Over the past two years, we have all become accustomed to long COVID. This term encompasses the various long-term sequelae that might follow a SARS-CoV-2 infection. What is less known is that other non-chronic viruses can also cause long-term sequelae. Such debilitating diseases might persist for months or years after the infection, with the mechanisms remaining mostly unknown.

Long–lasting consequences of acute infections

Following an outbreak of Chikungunya virus in Curacao in 2015, researchers followed a cohort of 248 people for two and a half years. Those infected with Chikungunya virus initially had a fever, headache, fatigue, skin rash, myalgia, and joint pain. These are typical symptoms of viral infection. But 141 of these patients were still affected two and a half years later. Fifty-four people reported debilitating arthralgia and weakness in the lower extremities, severe fatigue, increased pain intensity over time, and frequent relapses (1).

What causes such long-term disease remains unclear. The available evidence suggests the virus is not replicating in the affected body parts (PCR detected no trace of the virus). That leaves two likely explanations. An autoimmune disease might be triggered by the acute stage of the infection, or the onset of a strong inflammatory response during the early stages of the disease might be to blame (2, 3). Of these, the latter seems more likely.

The correlations with age, sex, and previous morbidities appear inconsistent across the literature, but there is consensus that long-term disabilities are more likely when the acute stage of infection has been severe. This suggests that early or prophylactic intervention could reduce the risk of sequelae.

Future work should attempt to describe the mechanisms driving long-term arthralgia. Also, there is a need for strategies to contain the acute stage of the infection.

Old and New World alphaviruses

Chikungunya virus is an Alphavirus belonging to the Togaviridae family (4).

Alphaviruses are single-stranded RNA, enveloped viruses. They are composed of three major structures: the nucleic acid (positive, single-stranded RNA), the protein coating that encases the RNA (C), and the envelope that encases the nucleic acid and the protein coating. Also, because alphaviruses have a compact and relatively simple genome, they may be suitable vectors for gene delivery.

The alphaviruses genus includes more than 30 members. These are commonly divided into two groups based on their geographical location. The Old World viruses include Chikungunya virus, Ross River virus, Sindbis virus, and Semliki Forest virus. The New World viruses include the equine encephalitis viruses (Venezuelan Equine Encephalitis virus, Eastern Equine Encephalitis virus, and Western Equine Encephalitis virus).

Old World viruses are usually associated with rheumatic disease in humans, while New-World viruses are associated with potentially fatal encephalitic disease, especially in the Americas.

This classification is useful to define these viruses’ origin and clinical manifestations. However, alphaviruses are evolving and becoming more diversely distributed around the globe. Most alphaviruses are transmitted through the bite of an infected mosquito, generally, Aedes aegypti, Aedes albopictus, Anopheles, and Culex spp. With few antivirals or vaccines available, targeting mosquitoes is currently the main control strategy for most alphaviruses.

Alphaviruses at Virology Research Services

Work with many alphaviruses, particularly Hazard Group 3 alphaviruses like Chikungunya virus, is tightly regulated in the UK, where these viruses are not endemic.

Here at Virology Research Services, we work with three models of arthritogenic alphaviruses: Ross River virus, Sindbis virus, and Semliki Forest virus. These are important human viruses with epidemic potential. Also, these viruses can be used to model Chikungunya virus infection.

Ross River virus is increasingly expanding in Australia and the Pacific Islands. Ross River virus causes similar symptoms and long-term sequelae to Chikungunya virus. A recent study has demonstrated the presence of the inflammatory cytokine IL17 and IL17-producing T cells and neutrophils in the serum of infected patients and the musculoskeletal tissue of infected mice. Encouragingly, treatment of mice with IL17 targeting antibodies appears to attenuate infection. These findings suggest that early intervention to reduce the inflammatory response may be beneficial (5).

Sindbis virus also causes arthralgia, rash, and malaise with long-term sequelae. Sindbis virus’s geographic distribution is most peculiar. Sindbis virus affects countries in Africa, China, and the Philippines. Also, it affects the North of Europe, including Finland, Sweden, and Russia, where it causes regular epidemics. Six to eight months after an outbreak in a non-endemic area of Sweden, 39% of the population still complained of chronic arthralgia. This was sufficient to severely affect their daily activities (6).

Semliki Forest virus belongs to the same serogroup as Chikungunya virus. So, from a phylogenetic perspective, Semliki Forest virus represents a close model of Chikungunya virus. Semliki Forest virus is less severe and debilitating than Chikungunya virus. It is mostly asymptomatic or causes mild febrile illnesses. Yet Semliki Forest virus is endemic in many African regions, and encephalitis, myalgia, and arthralgia have also been reported (5).

Semliki Forest virus has been used as a model to study virus entry, and several virus entry assays have been developed. These assays benefit from the high titers that Semliki Forest virus can reach in cell culture (4).

Should we worry about alphaviruses?

COVID-19 may have pushed alphaviruses off the radar and out of the mainstream news. But it is important to re-consider alphaviruses in the context of their long-term impact on health, the rising global temperatures (expanding the territory of their mosquito vectors), and their ability to mutate into fitter strains. For example, a mutation in the E1 protein (A226V) helps Chikungunya virus infect the Aedes albopictus. This allows Chikungunya virus to spread to those colder areas where this species is more distributed. Indeed, this has been the trend since 2013.

Alphaviruses have epidemic potential and long-term social and economic impacts. This makes it important to study this virus group. Efforts are needed to understand how these viruses trigger an inflammatory response, and new antiviral therapies are needed to control virus replication or the severity of inflammation.

References:

(1) Doran C et al. (2022). Long-term Chikungunya sequelae and quality of life 2.5 years post-acute disease in a prospective cohort in Curacao. PLoS Negl Trop Dis. 16(3):e0010142. https://doi.org/10.1371/journal.pntd.0010142

(2) Chang AY et al. (2017). Frequency of chronic joint pain following chikungunya infection: a Colombian cohort study. Arthritis Rheumatol. https://doi.org/10.1002/art.40384

(3) Chang AY et al. (2017). A cross-sectional analysis of chikungunya arthritis patients 22-months post-infection demonstrate no detectable viral persistence in synovial fluid. Arthritis Rheumatol. https://doi.org/10.1002/art.40383

(4) Sasha R et al. (2020). Epidemic alphaviruses: Ecology, emergence and outbreaks. Microorganisms. 8:1167. doi:10.3390/microorganisms8081167

(5) Mostafavi et al. (2022). Interleukin-17 contributes to Ross River virus-induced arthritis and myositis. PLoS Pathog. 18(2):e1010185. https://doi.org/10.1371/journal.ppat.1010185

(6) Gylfe A et al. (2018). Mosquito-borne Sindbis virus infection and long-term Illness emerging infectious diseases. Emerg Infect Dis. 24(6):1141-1142. doi:10.3201/eid2406.170892