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Reemergence of Chikungunya Virus

Thomas E. Morrison
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes acute fever and acute and chronic musculoskele-
tal pain in humans. Since 2004, CHIKV has caused millions of cases of disease in the Indian Ocean region and has emerged in
new areas, including Europe, the Middle East, and the Pacific region. The mosquito vectors for this virus are globally distributed
in tropical and temperate zones, providing the opportunity for CHIKV to continue to expand into new geographic regions. In
October 2013, locally acquired cases of CHIKV infection were identified on the Caribbean island of Saint Martin, signaling the
arrival of the virus in the Western Hemisphere. In just 9 months, CHIKV has spread to 22 countries in the Caribbean and Cen-
tral and South America, resulting in hundreds of thousands of cases. CHIKV disease can be highly debilitating, and large epi-
demics have severe economic consequences. Thus, there is an urgent need for continued research into the epidemiology, patho-

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genesis, prevention, and treatment of these infections.

C hikungunya virus (CHIKV), a mosquito-transmitted alphavi-

rus with a single-stranded, positive-sense RNA genome of
⬃12 kb, was first isolated from the blood of a febrile individual in
bean and Central and South America (Fig. 1). In addition, the
CDC has reported more than 230 imported cases of CHIKV in-
fection in the continental United States as well as locally acquired
Tanzania in 1953 during a large outbreak of disease characterized cases in Florida. Thus, in less than 10 years, CHIKV has spread
by crippling joint pains and severe fever, locally referred to as from the coast of Kenya throughout the Indian Ocean, Pacific, and
chikungunya (1). In 1958, CHIKV was isolated from patients in Caribbean regions, causing millions of cases of disease in over 50
Bangkok, Thailand (2), where it had spread apparently from Af- countries. In other words, CHIKV has reemerged as a true global
rica. Since these first documented epidemics, sporadic CHIKV pathogen.
outbreaks have been reported in numerous African and Asian
countries. CHIKV TRANSMISSION, GENETICS, AND REEMERGENCE
In April 2005, CHIKV was confirmed as the cause of an epi- In Africa, CHIKV circulates in an enzootic cycle involving forest-
demic of dengue-like illness on the Comoros Islands, which are dwelling mosquitoes and nonhuman primates. In Asia, CHIKV
located off the east coast of northern Mozambique; this was the primarily circulates in urban areas among Aedes aegypti or Aedes
first known emergence of CHIKV in the southwestern Indian albopictus mosquitoes and humans. However, some studies sug-
Ocean region. Due to clinical similarities, this outbreak was ini- gest that a sylvatic CHIKV transmission cycle may also exist in at
tially suspected to be caused by dengue virus, highlighting the fact least some parts of Asia, since CHIKV-specific antibodies have
that CHIKV disease is often misdiagnosed and the true number of been detected in wild monkeys in Malaysia. During acute CHIKV
cases in a particular region may be underestimated. Shortly there- infection of humans, there is high-titer viremia; thus, the virus can
after, the first cases of CHIKV disease were reported on Mayotte, be transmitted in a human-mosquito-human transmission cycle
Mauritius, and the French island of La Reunion. The number of and can be spread by viremic humans. For example, an outbreak
cases in these areas increased rapidly, due in part to attack rates as in Italy was initiated by a CHIKV-infected traveler from India.
high as 35% to 75%. By the end of 2005, after an apparent gap of Dense human populations and lack of herd immunity likely con-
about 32 years during which CHIKV was not detected, India re- tribute to the explosive nature of CHIKV epidemics in many re-
ported CHIKV disease in numerous states, with the official num- gions.
ber of suspected cases ultimately reaching more than 1.3 million. Three genotypes of CHIKV, called West African, East/Central/
The CHIKV outbreak continued to spread, causing large out- South African (ECSA), and Asian, have been defined (3). Phylo-
breaks in Sri Lanka and many other countries in Southeast Asia. genetic analysis showed that an ECSA genotype virus was respon-
During this epidemic, CHIKV was introduced into countries sible for the epidemics on islands in the Indian Ocean, and this
where it is not endemic by viremic travelers, and autochthonous ECSA virus had originated in coastal Kenya, where outbreaks of
transmission of CHIKV was observed for the first time in many CHIKV had occurred on Lamu Island and in Mombasa between
countries, including Italy, France, New Caledonia, Papua New May and December 2004 (4). The outbreak in Lamu Island likely
Guinea, Bhutan, and Yemen. The rapid and explosive spread of spread to islands in the Indian Ocean, whereas the outbreak in
CHIKV prompted the Pan American Health Organization Mombasa spread to the Indian subcontinent (5). Nucleotide se-
(PAHO) and the Centers for Disease Control and Prevention
(CDC) to release a preparedness guide that predicted potential
future CHIKV epidemics in the Americas. This prediction has Published ahead of print 30 July 2014
now come to fruition, as in December 2013, the World Health Editor: J. Pfeiffer
Organization (WHO) reported the first local transmission of Address correspondence to Thomas E. Morrison, [email protected].
CHIKV in the Western Hemisphere on the Caribbean island of Copyright © 2014, American Society for Microbiology. All Rights Reserved.
Saint Martin. By 18 July 2014, CHIKV had caused more than doi:10.1128/JVI.01432-14
440,000 cases of disease in more than 20 countries in the Carib-

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FIG 1 CHIKV in the Western Hemisphere. The World Health Organization (WHO) reported the first local transmission of CHIKV in the Western Hemisphere on the
island of Saint Martin in December 2013. By 18 July 2014, the Pan American Health Organization (PAHO) reported more than 440,000 suspected and confirmed cases
of chikungunya fever in more than 20 countries, with the majority of suspected and confirmed cases occurring in the Dominican Republic (251,951), Guadeloupe
(64,328), Haiti (62,436), Martinique (50,455), Saint Martin (4,453), and Dominica (3,243). CHIKV has also spread to countries on mainland South America (French
Guiana [881], Guyana [16], Suriname [17], Venezuela [2]), Central America (El Salvador [1,783], Costa Rica [1]), and the continental United States (Florida [2]). The
number of cases in most of these countries continues to increase, and the virus continues to spread to new regions. The map (Maps for Design) shows the incidence rate
of CHIKV infection in countries, territories, or states with autochthonous transmission as of 18 July 2014. (Case number and incidence rate data were obtained from
PAHO, http://www.paho.org/hq/index.php?option⫽com_topics&view⫽article&id⫽343&Itemid⫽40931.)

quencing of virus isolates also revealed genetic changes in viruses regions, including much of the southern United States, where A.
isolated during the second phase of the epidemic on La Reunion albopictus mosquitoes are more commonly found than are A.
island, including an alanine (A)-to-valine (V) switch at amino aegypti mosquitoes. However, at least in the laboratory, Asian
acid 226 of the E1 envelope glycoprotein, that were not present in genotype CHIKVs are efficiently transmitted by both A. aegypti
strains isolated during the outbreaks in coastal Kenya or on and A. albopictus mosquitoes collected from North, Central, and
Comoros. In contrast to coastal Kenya and Comoros, where A. South America (10).
aegypti was the primary vector, A. albopictus was the primary
CHIKV vector species in La Reunion, and the E1 A226V mutation CHIKUNGUNYA DISEASE: CLINICAL MANIFESTATIONS AND
was later shown to greatly enhance CHIKV infectivity of A. PATHOGENESIS
albopictus mosquitoes (6). Consistent with this, large CHIKV out- Clinical manifestations. Chikungunya, which translates as “dis-
breaks transmitted by A. aegypti occurred in several Indian states ease that bends up the joints,” is characterized by an abrupt onset
in the absence of the A226V mutation (7), while in 2007 in the of fever with severe joint pain, and the pain may persist for weeks
Indian state of Kerala, CHIKV isolates contained the E1 A226V to years (11). In contrast to infections with many other arbovi-
mutation and A. albopictus was the predominant vector. In addi- ruses, only 5 to 25% of CHIKV infections are asymptomatic. The
tion to being detected in La Reunion and India, the E1 A226V arthralgia is typically symmetrical and primarily affects peripheral
mutation was detected in CHIKV strains from outbreaks in Cam- joints, including wrists, knees, ankles, and the small joints of the
eroon in 2006 and Gabon in 2007, and A. albopictus played an hand. Additional disease signs and symptoms include arthritis,
important role in these and numerous other CHIKV outbreaks in with joints often exhibiting tenderness and swelling, tenosynovi-
the Indian Ocean region and Europe. Thus, the adaptation of tis, skin rash, and myalgia, particularly in the lower back and leg
CHIKV to A. albopictus mosquitoes likely contributed to the dra- muscles. In addition to these clinical features, severe neurologic
matic spread of CHIKV. and cardiac manifestations and, in some instances, deaths have
Since 2004, ECSA genotype viruses spread from the coast of been associated with CHIKV infection. These more severe out-
Kenya throughout much of the Indian Ocean region, princi- comes often occur in neonates, in patients more than 65 years of
pally by viremic travelers, causing a series of outbreaks of age, and in those with underlying medical conditions. In addition,
CHIKV infection of unprecedented scale. Thus, it was quite reports indicate that mother-to-infant transmission of CHIKV
unexpected when the ongoing outbreaks in the Caribbean re- during delivery results in high rates of morbidity (12). Chronic
gion were found to be due to an Asian genotype virus. Sequence CHIKV disease can be highly debilitating, and large epidemics
analysis revealed that the virus circulating in the Caribbean is have severe economic impacts, highlighting the significant public
phylogenetically related to Asian genotype strains recently cir- health threat posed by CHIKV.
culating in Indonesia, China, and the Philippines (8). To date, Pathogenesis. The pathogenesis of CHIKV infections is not
the outbreaks in the Caribbean region have been primarily well understood and is an area of intense investigation, with small
transmitted by A. aegypti, and studies have demonstrated that animal and nonhuman primate models of acute and chronic dis-
Asian genotype CHIKV strains are constrained in their ability to ease recently being developed (13). Studies of humans and animal
adapt to A. albopictus mosquitoes (9), suggesting that this may models have shown that disease signs and symptoms following
limit the spread of Asian genotype CHIKV strains into temperate infection with CHIKV are associated with CHIKV infection of

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cells in musculoskeletal tissues, such as fibroblasts and osteoblasts, ACKNOWLEDGMENTS

and infiltration of inflammatory cells— consisting predominantly I thank Kathryn V. Holmes and Mark T. Heise for critical readings of this
of monocytes, macrophages, natural killer cells, and T cells—in article. I apologize to all whose work could not be directly referenced due
musculoskeletal tissues. Recent work has demonstrated that both to formatting and length restrictions.
Rag1⫺/⫺ mice, which lack mature T and B cells, and CD4⫺/⫺ mice, Work in my laboratory was or is supported by NIH-NIAID grants U54
which lack CD4⫹ T cells, had reduced joint swelling and less severe AI065357, U19 AI109680, and R01 AI108725.
musculoskeletal tissue injury during the acute stage of CHIKV REFERENCES
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