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The causative agent of dengue fever is the dengue virus which is transmitted by the mosquito Aedes albopictees. So, dengue fever is considered as an acute viral disease.DEN-1, DEN-2, DEN-3 and DEN-4 are the four serotypes of dengue fever. Dengue fever is last for 3 to 7 days which accompanied by joint and muscle ache and headache. Sever dengue fever is presents with severe bleeding or fluid loss or sever organ damage and they will lead to death. Dengue fever is predominantly transmitted in the tropical and subtropical areas. The main affect of the virus is platelet production. This virus is limited the capacity of platelet production of the human body.1.5 Lakh - 2.5 lakh per unit volume is the range of platelet for normal person. Below 1.5Lakh per unit volume of platelet is dangerous and medical attention is required.
Dengue fever symptoms
Dengue fever may be complicated and result in dengue hemorrhagic fever (2). This complication usually occurs in people who have previously suffered from dengue fever. This can be a possibly cause of a shock.
The dengue fever symptoms appear after 1-2 days after incubation.
They are (1, 2),
1 .High fever 6.Asthernia
2. Reddish spot on the skin 7.Genaralized lymphadenopathy
3. Joint and muscle pain (arthralgia) 8.Muscular erythema
4. Loss of appetite 9.Moderate hepatomegaly
5. Vomiting sensation
Human immune system
Immunity can be define as the ability to resist damage from foreign substance such as microorganism, Chemicals, toxins etc. They are two main parts of immune system (3).
Present at birth. No immunological memory .Non specific
Innate immunity can be divided in to three parts.
Cell mediates Anatomical barriers Humoral (soluble mediated)
Has an immunological memory
Has faster, stronger and last longer response
Acquired immunity can be divided in to two parts.
Humoral immunity Cell mediated immunity
The structure of dengue virus
When outlining epitopes engaged by human antibody and the practical significances of antibodies binding the structural and maturation properties of dengue virus must be reflected. To dictating how antibody neutralize viruses, the structural arrangement of viral surface protein are involved .so, there needed a sufficient knowledge about the dengue viron structure to understand the responses of human immune system to dengue infection.
Dengue is produces a spherical particle with very small diameter and it is an enveloped, positive-sense, single-stranded, lymphotropic, RNA virus (4, 5). Two integral membrane proteins are existed on virus envelop named designated envelope (E) and pre membrane (PrM) (4). The virus envelop is derived from the host cell membrane and consisted of lipid bilayer. While viruses entering in to the cells E proteins bind to cellular receptors and facilitate fusion of virus and cellular membrane. Nevertheless E proteins are considered as a main target of antibodies. Native protein form a head to tail homodiameter as the individual subunit of E protein having with three beta-barrel domains designated domain 1 (ED1), 2 (ED2), 3(ED3). The locations of the hydrophobic viral fusion peptide are these domains. Each viral particle has 90 tightly packed dimers that are derived from 180 monomers of E proteins and they are lie flat on the surface of the viral membrane. Also individual E subunits are organized in 2, 3 and 5 fold axes of the T-3 icosahedral stricture of the viron. These all the E protein subunit are not in same environs on the viral surface and steric and other concern will effects in preferential relations of particular E subunits over other with receptors and antibodies . They are seven non-structural proteins NS1, NS2a, NS2b, Ns3, Ns4a, NS4b and NS5. With complement fixing action antibodies are made against the NS1 protein when dengue virus infection.
Skin dendritic cells, peripheral blood monocyte, tissue macrophages, hepatocytes are host cells for gangue virus replication (6). But endothelial cells are not considered as the host cells. DC-SIGN that are lying on the dendritic cells are co-receptors for virus entry. Complement activation and magnitude of viraemia and NS 1 antigenaemia are measurement of dengue disease severity. Cytokines and chemokines that are created by immune activation interrelated with disease severity. For systemic vascular leakage inflammatory cytokines may involve. This vascular leakage and endothelial permeability are increased the severity of dengue fever (7). In addition to plasma leakage, hemostatic abnormalities together with sever thrombocytopenia and bleeding are detected and production of anti-platelet autoantibodies occur during dengue infection. As well with the bleeding cross-reacting of antibodies to the envelope glycoprotein of the virus plasminogen are accompanying.
There is a synergistic interaction between the NS3 and E protein. By growing RNA synthesis and viral load the generation of recombinant viruses carrying specific E and NS 3 proteins mutation improved viral fitness both in vivo and vitro (8). To adjust the viral fitness the introduction of only pair of amino acid substitutions in to the genone of a non-mouse adapted dengue virus 1 strain was adequate.Dengue virus tropism in humanized mice recapitulates human dengue fever. As the result of specificity for infection and replication animal models of dengue virus diseases are very difficult to develop in certain human cells (9). Human stem cells from umbilical cord blood transplanted to immunodeficent mice. These mice display significant signs of dengue disease as human. Humanized mice displayed infections in human cells in bone marrow, spleen and blood after infection with the most virulent strain of dengue serotype 2. In to the mouse blood stream cytokines and chemokines were secreted by these human cells. Pathology of dengue virus infection these mouse follows that report in human patients. So, human have grate risk of getting infection in dengue virus.
Innate immune system
Soluble mediators of innate immune system
Though adaptive immune system acts major role of destruction of dengue virus, the innate immune system also fights with dengue virus to protect body. Interferon (IFN) is a type of cytokines. Complement inhibitors and cytokines are involved in raising the vascular permeability and decreasing the endothelial damage (10). In dengue infection type 2 and type 3 IFN of innate immune system act non -overlapping role in dengue infection and control the viral replication (11). Different kinds of IFN are response to dengue virus in different ways. Some may exert disease-related effects on the host while some IFN are protective. Not only the IFN but also other cytokines have also been implicated in dengue pathogenesis. These soluble mediate innate immune system with cytokines act upon an advanced network of events to provoke the disease. As a result of secondary infection cytokines storm is normally attributed to massive T cell activation. But cytokines also have contributing effect in sever cases of primary dengue infection. Soluble factors of vector saliva influence to pathogen transmission and establishment by altering the immune reactions. Antiviral effect of type 1 IFN can attenuate the dengue viral non structural protein. When acute dengue fevers, Natural killer cells are activated and involve in killing of infected cells by releasing of cytokines (12). Not only natural killer cells but also complements are also contributing in acute dengue fever which is activated by NSI. An antigen presenting cell, the dendritic cells also contribute to antigen presentation and also regulate the acquired immune system. A receptor of viral entry in to the cell is dendritic cells which are in dermis or lymphoid tissue. Dendritic cells maturated by infection modulate of dengue virus. But it is accompanied with secretion of inflammatory and immune modulate cytokines.
Mast cells are essentially contributed to defect the dengue virus by stimulating and degranulation (5). As the result of dengue virus infection mast cells are triggered,
Melanoma differentiation -associated gene (MDA5)
Retinoic acid inducible gene-1 (RIG-1)
Antiviral intracellular host response pathway
Chemokine such as CCL5, CXCL12 and CXCL1
Cytokines including TNF-alpha an d IFN alpha
Lectin switching during dengue virus infection
For destruction of dengue virus the mannose-binding lectin (MBL) that is a part of a human immune system is involved. On the outside of the dengue virus MBL identifying sugar are existent. Therefore MBL sugar is activated the complement system when the dengue viruses are targeted by them. As the result of tis it can says that complement system not only takes a hit during dengue infection but also involved in getting rid of dengue fever.
Unfortunately this MBL sugar not distributed in same amount trough the humans. Some people have large amount of MBL sugar while others having low amount. This is a reason for some people suffering from severe dengue while others are fighting and getting rid of dengue fever quickly.
Dendritic cell- specific intracellular adhesion molecule 3 (ICAM-3) -grabbing nonitergrin (DC-SIGN) and its close homologue liver/lymph node specific ICZM-3-grabbing intergrin (L-SIGN) are the two C-type lectin molecules which promoting infection by attaching with dengue (13). Although virus created in primary DCs are infectious for L-ISGN-expressing cells they are not capable to interact with DC-SIGN. Although DCs not involving in huge scale virus replication, skin resident DCS may be a position of initial infection by insect-produced virus during dengue infection.
In human innate system manose binding lectin is a key soluble pathogen recognition protein which binds specific manose containing glucose on the surface of microbial agent and initiate complement activation via the lectin pathway (14). Restricted the pathogenesis from the MBL dependent activation via the lectin cascade by neutralizing insect cell- derived West Nile Virus (WNV) in cell culture. Through complement activation dependent and independent pathways human MML also bind to dengue virus and neutralized infection of all four dengue virus serotypes.
Down regulation of cytokine production
To down regulate cytokine production, dengue virus serotype 2 is blocked Extracellular Signal-Regulated kinase and Nuclear Factor -KB Activation (15). In the innate immune system type 1 IFN and cytokine production are very important. Dengue virus serotype 2 leading to reduced production of IFN- Î² in the early phase of infection by stimulating low levels of IFN regulatory factor 3 and NF-KB activation. Dengue virus infection is also activated cytokine production triggered by Toll-like receptor (TLR) signaling. Thus dengue virus-2 is a great inducer of type 1 IFN and cytokines to down regulate the host innate immunity and it is also block the TLR-triggered ERK-NK-KB activation and cytokine production.
RNA interference leads to inhibition of dengue virus entry and multiplication in to monocytes
Dengue virus enter target cells via receptor mediated endocytosis after the viral envelope protein E attaches to the cell structure receptor (16). Inhibition of dengue virus access and multiplication of the virus in the monocytes can be done by silencing the cell surface receptor and clathrin mediated endocytosis using RNA interference. This may serve as a new promising therapeutic target to attenuate dengue infection and thus diminish broadcast as well as progressing to severe dengue hemorrhagic fever.
Adaptive immune system
Multi hit threshold model of dengue neutralization
Antibodies which are compartment of adaptive immune system are involved in neutralization or enhancement of dengue virus infection (4). To study interaction between dengue virus and antibodies, mouse mucosal antibodies are used. Multiple antibodies are wanted to neutralization of dengue virus. Therefore it is considered as the "multiple hit" phenomenon. Mouse MAbs that most potently neutralization the dengue viruses are bounded to surface exposed epitopes on domain 3 of the dengue envelop (e) protein as MBL are serotype- specific. When neutralizing the dengue viruses the key target of mouse MBL are the two partly overlapping epitopes on ED labeled the lateral ridge and A stranded epitopes (17). With serotype- specific toughly neutralizing antibodies the lateral ridge epitopes are interacted. Cross react with more than one serotype of dengue virus, the mouse MAbs that bind to the A stranded epitopes bind to E protein. They are 180 binding sites on the viron for an antibody. As the result of steric effects and limited accessibility of some epitopes all the 180 molecules are not bind by antibody in every time.
The human antibody response is complex as it involved polyclonal response to primary and secondary infection with four different serotypes (4). To study reactions of human antibody, immune serosa and isolated MAbs from people who are exposed to dengue virus are examined. Weakly neutralization and binding to multiple dengue viruses are the features of most dengue specific antibodies in human immune serosa. A lesser fraction of the total dengue virus specific antibody response represent the potently and type specifically neutralize dengue virus. As well these neutralizing antibodies act to fix to novel epitopes comprising complex, quaternary epitopes that are only preserved on the intact viron. According to above results it can be suggested that mouse and human antibodies identify distend epitopes on the dengue viron.
Mammalian cell stated dengue virus like particles are accomplished to prompt virus like particle- specific humoral and cellular immune responses (18).
Involvement of the antibodies in the development of immunity
The antibodies such as IgM, IgG are done a major role for acute influence in the resolution of the dengue viraemia and long term immunity (19). Human antibodies are supplied immune defense by antibody dependent cellular cytokines which are related with severe dengue and by obstructing cellular attachment, viral fusion. It is not certain that surviving in vitro assays acculatory characterize the anti-dengue activity of the antibodies as they exist in vivo. Neutralizing monoclonal antibodies are targeted E protein, epitopes and protein domains. The knowledge of the action of the anti-Ns 1 antibodies in the resolution of viraemia and immunity is also significant. The description of dengue virus - specific human monoclonal antibodies from immune donors will offer further understandings in to the molecular basis of antibody function in neutralization or infection enhancement.
From dengue antibody positive donors dengue- antigens are induced the proliferation reaction of peripheral blood mononuclear cells (PBMC) (17). But there is no exact proliferative response from dengue antibody negative donor. Infection IFN is detected in the culture fluid of dengue immune PBMC stimulated with dengue antigen. Dengue specific T cell clones which occurred in dengue 3 infected patient have CD3+, CD4+, and CD8+phenotypes and produced IFN in response to dengue antigen. CD4+ cells which are in PMBC from dengue immune donors are proliferated and produced interferon after stimulation with dengue antigen. By increasing the number of dengue infected monocytes in the presence of cross reaction anti dengue antibodies these IFN are contributed to the pathogenesis of dengue hemorrhagic fever and dengue shock syndrome.
Dengue virus uses exploits enhancing antibodies for intracellular immune evasion as well as the preexisting enhancing antibodies to promote its entry in to Fc receptor bearing cells by two ways (20). First way is immune evasion is mediated by the suppressive cytokine interleukin 10 (IL-10). Inactivation the Janus kinase-signal transducer and activation of transcriptional pathway occurs as the result of high levels of IL-10 activated expression of suppressor of cytokines signaling 3-gene. Suppressed the dengue virus replication and restored inducible nitric oxide synthase by inhibition of IL-10 production by small interfering RNA down regulated suppressor of cytonine signaling 3 gene expressions. The second way is the activation the negative regulators, dihydroacetone kinase and autophagy - related 5- autophagy - related 12 when entering of dengue virus antibody complexes in human monocytic cells. Then this method causes to suppression of interferon mediated antiviral responses as the result of the disorder the retinoic acid incucible gene 1 and melanoma.
Antibody enhancement of dengue infection
Although antibodies protect against homologous dengue virus infection promote severe dengue by heterotypic virus entry via FcR receptors (19). Anti- dengue virus monoclonal antibodies are generated when memory B cells alter primary and secondary infection. Sever dengue can be accompanied first dengue virus infected infant less than one year who are born to mother who are immune to dengue or secondary dengue infected older people (21). When second infection occurs after long time from first infection the severity may be enormous. These people have a single immune factor-IgG dengue-reactive antibodies. The phenomenon of antibody - dependent enhancement (ADE), whereby dengue antibodies at sub-neutralizing enhance dengue virus infections for the low occurrence of severe dengue given the total number of heterotypic infection is that cross- reactive dengue neutralizing antibodies will block industrious infection.
After primary dengue infections dengue virus E- specific B cells were highly serotype-specific (22). Serotype cross reactive and secreted antibodies with higher avidity to heterologous dengue virus serotype are the features of E specific B cells in patients with secondary infected.
Though an FcR-dependent pathway (antibody dependent enhancement (ADE)) human monocytes are susceptible to dengue virus infection (23). Binding of dengue virus antibody immune complex to monocyte is not correlates with the input amount of antibodies and it is peaked at suboptimal antibody concentration. But it is correlated with the observed infection enhancement. So, immune complex are involve in hindering dengue virus from binding to FcR-bearing cells. If this protective feature is weakened viral attachment and Ade are enhanced. Increased cytokine production and costimulatory marker expression were associated with infection enhancement causing to pathological role of ADE affected monocytes in dengue hemorrhagic disease.
Secondary dengue virus infection and immune system
Dengue serotypes show antibody epitopes that are unique to each serotypes (4). The antibodies that are reacting with four serotypes are formed in the people who have recovered from primary dengue virus infection. Although these antibodies prevent re-infection by same serotype they are not involving in prevention of different serotypes. The people who are secondary infected by different serotype are facing greater risk for having dengue hemorrhagic fever. Most widely supported theory that explaining the higher risk of the dengue hemorrhagic fever that associated with secondary infection are the antibody dependent enhancement of dengue virus.
As the responses of dengue viral antigens, the immune cells are profiled and highlighted bystander T cell activation of healthy people in an endemic area (6). Because of bystander cell stimulation in dengue viral infection could expose the immune mechanism that safeguard or enhance pathogenesis of secondary dengue infection.
There is a proliferation, programmed cell death and massive activation of dengue specific T cells in acute secondary dengue infection (24). Cross -reacting memory T cell clones that are created during previous infection are the causative for these responses. Therefore there is a relationship between disease severity and amount of peripheral T cells responses. Large serotypes cross-reactive T cell clones react in a different method to antigens in different dengue virus serotypes. Because of that modified cytokine are produced. Profound T cells activation, cytokines release and cell death will contributed to systemic disturbances causing to sever dengue. Delaying the viral elimination by original antigenic T cell responses is causing to increase viral loads and immunopathology. Throughout the febrile phase of illness dengue specific T cells are not generally measureable in the peripheral blood.