences in mortality rates in infections in mice and plaque sizes in cell culture.^{30, 66} ‘Irish’ LIV appears to be more virulent than viruses from other regions. However, there is little detectable association between the sequence of the envelope protein and the virulence characteristics, implying that the LIV virulence is multigenic and other genomic regions must be investigated to understand the determinants of virulence.⁶⁶

Flavivirus particles measure 37 to 50 nm in diameter and consist of a spherical ribonucleoprotein core surrounded by a lipoprotein envelope. There are three structural proteins: a 13–16 × 10³ MW nucleocapsid or core protein (C) that is intimately bound to the genome, a non-glycosylated 7–9 × 103MWmembrane protein (M) bound to the core, and a 51–59 × 10³ MW envelope protein (E) that is usually glycosylated and is inserted as spikes or projections into the lipid bilayer envelope derived from host cell membranes. The E protein is presumed to carry recognition sites for the attachment of virus to receptors on susceptible cells and is responsible both for the haemagglutinating property exhibited by most flaviviruses and for stimulating the production of antibody demonstrated in haemagglutination-inhibition tests and protective immune responses in the host. It bears separate antigenic determinants that are either serotype specific, cross-reactive within an antigenic complex, or group-reactive with all flaviviruses.^{69, 97} The structure of the E protein appears to be at least one of the determinants of virulence in flaviviruses: comparison of virulent and vaccine strains of yellow fever virus reveal differences in the amino acid composition of the E protein, fuelling speculation that the changes may...