Reported cases of DENV/CHIKV coinfections. a NS: Not specified.
Both Dengue (DENV) and Chikungunya (CHIKV) viruses can be transmitted by Aedes mosquito species and the diseases that they cause have several clinical symptoms in common. Co-circulation of DENV and CHIKV is increasing around the world and must therefore be considered as an emerging threat with an important public health concern. At present, very little is known about the clinical manifestations and biological consequences of coinfection by both viruses. Thus, numerous questions such as clinical severity and dynamics of viral replication of DENV and CHIKV coinfections, as well as vectorial competence, have yet to be addressed in this important and challenging research area. The ensuring knowledge will enhance the clinical surveillance and the development of diagnostic tools able to differentiate DENV and CHIKV in order to early detect virus invasion and local transmission, as well as to improve patient care and timely control measures. In this review, we highlight the current knowledge on DENV and CHIKV coinfections. We also discuss research perspectives and challenges in order to further understand the ecology and biology of this phenomenon.
Arthropod-borne viruses represent a global threat for public health as they can be transmitted to humans by hematophagous arthropods that are rapidly spreading worldwide. These viruses belong to four major families,
Dengue virus (DENV) is perhaps the most relevant arbovirus in terms of morbidity, mortality, and socioeconomic impact, threatening more than 2.5 billion individuals worldwide . It belongs to the
Chikungunya virus (CHIKV), on the other hand, belongs to the
Although similar in some aspects, the history traits and epidemiology of DENV and CHIKV have followed different patterns, both intrinsically linked to the ecology of the mosquito vectors. These topics will be reviewed individually for each virus and the cases of coinfection will be finally analyzed.
2.1. Dengue virus
2.1.1. History and epidemiology
The name dengue seems to derive from the Swahili
Although the virus was initially thought to have originated in Africa, serological and phylogenetic studies rather point toward an Asiatic origin with a subsequent propagation to the African continent and to the Americas . By analyzing the substitution rate of the Envelope (
It is believed that the sylvatic forms of DENV have caused sporadic and accidental outbreaks in humans, essentially among rural communities. The burden of dengue disease seems to be linked to the widespread colonization of the tropics by
2.1.2. Transmission and vector competence
Two main cycles of transmission have been described for DENV (Figure 1). The primitive sylvatic enzootic transmission, in Asia and Africa, involves
Other species, such as
2.2. Chikungunya virus
2.2.1. History and epidemiology
The name Chikungunya, meaning “the disease that bends up the joints” comes from the Makonde people in Tanzania, where the virus was first recognized in 1952 [64, 65]. Although arthralgia is one of the characteristic symptoms of chikungunya disease, most of the clinical manifestations are almost indistinguishable from those of Dengue. Thus, it is difficult to trace back the first epidemics of CHIKV in the literature and historical records. Nonetheless, it is generally assumed that the virus has been responsible for episodic outbreaks in Africa for several centuries before being imported to Asia and America by sailing ships during the eighteenth and nineteenth centuries [66–68].
On the basis of the phylogenetic analysis of the open reading frame of several CHIKV strains, the virus has been divided into three clades: West African (Waf), Asian, and East/Central/South African (ECSA), . According to this study, the current CHIKV strains derived from a common ancestor that existed around 500 years ago. The divergence between the ECSA and the Asian clades occurred during the end of the nineteenth and the beginning of the twentieth centuries. Interestingly, despite their close geographic proximity, the ECSA and West African strains are highly divergent for reasons that are not yet completely understood. The recent Indian Ocean monophyletic lineage (IOL) originated from the ECSA group at the beginning of the twentieth century .
It is assumed that CHIKV originated in Africa, where it circulated in an enzootic cycle responsible for sporadic human epidemic outbreaks during the twentieth century in Tanzania in 1952 , Uganda in 1958 , South Africa in 1976 , Sudan in 1988 , and Senegal in 1996 , all arising from rural communities in close proximity to forested areas. However, more recent CHIKV outbreaks linked to indigenous ECSA strains have arisen in urban centers, as observed in Congo, Cameroon, and Gabon during 2000–2010 [74–76].
In Asia, the virus was first isolated in Thailand in 1958  and was responsible for large epidemics affecting millions of people in Sri Lanka and India between 1963 and 1973, when the last CHIKV epidemic was recorded in 2005 [78–80]. This year marks the reemergence of CHIKV on the Indian subcontinent with the introduction of the IOL coming from islands in the Indian Ocean [80–82]. Indeed, after its initial detection in Kenya in 2004 , IOL subsequently spread to these islands, among which Mauritius, Comoros, Mayotte, Seychelles, La Réunion, and Madagascar, during 2005–2006 [84, 85]. The extent of the epidemics by this new strain is reflected by the example of La Réunion, where 266,000 individuals, a third of the island population, became infected, which resulted in around 260 deaths, most of them elderly people [86, 87]. After its introduction in India and Sri Lanka, the IOL CHIKV strains spread quickly throughout Southeast Asia, being responsible of outbreaks in Malaysia , Singapore , and Thailand  in 2008, China in 2010 , Cambodia in 2011 , and Bhutan in 2012 . Overall, it is estimated that CHIKV has caused more than two million cases since 2004 in Africa and Asia . IOL strains also have become a concern in Europe, where they were imported by infected travelers returning from India and were responsible for outbreaks in Italy in 2007  and France in 2010  and 2014 , both likely transmitted by resident populations of
In America, the presence of CHIKV has formally been identified in 2013 in Saint Martin Island during a large and ongoing epidemic in the Caribbean basin , although it is suspected to be responsible for several epidemics since the nineteenth century. Since then, CHIKV has spread to the other Antilles islands where
2.2.2. Transmission and vector competence
Similar to DENV, two modes of transmission have been described for CHIKV that rely on the same
In Asia, CHIKV has traditionally circulated in an urban cycle associated with the presence of
Vector competence studies, (reviewed in ), have shown that both
Another interesting observation is that A226V mutation appeared in ECSA CHIKV strains and not in the Asian strains circulating in areas where
In addition, a recent experimental study conducted by Stapleford et al.  showed the emergence of two new mutations V80I and 129V on E1 glycoprotein of the CHIKV A226V strain. Positive selection of these mutations appears to improve the stability and fusogenic activity of these variants. This study offers an interesting predictive approach to guide the monitoring of CHIKV strains involved in future outbreaks .
2.3. DENV-CHIKV coinfections
2.3.1. History of reported cases
To date, the number of diagnosed cases of DENV-CHIKV coinfections is surprisingly small and available information is often incomplete, making it difficult to establish epidemiological trends. However, it is noteworthy that the number of reported cases has increased considerably during the past 10 years (Table 1, Figure 2), indicating that the phenomenon is becoming a concern among the scientific community because of its potential impact on human health and economy. Indeed, although the first documented cases of DENV-CHIKV coinfections date back to the 1960s in Vellore, South India, when 14 cases were reported during a CHIKV epidemic outbreak [116, 117], and in Thailand , where nine cases were documented, it was not until 2006 that the diagnosis of concomitant infections experienced a real interest, possibly due to the burden of cases of chikungunya infection in the Indian Ocean’s island and Southeast Asia where DENV is endemic.
In 2006, two cases of coinfection corresponding to two female patients were described in Malaysia, and 20 more were recorded during the CHIKV outbreak in La Réunion the same year. More cases of coinfection were reported in Madagascar and Sri Lanka in 2006–2007 and in Gabon, India, Nigeria and Singapore during 2007–2010, coinciding with the epidemics of CHIKV caused by IOL strains during this period in the area. The most recent cases were diagnosed in South America, India and Nigeria in 2013–2014. Of note, two of these cases corresponded to infected travelers returning to Portugal and Germany after being infected in Angola and India, respectively [119,120], raising concern about the possible spread of coinfection cases in Europe where
|Number of cases||Location||Year||DENV serotype||CHIKV clade||Severe symptoms||Vector||Reference|
|14||Vellore, India||1964||DENV-2||NS||Absence||NS||[116, 117]|
|2||Kinta District, Malaysia||2006||DENV-1||X||1 case of DHF||NS|||
|3||Kandy, Sri Lanka||2006- 2007||NS||NS||1 case with Guillain barré syndrome||NS|||
|X||2 DHF, 1 dead||NS|||
|43||Maharashtra and Odisha, India||2013||DENV-2|
|X||3 cases of DHF||NS|||
As shown in Table 1, the four serotypes of DENV can be found in association with both the Asian and ECSA CHIKV clades, depending of the strain of CHIKV that cocirculates with DENV in a particular area, pertaining to Asian CHIKV strains in America and ECSA strains in Asia and Africa. However, it would be interesting to study if some particular associations of DENV and CHIKV genotypes are favored in nature. For example, is the circulation of some virulent DENV strains associated with the simultaneous presence of specific CHIKV genotypes? Such preferential associations could provide insight into viral coevolution and allow to define strategies to limit the morbidity associated with certain highly pathogenic viral strains.
2.3.2. Transmission and vector competence
Some of the studies reported in Table 1 provide interesting information about the relative importance of
During this study, mosquitoes were captured around the coinfected patient’s homes. After identification of the species, viral presence was determined by quantitative PCR from pooled mosquitoes abdomen. In total, 661
Besides its greater susceptibility to CHIKV and DENV,
These data indicate that
The disproportion in the abundance of
This trend and the role of
Vector competence studies performed in laboratory conditions have shown that
Taken together, these results reveal an important and threatening role of
Another important topic related to CHIKV/DENV coinfections, is the mode by which these viruses can be transmitted to humans. Two main possibilities could be envisaged: an individual transmission of each virus by different monoinfected mosquitoes or concomitant transmission by a coinfected vector. In that sense, the study performed by Caron et al.  gives several interesting clues based on the analysis of viral loads detected in coinfected Gabonese patients. The results revealed the presence of two distinctive groups of patients, based on the presence of viral RNA-derived complementary DNA (cDNA): one group with a high DENV-2 cDNA load and low CHIKV cDNA load and the other with high cDNA levels of both viruses. According to this pattern of infection, the authors suggested two different modes of transmission. In patients with the highest DENV-2 cDNA, the blood samples were most likely taken during the acute phase of DENV infection and the early or late stage of CHIKV infection, suggesting that the viruses were more likely to have been transmitted by the bite of two different mosquitoes each infected with one virus, although with several days of interval, which might explain the gap between the replication kinetics of either virus. However this interpretation should be taken with caution, as several other possibilities may exist. For example, both viruses could have been transmitted by the same mosquito and DENV-2 might have replicated more efficiently than CHIKV due to genetic factors intrinsic to the human host, thus establishing a competitive state in which CHIKV could have been disadvantaged. Alternatively, DENV-2 viral load in the coinfected mosquito salivary glands may have largely exceeded that of CHIKV. As a result, the number of DENV viral particles transmitted to the human host during the mosquito bite may have been higher than for CHIKV, consequently explaining the difference in the observed cDNA loads. Another possibility, noted by Caron et al. , is that the immune response against DENV may have limited the replication of CHIKV. In the second group of patients with high cDNA loads for both viruses, indicative of a blood sample taken during the acute phase of both CHIKV and DENV-2 infections, the dual infection may have resulted from two rapidly succeeding bites of different mosquitoes, each infected by one virus or from the bite of a single coinfected mosquito .
From a public health perspective, the concern about coinfections is their possible impact on the pathogenesis and the outcome of dengue and chikungunya diseases. Is there a correlation between the cases of coinfection and the severity of symptoms? Because, in terms of morbidity, severity and mortality DENV has a higher impact on human health than CHIKV, the major preoccupation is that CHIKV/DENV coinfection could increase the incidence of DHF and DSS.
DHF symptoms appear around the time of defervescence, 3–7 days after the first symptoms of DF. It is characterized by an increase in capillary permeability with a loss of plasma volume that is preceded by thrombocytopenia and leukopenia. Hamorrhagic symptoms include petechiae, ecchymoses, and purpuric lesions. If a critical volume of plasma is lost through leakage, DSS may follow. This phase is characterized by a narrow pulse pressure that can be underestimated as most of the patients remain conscious and lucid. Prolonged hypotensive shock and hypoxia may result in organ failure, acidosis, intravascular coagulation, and death if not corrected in time [3, 4].
Although the pathogenesis of DENV infection is not well understood, several risk factors may increase the severity of the disease: the viral genotype (the Asian genotype of DENV-2 is considered to be a virulent strain), the age (children are less able to compensate plasma leakage than adults), the ethnicity (Caucasian are more susceptible to develop severe forms of the disease), chronic diseases (individuals with allergies, asthma, and diabetes are at higher risk than healthy people) and secondary infection with a new DENV serotype [140–143]. The latter issue has received particular attention, because it may be a major determinant for the development of severe cases of dengue. Indeed, when preexisting antibodies from a primary DENV infection bind to an infecting DENV particle during a subsequent infection with a different dengue serotype, the antibodies from the primary infection cannot neutralize the virus. Instead, the resulting antibody-virus complexes attach to Fc receptors at the surface of monocytes, macrophages, and dendritic cells (DCs), resulting in increased infection [113, 144, 145]. This phenomenon, known as antibody-dependent enhancement of infection (ADE), may explain the higher viremia and levels of circulating antigens detected in patients with DHF as compared to patients with DF [146, 147]. ADE accounts for the particular propensity of populations living in DENV hyperendemic regions to develop severe forms of dengue. ADE may also contribute to increased capillary permeability and to a “cytokine storm” that could aggravate the disease [148–150]. Another phenomenon increasing the risk of severe disease during secondary infections with DENV is the original antigenic sin or Hoskins effect. This effect refers to the tendency of the immune system to respond to a secondary infection through the activation of memory B and T cells induced by the primary infection. These cells show a decreased affinity for secondary antigens and are less effective in the control of the infection . In particular, it has been shown that during the secondary infection by a different strain of dengue virus, the cytotoxic T lymphocytes release cytokines, rather than causing the lysis of infected cells, thereby increasing vascular permeability and exacerbating the damage of endothelial cells . Taken together these data indicate that secondary heterotypic infections with DENV are an important factor in the aggravation of dengue disease.
However, despite the identification of risk factors, little attention has been paid to the potential effect of the simultaneous presence of CHIKV on the propensity to develop DHF. To date, the scarcely available clinical data about coinfections impedes to establish clear conclusions. The large majority of the studies analyzing the clinical symptoms of CHIKV/DENV coinfected patients failed to identify a particular predisposition to develop DHF, as no severe symptoms were observed (Table 1). Furthermore, two studies that compared the biological and clinical symptoms between monoinfected and coinfected patients did not observe more severe manifestations or biological disorders in patients with a mixed infection, suggesting that the two viruses do not exert additive effects [124, 153].
The rare cases of DHF in coinfected patients were observed in one of the two patients coinfected in Malaysia  and in India in 2009 . The latter case deserves further attention: during this episode of DENV/CHIKV coinfections in Delhi, 69 blood samples were taken from patients with acute fever. Forty-eight were DENV-positive, eleven tested positive for ECSA lineage and six were positive for both viruses. From these six samples, three were positive for DENV-3, one for DENV-4, one for DENV-3/DENV-4 and one for DENV-1/DENV-4, constituting the first cases of concomitant infections with multiple DENV serotypes in CHIKV/DENV infected patients. Two of the six patients manifested severe hamorrhagic symptoms with central nervous system involvement and one died. It was not specified whether the severe cases corresponded to patients infected with a single DENV serotype or with two different serotypes, making it difficult to link the severity of the disease to the concomitant presence of CHIKV or to the presence of two different DENV serotypes. However, the particular high incidence of severe symptoms following superinfection by CHIKV and several DENV serotypes highlights the potential threat of CHIKV infection to human health in areas where DENV is hyperendemic .
Overall, these results do not establish a clear association between the severity of dengue and chikungunya diseases and the concomitant presence of both viruses. However, the number of CHIKV/DENV coinfections reported to the date is too small to draw firm conclusions. Further studies need to be undertaken with large cohorts of infected patients to gain better insight in this process, particularly taking into account that many severe cases associated with coinfections may have passed unnoticed, as the diagnosis of both viruses has not systematically been undertaken in the past. Moreover, the increase in coinfections with both viruses could lead to a rapid viral evolution, potentially resulting in the appearance of highly infective and pathogenic CHIKV and DENV strains.
4. Cell biology of CHIKV/DENV coinfections
Very little is known about the interactions that are established by the viruses and their host cells during coinfections. The fact that viral RNA of both viruses has been detected in
In this study, Potiwat et al.  infected
In the work of Potiwat et al. , competitive suppression was only observed when the amount of viral particles from DENV largely exceeded the one from CHIKV and not the reciprocal. Both viruses are able to exploit similar cell surface receptors for attachment, such as prohibitin and heat shock proteins that can be found in mosquito cells [157–160], leading to possible competitive interactions between both viruses for attachment and viral entry. However, it is highly unlikely that this is the reason for the suppression of CHIKV replication by DENV, as no inhibition of DENV replication was observed when CHIKV particles outnumbered DENV particles, as it would be expected if the viruses rely on the same receptors for infectious entry. An alternative, is that the viruses are able to exploit different receptors on the same cell, and that an excess in DENV particles attached to the cell surface sterically interfere with CHIKV-receptors interactions. Another possibility is that the excessive entry of infectious DENV particles leads to the hijacking of cellular components necessary for CHIKV replication, or to the production of viral components that inhibit CHIKV infection.
There is no information about the cellular biology of CHIKV/DENV coinfection in mammalian cells and we can only speculate about the possible mechanisms involved in viral replication. As summarized in Table 2, CHIKV and DENV share similar mechanisms of entry, which could lead to suppressive competition between the viruses in the early steps of infection. For example, they are able to exploit similar cellular receptors for attachment, they are internalized mainly by clathrin-mediated endocytosis and their fusion occurs in the endosomal system. The cellular tropism is also similar, although it seems to be larger in the case of DENV, a phenomenon that could be explained by the longer and more frequent circulation of the virus among human beings, allowing it to adapt and exploit a more diverse range of cellular targets. However, the viral RNA of both viruses can be detected in the blood of coinfected humans, suggesting that they are both able to concomitantly invade, replicate and spread in different organs to establish a systemic infection resulting in viremia. Thus, these viruses seem to have adopted different replicative strategies to overcome the potential competition for cellular resources when they infect the same mammalian cells, and/or have established cooperative interactions to guarantee their survival and propagation in human hosts. For example, during the cellular attachment step, the viruses may use different not yet characterized receptors or use an abundant cell surface molecule to limit competition. Also, although both viruses enter cells by clathrin-mediated endocytosis, some differences exist in the pathways and molecular partners involved in the process between CHIKV and DENV. Indeed, the depletion of the fuzzy homologue (FUZ), a cytoplasmic effector protein involved in planar cell polarity, ciliogenesis, and mammalian embryonic development, strongly inhibits clathrin-mediated endocytosis of CHIKV and other alphaviruses without affecting DENV entry . This suggests that both viruses exploit parallel clathrin pathways involving different effector proteins. Furthermore, DENV and CHIKV membrane fusion, a step necessary for the release of the viral genome in the cell, takes place in distinct cellular compartments: the first one occurs in Rab7+ late endosomes, while the second one takes place preferentially in Rab5+ early endosomes [162–164].The explanation for the selective use of these compartments could be linked to the lipidic composition of the endosomes: fusion of flaviviruses seems to require the presence of anionic lipids such as phosphatidylserine and bis(monoacylglycero)phosphate that are present in the late endosomes , while alphaviruses may have distinct requirements.
|Tropism in humans|
(main cell targets)
in mammalian cells
(name of the specific receptors)
|Glycosaminoglycans||+||+||Reviewed in [173, 174]|
|Heat Shock Proteins||+|
|Prohibitin||Used in mosquitoes||+|
CLEC5A Mannose receptor
|Clathrin-dependent endocytosis||Clathrin-dependent endocytosis||[161, 164, 170, 174–179]|
|Late endosomes||Early endosomes||[162–164]|
|Synthesis of a single polyprotein cleaved by viral and cellular proteases to generate individual viral proteins; replication of viral genome in RCs associated to ER-derived membranes||Inferred from other Alphaviruses: synthesis of two polyproteins from two ORFs autoproteolytically cleaved to generate individual viral proteins; replication of viral genome in RCs associated to endosomes/lysosomes-derived membranes||[5,180–190]|
|ER membrane||Plasma membrane||[191–194]|
|Secretion||Budding at the plasma membrane|
Also, fusion of alphaviruses seems to depend on the activity of the TSPAN9 tetraspanin protein, as depletion of the protein selectively blocks the fusion of Semliki Forest Virus (SFV) without altering the one of DENV. TSPAN9 may control the correct routing of the viruses to the early endosomes and maintain these compartments in a permissive state for alphaviruses fusion but not for flaviviruses .
There are also differences in the mechanisms involved in CHIKV and DENV synthesis of viral proteins, genome replication and assembly of the viral components to form mature infectious virions (Table 2). In the case of CHIKV, almost all the information about these processes has been inferred from studies performed with related alphaviruses such as SFV and Sindbis Virus (SINV). Once the viral genome is released into the cytoplasm, it is translated from two different open reading frames to generate the nonstructural (nsP1234) and structural (C-pE2-6K-E1) polyproteins [5, 180]. The nonstructural polyprotein is cleaved by the nsP2 viral protease to generate the individual nonstructural proteins that are going to form replication complexes (RCs) in charge of the viral genome replication . These RCs are associated to virus-induced membranous cytoplasmic structures that are derived from the endosomes and lysosomes [181–184]. The structural polyprotein is cleaved autoproteolitically by the C protein which is released in the cytoplasm. The rest of the polyprotein (pE2-6K-E1) is translocated to the endoplasmic reticulum (ER) where it is further processed by the host cell signal peptidase to generate the individual PE2, 6K, and E1 proteins . These proteins are then routed to the plasma membrane through the Golgi network where the furin-like protease cleaves the pE2 to generate the E2 and E3 mature proteins. At the plasma membrane, all the structural proteins gather together along with the genomic viral RNA, and the interaction between the C and E2 proteins drives the budding process, giving rise to enveloped virions that are released to external medium [191, 192].
In the case of flaviviruses, upon release of the viral genome into the cytoplasm, the nonstructural (NS) and structural proteins are translated from a single ORF to generate a large polyprotein that translocates to the membrane of the ER. There, the viral NS2B-NS3 protease and the host cell signalase cleave the polyprotein to generate the individual nonstructural proteins and the C, pre-Membrane (prM) and E proteins [185–188]. The nonstructural proteins form RCs associated to virus-induced membranes derived from the ER, known as vesicle packets, and drive the replication of the viral genome [189, 190]. Flavivirus assembly results from the association of C proteins with the genomic RNA into ER-derived membranes where all the structural proteins are displayed. The assembly generates immature viral particles that acquire their lipid envelope by budding into the lumen of the ER. These particles are routed through the Golgi network, and final maturation occurs at the trans-Golgi where the furin cleaves the prM to generate the mature M protein. These mature virions are then secreted to the external medium [193, 194].
Thus, the different replicative strategies, assembly compartments and release mechanisms used by flaviviruses and alphaviruses, may allow CHIKV and DENV to replicate simultaneously without a substantial overlap in their cellular requirements.
Another tempting possibility is that both viruses contribute to shut-off the antiviral cellular mechanisms, creating a favorable environment for viral replication. For example, the type I interferon response (IFN I) represents an important antiviral response against DENV and CHIKV. Accordingly, treatment with either IFN-α or IFN-β suppresses the replication of both viruses in cell culture [170, 197, 198]. Therefore, CHIKV and DENV have developed strategies to counteract the cellular defense system. In the case of DENV, almost all the nonstructural proteins are able to alter the IFN I response. Indeed, NS2A and NS4B inhibit the interferon α/β response by blocking the activation and translocation of the signal transducer and activator of transcription 1 (STAT1) to the nucleus and the subsequent transcription of antiviral genes . Furthermore, DENV NS2B/NS3 proteolytic activity has been involved in the inhibition of type I IFN response by degrading human stimulator of interferon gene (STING) protein in dendritic cells, which are known to be a primary target of DENV [200, 201]. STING is an adaptor protein that senses nucleic acids of incoming pathogens and triggers signaling pathways that activate the expression of IFN I and proinflammatory cytokines [202, 203]. DENV NS5 protein is also able to interact with STAT2 and bridge the protein to cellular ubiquitin ligases, thereby promoting the STAT2 proteasome-dependent degradation [204, 205].
In the case of CHIKV, it has been established that nsP2 is a potent inhibitor of the type I and II IFN-stimulated JAK-STAT signaling by blocking the phosphorylation of STAT-1 and its translocation to the nucleus . Therefore, a scenario could be envisioned in which the IFN response inhibitory effects of CHIKV and DENV nonstructural proteins are added to create a more potent shut-off of the antiviral cellular response that would be beneficial for both viruses.
5. Perspectives and challenges
Very little is known about the ecology and biology of CHIKV and DENV coinfections. Since a decade, the increasing number of reported cases in Asia, Africa, and America shows that it is a generalized phenomenon that has been underestimated. Both
The clinical consequences of CHIKV/DENV coinfections remain largely unknown. Indeed, the available data is not enough to conclude if the concomitant infection by both viruses is able to aggravate the clinical symptoms caused by DENV and CHIKV monoinfections. A systematic and larger clinical survey should be done to assess if coinfections are associated to severe forms of dengue and chikungunya diseases. This is particularly important, as clinical studies may justify further research on the pathogenesis of CHIKV/DENV coinfections to understand the immunological events that are triggered. This information could be useful to design and improve prophylactic vaccines against each virus.
Finally, the almost complete absence of information on the cell biology of CHIKV and DENV coinfections open a large range of research opportunities. In that sense, the mechanisms by which the viruses avoid competition or find cooperative mechanisms to replicate simultaneously are two major axes of research that should be addressed more deeply. By identifying common cellular targets of both viruses, antiviral drugs may be designed to treat coinfected patients or even to produce vaccines that are able to concomitantly immunize against both viruses.
This work was supported by grants from the Agence Nationale de la Recherche (grants ANR-12-BSV3-0004-01 and IRD.
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