Dengue was first reported in 1779 with the appearance of a dengue-like disease; however researchers suggest that it has been around longer than that (Gupta et.al, 2006). According to CDC, over 100 million people worldwide get infected with the Dengue virus (CDC 2010). Dengue is caused by the Dengue virus and is one of the most deadly infectious disease in India. It has been known to cause an epidemic there. In places like India and other developing countries in South Asia, Dengue fever spreads due to the overwhelming mosquito populations in stagnant water found on the roadsides and trash disposal areas (Gupta et al, 2006). Mosquitoes breed in this stagnant water and when these mosquitoes bite people, the individual that was bit gets Dengue Fever which can then lead to a more serious manifestation if not resolved by the individual's immune system, namely: Dengue Hemorrhagic Fever and later Dengue Shock Syndrome (Gupta et al, 2006). Dengue virus infection does not spread from person to person (Gupta et al, 2006). Nevertheless, due to poor hygiene practices resulting in over breeding of Dengue virus carrying mosquito vectors, Dengue infection is a threat in India and its surrounding countries (Gupta et al, 2006).
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This paper will introduce the Dengue virus and its properties, its reproductive cycle in the host, its virulence and the mechanism by which Dengue Fever can manifest onto Dengue Hemorrhagic Fever and Dengue Shock Syndrome. Hosts protection strategies against this virus as well as host mediated enhancement of virulence will also be discussed.
Dengue viruses are single stranded plus sense RNA viruses belonging to the flaviviridae family (Lindabach et al, 2003). Morphologically, they are small, enveloped and icosahedral. They belong to group IV under the Baltimore Classification system (Lindabach et al, 2003). The genome is approximately 10700 bases in length surrounded by a nucleocapsid and covered by a lipid envelope containing the envelope and the membrane proteins (Clyde et al, 2006). The genome has a single open reading frame which encodes a precursor polyprotein and is flanked by two non-translated regions (Clyde et al, 2006). This gene then undergoes translational and post-translational proteolytic cleavage of the precursor. Cleavage gives rise to the three structural proteins: capsid (C), membrane (M) and envelope (E) and seven non-structural proteins: NS1, NS2a, NS2b, NS3, NS4a, NS4b and NS5 (Zybert et al, 2010). From these proteins, the ones that are important for virulence are E, prM, NS1 and NS3 genes. These proteins are used to initiate and maintain infection in hosts (Zybert et al, 2010).
Most of the Dengue virus infection is reported in Tropical countries- Caribbean region, South America, Africa and South Asia (CDC 2009). This is because the virus vector which is a mosquito requires a warm climate (CDC 2009). Dengue virus is transmitted to people through the bites of mosquitoes: Aedes aegypti and Aedes albopictes (CDC 2009). The virus is transmitted when a mosquito of the Aedes genus bites a person infected with dengue virus (CDC 2009). Essentially, the virus in the blood of the infected individual infects the mosquito and travels from the mosquito's gut to its salivary glands where the virus multiplies. So, the next time when this mosquito bites another person, the virus is injected into the person (CDC 2009). Mosquito transmits the disease by preventing blood clotting when feeding on the person; so the person gets the dengue virus. As long as the mosquito is alive, it retains the virus and is able to infect another person with the Dengue virus (CDC 2009).
In recent years, Dengue virus has been a huge concern in developed countries in North America and Europe because scientists fear that the mosquitoes will be able to resist cooler climates and be able to infect people in temperate climates as well (Zybert et al, 2010). Dengue virus is now believed to be the most common arthropod-borne viral infection in the world (CDC 2010). This virus infects a wide range of hosts; from mosquitoes to humans, hamsters and rodents. This implies they do not really have a preference; they will be virulent and transmitted through the mosquito vector whenever the mosquito bites its prey- human or animal (CDC 2010).
Dengue virus has 4 antigenic serotypes. These 4 serotypes are different strains of Dengue virus but they have about 60-80% homology between each other (Clyde et al, 2006). All four Dengue virus serotypes are prevalent in the sub-tropical regions of the world (CDC 2010). The majority of the Dengue virus infection proceeds without symptoms or result in self-limited dengue fever (Clyde et al, 2006). This is because the infected individual's immune system successfully resolves the infection. But the problem arises when patients show a more serious manifestation of this virus that causes Dengue Hemorrhagic Fever (DHF) and the Dengue Shock Syndrome (DSS) (Clyde et al, 2006). Majority of death that results from dengue infection is therefore not due to the more common Dengue fever (DF) but due to DHF; there is a 5% chance of fatality with DHF but if the patient goes onto develop DSS, then the fatality reaches as high as 40% (CDC 2010).
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After the person gets infected, the incubation period of the Dengue Virus is approximately 4 days (Zybert et al, 2010). The person will come down with fever and mild flu-like symptoms as well as present a macular or maculopapular rash. During this time, it is difficult to distinguish dengue fever from other viral diseases and the person usually recovers in 5 days (Zybert et al, 2010). In a more severe case, fever and rash are accompanied by headache, myalgia, backache, sore throat and abdominal pain. The patients also become lethargic and experience anorexia and nausea. DHF has a similar incubation period as dengue fever and many of the same symptoms. However, the fever is more severe and the other mentioned symptoms are more extreme (Zybert et al, 2010). The patient undergoes increased vascular permeability: plasma leakage, loss of endothelial integrity and abnormal homeostasis. This causes the patient to lose more blood, experience hypertension, go into Dengue Shock Syndrome and die (CDC 2009). This means DF when unresolved by the hosts' immune system leads to DHF and when the loss of blood during DHF is extreme; the patient undergoes DSS and dies if immediate medical attention is not given (CDC 2009). Therefore, Dengue virus infections can be subclinical or cause illnesses ranging from mild, flu-like symptoms with rash (DF) to a severe and sometimes fatal disease characterized by capillary leakage and systemic shock (CDC 2009).
Also, it is important to note here that infection with one dengue virus serotype does not confer protective or long-term immunity against other serotypes (Clyde et al, 2006). Also, unlike the immune system's interaction with other disease causing pathogens, where secondary infection with the same pathogen is less severe and quickly resolved, in the case of Dengue virus; secondary infection is much worse (Clyde et al, 2006). The mechanism through which this happens is termed Antibody-Dependent Enhancement or ADE. ADE is mediated by host's own immune system which increases the activity of immune cell proteins like interferons, cytokines, compliment which then increase the loss of endothelial integrity and capillary permeability of the plasma membrane leakage is a hallmark of DHF (Clyde et al, 2006).
Naturally, immune system cells like macrophage, monocytes and dendritic cells are the targets for Dengue infection (Lindabach et al, 2003). Dengue virus replication involves the same general steps used by other RNA viruses: Dengue virus attaches to the host cell surface, enters the cytoplasm, translates its viral proteins, replicates its RNA viral genome, forms virions with capsids and then finally exits from the cell (Lindabach et al, 2003). Specifically, Dengue virus binds to the cell by using its major viral envelope (E) glycoprotein. This protein is absolutely essential for infectivity (Zybert et al, 2010). The E binds to the viral receptors on the cell surface which is usually a heparin sulfate or the high-affinity laminin receptor (Zybert et al, 2010). Like other Flaviviruses, Dengue virus also uses clathrin-mediated endocytosis for cell entry (Lindabach et al, 2003). The fusion of viral and cellular membranes is mediated by the low pH/acidified vesicles of the endosome. After the fusion, the viral RNA enters the cytoplasm of the host cell (Lindabach et al, 2003). Then it uncoats its nucleocapsid; after uncoating, the RNA molecule is translated as a single polyprotein (Lindabach et al, 2003). The polyprotein then gets processed into 3 structural and 7 non-structural proteins mentioned above. The cleavage of several of the viral proteins requires a functional viral protease that is encoded in the nonstructural protein NS3 (Zybert et al, 2010). The non-structural protein NS5 is the RNA-dependent RNA polymerase which assembles with several other viral proteins and host proteins to form the replication complex (Zybert et al, 2010). This complex is the one responsible for transcribing the viral RNA to produce negative-strand viral RNA which then serves as a template for the production of the viral genome (Zybert et al, 2010).
The first line of defense against Dengue viral infection is the production of interferons by the hosts' immune system (Clyde et al, 2006). Interferon mediated immune responses create an anti-viral state and initiate a variety of processes including metabolic control to limit virus infection. Also, these responses trigger the adaptive immune response (B cells and T cells) to step in and take action. Humoral immunity which is another term for B cell response or antibody response takes place six days post bite from the infected mosquito (Clyde et al, 2006). The antibody response is mainly directed against the E and the prM glycoproteins present on the surface of the virus. In doing so, antibodies suppress the virulence of the virus by neutralizing the viral antigens (Clyde et al, 2006). Hence, only a mild Dengue fever or asymptomatic Dengue infection is the result. Neutralizing antibodies basically block the attachment of the virus to its natural receptor on the cell surface or inhibit subsequent steps in the entry process of the virus (Clyde et al, 2006). However, in the worst case scenario, the same protective antibodies can enhance virus infectivity and cause DHF or even worse, DSS (Clyde et al, 2006).
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Studies have shown that secondary infection with a different Dengue virus serotype or first time infection of infants born to dengue immune mothers highly increases the risk to develop severe disease (Zybert et al, 2010). These observations have led to the Antibody-Dependent Enhancement hypothesis of Dengue virus infection (Zybert et al, 2010). Studies with E-specific antibodies have shown that when the virus antigen neutralization by the B cell antibody occurs at a threshold lower than the one required for virus neutralization; these antibodies especially direct the virus particles to cells with FcR receptors; these FcR receptors are usually the natural targets of the virus, so directing the virus towards them is a bad move (Zybert et al, 2010). Macrophages, monocytes and dendritic cells all have FcR. Binding of the virus antigen to the FcR on these phagocytic cells facilitates the entry of virions via FcR mediated endocytosis (Clyde et al, 2006). To this date, the molecular mechanisms underlying antibody-dependent enhancement has not been uncovered (Zybert et al, 2010). .
Uptake of the Dengue virus-immune complexes via FcR mediated entry not only leads to a higher number of infected cells but it can also increase the number of virus particles produced per infected cell (Zybert et al, 2010). So far, most of the research has focused on innate and humoral immunity against Dengue Virus (Zybert et al, 2010). However, a recent study on T cell response has shown that CD8 (cytotoxic) cells especially known for their killing of virally infected cells fight against Dengue infection and in doing so induce a cytokine storm - massive release of inflammatory cytokines into the hosts' body (Zybert et al, 2010). However, this does more harm to the host than good. The hallmark of DHF/DSS is the loss of endothelial integrity which is due to the abnormal immune response to the virus (Zybert et al, 2010). Clinical studies have shown that patients suffering from DHF/DSS show a tremendous increase in all major cytokines, i.e. TNF-a, IL-1b, IL-4, IL-6 etc (Zybert et al, 2010). Both the ADE and cytokine storm theories suggest that the exacerbation of Dengue infection is not because of the virus itself but more due to the immune system's response to the infection.
Apart from the immune system, there are other factors also involved in controlling Dengue virus infection. Each Dengue virus serotype (there are a total of 4) have multiple genotypes (CDC 2010). Research has shown that some genotypes are more associated with DHF than others (Zybert et al, 2010). These genotypes are: DENV-2 and DENV-3. The first outbreak of DHF in the Americas happened at the same time as the introduction of the DENV-2 Southeast Asia genotype did (Zybert et al, 2010). In America, this DENV-2 genotype almost exclusively caused Dengue fever and not Dengue hemorrhagic fever (Zybert et al, 2010). But in Southeast Asia, the same genotype caused DHF (Zybert et al, 2010). This showed that the Southeast Asian DENV-2 genotype is more dangerous than the DENV-2 genotype in the Americas (Zybert et al, 2010). This suggests that the same Dengue virus genotype can result in different pathological conditions depending on the geographical locations (Zybert et al, 2010). When detailed genomic analysis was done on the Asian and the American genotype of the DENV-2, nucleotide differences were seen in the genes of the important viral proteins (Zybert et al, 2010). It was also shown that the Southeast Asian DENV-2 genotype had a higher replication rate in human macrophages and dendritic cells compated to the American DENV-2 genotype (Zybert et al, 2010). .
Secondly, virulence is also enhanced due to glycosylation of the E and NS1 proteins (Zybert et al, 2010). Glycosylation refers to addition of carbohydrates. Glycosylation results in a stable binding interaction between the virus E protein and the DC-SIGN of the dendritic cells in host making the receptor mediated endocytic fusion much easier (Zybert et al, 2010).
Finally, not all individuals respond to the Dengue virus infection in the same way. Differences in disease symptoms are also seen within certain human populations (Zybert et al, 2010). No Dengue hemorrhagic fever or Dengue shock syndrome was seen in Haitian population despite infection by several Dengue serotypes (Zybert et al, 2010). Also, it was shown that Black people developed severe dengue less frequently than White people (Zybert et al, 2010). This caused the scientists to hypothesize that variation in genes and gene mutations contribute to the variable susceptibility to Dengue virus in humans (Zybert et al, 2010).
Some genes have in fact been implicated in conferring protection against severe Dengue infection as well as making individuals susceptible to severe Dengue infection (Zybert et al, 2010). The genes that do this are both from the Human Leukocyte Antigen (HLA) family of immune system genes. It was found that people with HLA class I alleles: A*01, A*0207, A*24, B*07, B*46, B*51 and HLA class II alleles like DQ*1, DR*1 and DR*4 were associated with severe Dengue virus infection. On the contrary, individuals expressing HLA-B*13, HLA-B*14 and HLA-B*29 were found to be protected against severe Dengue virus infection (Zybert et al, 2010).
There are also other host factors that confer different level of immunity or susceptibility to Dengue infection. People with glucose 6-phosphate dehydrogenase deficiency have a higher risk of developing DHF upon Dengue virus infection (Zybert et al, 2010). This was known because the monocytes taken from these individuals supported a higher than normal replication rate for the Dengue virus (Zybert et al, 2010). Also, immunocompromised individuals like the ones suffering from diabetes mellitus are more susceptible to develop severe Dengue (Zybert et al, 2010). An explanation for this phenomenon was that there is an increase in the production of cytokines in diabetes mellitus patients and this makes them more prone to vascular leakage. This leakage as mentioned already is an important characteristic of DHF (Zybert et al, 2010).
Despite the discovery of many genetic and environmental factors as well as many host and viral proteins being uncovered; it is very difficult to pinpoint at the exact interaction between the Dengue virus and the immune system cells in natural hosts. A lack of a better animal model exacerbates the situation. Hence, it is difficult to explain molecularly why ADE is initiated and how ADE leads to Dengue hemorrhagic fever and Dengue shock syndrome (Zybert et al, 2010).
To reiterate, after a person is infected with dengue virus, they develop an immune response to that particular dengue serotype. The immune response produces specific antibodies to that serotype's surface proteins that prevent the virus from binding to the macrophage cells of the host and gaining entry. Thus in mild cases of Dengue virus infection, the host's immune system resolves the infection on its own with just the Dengue Fever as an outcome. However, if another serotype of Dengue virus infects the same person, the virus will activate the immune system to attack it as if it were the first serotype. The immune system becomes confused because the four serotypes have very similar surface proteins/antigens. The antibodies bind to the surface antigens but do not inactivate the virus. Instead, ADE follows and FcR on phagocytic cells are turned on. This makes the viral infection much more severe. The body then releases cytokines that cause the endothelial tissue to become permeable which results in hemorrhagic fever and fluid loss from the blood vessels.
Due to the presence of the four similar but antigenically distinct Dengue virus serotypes, Vaccine development has been very difficult (Clyde et al, 2006). As mentioned earlier, if a person develops immunity to one serotype and then tries to launch an immune response to another serotype, then the person will get Dengue hemorrhagic Fever as well as might get Dengue Shock Syndrome later (Clyde et al, 2006). As of now, researchers are working on making a tetravalent vaccine that works against all four serotypes (CDC 2010). So far, the only way to protect oneself from dengue virus infection is mosquito control which has been proven to be quite difficult in countries like India due to poor sanitation practices as well as the costs of mosquito repellent being high (Gupta et al, 2006).
As of now, there are not many treatment options available (CDC 2006, 2010). After infection with Dengue virus and suffering from Dengue hemorrhagic fever, the main priority is to stabilize the plama membrane's permeability in order to avoid plasma leakage and subsequently preventing the patient from going to DSS (CDC 2010). For this reason, patients suffering from Dengue Hemorrhagic Fever are given drugs like corticosteroids or carbazochrome sodium sulfonate (CDC 2010). However, in poorer parts of India and its neighboring countries, healthcare and drugs are inaccessible due to lack of transport as well as money; therefore there is a high fatality rate if the patient goes into DHF (Gupta et al, 2006).