Sindbis virus as a human pathogen : epidemiology, virology, genetic susceptibility and pathogenesis

Sindbis virus (SINV), an arthropod-borne, enveloped single-stranded RNA virus belongs to genus Alphavirus in the family Togaviridae. SINV is found in Eurasia, Africa, and Australia but clinical SINV infections occur particularly in Finland where the infection is known as Pogosta disease. SINV epidemics have a peculiar cyclic appearance in Finland and since 1974, major outbreaks involving hundreds or even thousands of cases have occurred approximately every seven years. This study aimed to characterise descriptive, analytical and molecular epidemiology, to develop a PCR-based detection method and to study the pathogenesis and genetic susceptibility to SINV infection. The epidemiology of a SINV outbreak in 2009 was described and compared to the outbreak pattern of previous major epidemics. The anticipated seven-year cycle did not recur as a relatively mild epidemic was observed. The data indicated that changes in grouse population and weather factors may contribute to the human epidemiology of SINV infection as speculated earlier. We identified risk factors for SINV infection in a large population based case-control study and extended the data on clinical features and patient characteristics. In the final multivariable analysis, mosquito bites and spending time in woods or marshland remained as independent risk factors with a significant dose-response effect. Exposure to other arthropods was not positively associated with SINV infection. A new estimate of the median incubation period of SINV infection was 4 days. The SINV-infected patients were found to have previous or ongoing medical conditions affecting joint or connective tissues more frequently than controls. SINV was isolated from mosquitoes in Finland for the first time. Sequence analyses on the full-length coding sequences of all Finnish SINV strains, significantly expanding the available data on SINV sequences, demonstrated that the novel SINV isolate is closely related to Finnish human SINV isolates and to strains isolated previously from mosquitoes in Sweden and Russia. The data further established that SINV has had a local circulation in the endemic Northern Europe during the past decades. Sequence analyses also identified amino acid signatures, particularly in the nsP3 protein, shared by Northern European strains that may be associated with vector or host species adaptation. We developed a specific and sensitive real-time RT-PCR assay for the detection of SINV RNA with a detection limit of 9 copies/reaction. The assay demonstrated low levels of viraemia (< 103 copies/ml) in sera of SINV-infected patients and only 12% of the serum samples were positive in the assay. Thus, the assay was found to have limited value as a diagnostic technique using serum samples but could be used for screening SINV in e.g. wildlife. These findings on low viral load may be associated with the pathogenesis and epidemiology of SINV infection. The pathogenesis of myalgia was studied by examining a unique muscle biopsy obtained from a SINV-infected patient with chronic myalgia and arthralgia and by performing SINV infections of primary human myoblasts and myotubes. Evidence of muscle regeneration due to previous necrosis likely caused by earlier SINV infection was found in the biopsy. We further showed that human primary myoblasts and myotubes were susceptible in vitro for SINV infection. Overall, the study provided new information on SINV tropism and the mechanisms behind myalgia in SINV infection. The role of HLA and complement C4 genes in the susceptibility and outcome of SINV infection were investigated. The frequency of DRB1*01 allele was significantly higher in patients with SINV infection than in the reference population (OR=3.3, P=0.003). The frequency of DRB1*01 allele was particularly prominent among patients who at three years post infection experienced joint manifestations. The data further suggested that the combination of HLA-B*35- DRB1*01 alleles and C4B deficiency may be associated with a more prominent or persistent form of the disease. A set of autoantibodies was measured in SINV-infected patients at the acute phase and three years post infection to assess autoreactivity. The frequency of rheumatoid factor at three years post infection was 29.5% and showed significant increase (P=0.02) during the three-year follow-up. The antinuclear and anti-mitochondrial antibodies were also present in serum three years post infection with frequencies of 15.9% and 6.8%, respectively. Thus, the data demonstrated that symptomatic SINV infections show association to the HLA system and that autoantibody titres are elevated in patients three years post infection. These findings indicate that SINV-induced arthritis shares features with autoimmune diseases.

Grantor dc:publisher

Helsingin yliopisto

Year dc:date.issued

2012

Author dc:creator

• Sane, Jussi

• lääketiede (Virologia)

Statement dc:rights

• Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.
• This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited.
• Publikationen är skyddad av upphovsrätten. Den får läsas och skrivas ut för personligt bruk. Användning i kommersiellt syfte är förbjuden.

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/10138/35741

OAI record oai:identifier

https://helda.helsinki.fi/server/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Ahelda.helsinki.fi%3A10138%2F35741