Chikungunya: researchers could stop the debilitating condition


Chikungunya virus, once confined to the Eastern Hemisphere, has infected more than 1 million people in the Americas since 2013, when mosquitoes carrying the virus were discovered in the Caribbean.

Most people who become infected develop fever and joint pain that last about a week.

But in up to half of patients, the virus can cause severe arthritis that persists for months or years.

There is no treatment to prevent the short-lived infection from persisting into chronic arthritis.

Chikungunya, a mosquito-borne disease endemic to tropical regions, has emerged as an epidemic threat over the past 15 years.

It infects over one million people per year and causes debilitating joint pain [1].

The name “chikungunya” derives from a Makonde phrase meaning “that which bends up” or “to become contorted”, referring to the bent posture of affected patients.

Chikungunya fever (CHIKF) is caused by Chikungunya virus (CHIKV), a pathogen of the genus alphavirus and the family Togaviridae [2].

Within this genus, there are 30 species of arthropod-carried alphaviruses (also referred to as arboviruses, stemming from arthropod-borne viruses), all sharing seven specific antigenic complexes [3].

CHIVK is closely related to several other alphaviruses, including Ross River virus, Barmah Forest virus, o’nyong-nyong virus, the Sindbis group of viruses, and the Mayaro virus, all of which are known to cause arthritis [4].

CHIKV has three genotypes: Asian, West African, and East Central South African, all named after their geographical distributions.

The virus itself is a positive-sense, single-stranded RNA virus approximately 11.8 kb long [5]. It has an icosahedral capsid which is covered by a lipid layer, a diameter of approximately 65 nm, and is sensitive to temperatures greater than 58 °C [6].

It contains two open reading frames (ORFs), one on the 5′ end and the other on the 3′ end [7], with the ORF at the 5′ end producing four non-structural proteins (nsP 1–4) and the ORF on the 3′ end producing the structural proteins, which are composed of a capsid protein, two envelope glycoproteins (E1 and E2), and 2 small cleavage products (E3 and 6K) [8].

1.2. History/Origins

CHIKV was not recognized in the early 19th century, but what we now know as CHIKF was.

It was not until the early 1950s that CHIKV was first characterized in East Africa [9].

It was more specifically outlined in southern Tanzania in 1952, where it was first isolated in a human [10].

Following its discovery, the disease was largely confined to pockets of land in Asia and Africa.

The disease was marked by long gaps of inactivity interspersed with sudden outbreaks [11], though this characterization has been disputed [12].

It was not until the late 1990s and early 2000s that CHIKV began to re-emerge on a global scale.

Many of these recent epidemics differed from those previously reported in both their increased scale and more rapid movement, with many originating from migrant populations moving from areas with endemic CHIKV.

Malaysia had an outbreak in 1998 that was present primarily in adults and speculated to be re-introduced through the movement of workers [13], while Indonesia had a major outbreak in 2001–2003 after a 20-year hiatus of epidemic CHIKV [14].

The 2005 Indian epidemic, one of the most severe of the recent outbreaks, provided a possible template for envisioning future outbreaks and their consequences.

The outbreak occurred after a 32-year gap of epidemic CHIKV in the region and eventually affected 1.3 million people [15].

The national burden from the outbreak was estimated to be nearly 26,000 disability-adjusted life years (DALYs) lost, equating to approximately 45.26 DALYs per million people [16]. 2005 also saw a severe CHIKV outbreak on Réunion, an island found in the Indian Ocean east of Madagascar.

This outbreak affected one-third of the island’s population [17] and was notable in that its neural, hepatic, and myocardial symptoms led to an unusually high mortality rate as compared to previous CHIKV outbreaks [18]. Table 1 summarizes recent large-scale outbreaks of CHIKV in the 2000s.

Table 1

Recent selected large-scale CHIKV epidemics in the 2000s.

Lamu Island, Kenya200413,500
La Réunion2005–2006255,000
Republic of Congo20118000
French Polynesia2014–201566,000

As global travel has increased, there has been an increase of CHIKF cases described in Western nations.

In September 2007, a small outbreak of CHIKV stemming from an imported case was noted in Italy and was especially concerning as it was spread via local infected mosquitoes [19].

There were no locally acquired cases in the USA from 1995 to 2009, but there were reports of imported cases during that time [20].

Similarly, imported cases coming from the Caribbean were noted in Spain in 2013 [21].

Of note, various autochthonous outbreaks have occurred in Europe, highlighting the ability of the virus to cause disease in these more temperate climates [22,23].

CHIKV was not noted in the Americas before 2013, but has since rapidly spread throughout the region.

In the years following the emergence of CHIKV in the Americas, it has caused between 795,000 and 1.1 million cases, and spread to 43 countries and territories.

During a 2014 outbreak on the islands of Martinique and Guadeloupe, an estimated 308,000 people were affected [24], and from October 2014 to March 2015, 66,000 people in French Polynesia were infected, equating to an infection rate of 25% [24].

In addition, CHIKV establishment in the Americas was followed by a sharp increase in travel-related CHIKF with upwards of 1600 passengers coming to the US with CHIKF in the year following its emergence, compared to a previous average of 28.

1.3. Symptoms

Though it can appear similar to dengue fever and Zika, CHIKF is indicated by several characteristic symptoms. CHIKV is remarkable in that it creates symptoms in a higher proportion of infected individuals as compared to other alphaviruses, with 10–70% of persons living in an affected area becoming infected, and 50–97% of the infected developing a clinical presentation [1].

Symptoms typically appear after an incubation time of 4–7 days [25].

The disease has a more severe effect on neonates and the elderly [26], and in neonates it is associated with encephalitis [27].

The mortality rate is five times higher in individuals 65 and above compared to those less than 45 years of age [28].

The disease course is divided into an acute stage, lasting approximately one week, and a chronic stage, also known as the persistent stage, which can last from months to years.

Acute fever and polyarthralgia are highly indicative of an infection [25], with arthralgia appearing in 30–90% of cases [5,6].

This joint pain is often bilateral, symmetric, and debilitating. There are occasional ophthalmic [29], neurological [30], and cardiac [31] symptoms.

Chronic CHIKV infection is less studied but represents a significant health complication for those afflicted and a public health problem for their communiti

In a case report investigating the Réunion outbreak, it was reported that two years post-infection, 43–75% of patients continued to have symptoms attributed to their infection [32].

The most prominent symptoms one month post-infection were rheumatism (75%) and fatigue (30%), with joint pain, fatigue, and neuritis being present after ten months [33].

Another study suggests that 50% of people infected with CHIKV will go on to experience chronic pain [34].

Chronic CHIKF demonstrates specificity to bone and joint tissue with symptoms such as rheumatoid arthritis and ankylosing spondylitis [35].

In part due to the symptoms noted, CHIKV is associated with low mortality but high morbidity.

During the Réunion outbreak, a case-fatality rate of 1/1000 was reported [36].

However, during the outbreaks occurring in 2004–2008, an increase in death rates was noted, with the deaths following the previously established pattern of affecting the elderly proportionately more than younger adults [37].

It has been argued that the fatality of CHIKF has been underestimated [38].

When laboratory tests are performed, the primary lab finding is lymphopenia, delineated as having <1000 lymphocytes/mL3 [6].

Along with the lymphopenia, there is occasional leukopenia, elevated liver enzymes, anemia, elevated creatinine, elevated creatinine kinase, and hypocalcemia [6]. The acute stage of CHIKV is noted to have a high viremic load, with an average of 107 pfu/mL [6].

Now, researchers have uncovered information that could help stop the debilitating condition.

A team at Washington University School of Medicine in St. Louis has snapped high-resolution pictures of the virus latched onto a protein found on the surface of cells in the joints.

The protein used in the study was taken from mice, but people have the same protein, and the virus interacts with the mouse and human proteins in virtually identical ways.

The structures, published May 9 in the journal Cell, shows in atomic-level detail how the virus and cell-surface protein fit together – data that promises to accelerate efforts to design drugs and vaccines to prevent or treat arthritis caused by chikungunya or related viruses.

Chikungunya arthritis comes on very suddenly and can be very painful – people can barely walk around – and we have nothing specific to treat or prevent it,” said co-senior author Michael S. Diamond, MD, Ph.D., the Herbert S. Gasser Professor of Medicine, and a professor of molecular microbiology, and of pathology and immunology.

“Now that we have these new structures, we can see how to disrupt the interaction between the virus and the protein it uses to get inside cells in the joints and other musculoskeletal tissues in order to block infections,” added co-senior author Daved Fremont, professor of pathology and immunology, of biochemistry and molecular biophysics, and of molecular microbiology.

Chikungunya and its cousins – Mayaro, Ross River and O’nyong-nyong viruses – belong to a family of alphaviruses that are spread by mosquitoes and cause joint pain.

In recent years, such viruses have been infecting people and animals in ever larger regions of the globe.

In 2018, Diamond, Fremont and colleagues including postdoctoral researcher Rong Zhang identified the protein Mxra8, which is found on the outer surface of cells in the joints, as the molecular handle that chikungunya and related viruses grasp to gain entry into cells of mice, humans and other species.

The human and mice versions of Mxra8 are 79 percent identical, and chikungunya virus interacts with both versions in the same way.

Viruses need to latch onto the protein to cause disease; in mice, thwarting chikungunya’s attempts to attach to the protein using blocking antibodies or decoy receptors reduced signs of arthritis.

To design effective drugs and vaccines that interfere with attachment, researchers need a detailed picture of the molecular interactions between the virus and the protein.

Fremont worked with graduate students Katherine Basore, the paper’s first author, and Arthur Kim, to visualize the virus bound to the cell-surface protein.

The researchers used a technique called cryo-electron microscopy (cryo-EM) at Washington University’s Center for Cellular Imaging, which installed a state-of-the-art cryo-EM machine in 2018.

Images were obtained using a chikungunya virus-like particle – which has the shape of a virus but cannot cause infections because it carries no genetic material inside – as well as fully infectious chikungunya virus.

The virus-like particles are being evaluated in clinical trials as a potential vaccine for chikungunya.

To visualize how the virus interacts with the cell-surface protein, the researchers first flash-froze the viral particles attached to the protein.

The snap freeze was necessary to keep the particles from being destroyed during the experiment.

Then, the researchers shot a beam of electrons through the sample, mapped where the electrons landed on a detector, and used computer programs to reconstruct the electron density patterns and thereby the 3-D structure of the viral particles bound to the cell-surface protein.

“Our cryo-EM maps allow us to view the whole virus particle with Mxra8 bound to it, but not at a high enough resolution to pinpoint precise atomic locations,” Basore said.

“So we used existing high-resolution X-ray crystal structures of the components of the virus, in addition to our own crystal structure of Mxra8, to build an atomic model of the entire assembly.

This allowed us to see the full scope of these interactions that we couldn’t achieve from either X-ray crystallography or cryo-EM alone.”

The high-resolution structure will aid efforts to screen experimental drugs for their ability to block attachment to the protein on cells in the joints, evaluate whether the antibodies elicited by investigational vaccines are likely to prevent infection, and analyze whether mutations in viruses affect their virulence.

More information: Katherine Basore et al. Cryo-EM Structure of Chikungunya Virus in Complex with the Mxra8 Receptor, Cell (2019). DOI: 10.1016/j.cell.2019.04.006
Journal information: Cell
Provided by Washington University School of Medicine in St. Louis


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