Immunopathophysiology of Dengue Infection

wp-1466364012376.jpgImmunopathophysiology of Dengue Infection

The pathophysiological basis of severe dengue disease (i.e., dengue hemorrhagic fever [DHF]), appears to be multifactorial, involving complex interactions among viral factors, host genetics, and the immunologic background of the host, principally prior exposure to dengue virus. Analysis of these processes has been limited to observational studies of naturally infected humans because there have not been useful animal models of dengue disease. Substantial evidence points to dengue virus-reactive T cells as a critical effector in the development of DHF. The critical elements of T-cell epitope specificity and functional responses that contribute to DHF. Additional studies in well-characterized patient cohorts from different geographic regions will be needed to advance this research and guide new approaches to prevention and treatment of DHF.

Dengue viruses (DENV), a group of four serologically distinct but related flaviviruses, are responsible for one of the most important emerging viral diseases. This mosquito-borne disease has a great impact in tropical and subtropical areas of the world in terms of illness, mortality and economic costs, mainly due to the lack of approved vaccine or antiviral drugs. Infections with one of the four serotypes of DENV (DENV-1-4) result in symptoms ranging from an acute, self-limiting febrile illness, dengue fever, to severe dengue haemorrhagic fever or dengue shock syndrome. We reviewed the existing mouse models of infection, including the DENV-2-adapted strain P23085. The role of CC chemokines, interleukin-17 (IL-17), IL-22 and invariant natural killer T cells in mediating the exacerbation of disease in immune-competent mice is highlighted. Investigations in both immune-deficient and immune-competent mouse models of DENV infection may help to identify key host–pathogen factors and devise novel therapies to restrain the systemic and local inflammatory responses associated with severe DENV infection.

The increased risk for severe dengue disease during secondary dengue virus (DENV) infections, along with the clinical and pathological evidence pointing to cytokines as the proximal mediators of disease, has interested cellular immunologists in exploring the role of DENV-specific T lymphocytes in the pathogenesis of dengue-associated plasma leakage. Recent technological advances in the analysis of virus-specific T cells, applied to blood samples collected before, during and after acute DENV infections, have demonstrated that memory DENV-specific T cells from a prior infection respond with altered cytokine production to heterologous DENV serotypes and that the level of activation and expansion of these memory cells during acute DENV infection correlates with disease severity. Limited data suggest that specific T cell response profiles may predict a higher risk for severe disease during secondary infection. Application of these techniques and principles to animal models and to clinical trials may advance the development of novel therapeutics and protective vaccines.

Dengue fever is a mosquito-borne viral disease caused by 1 of 4 closely related but antigenically distinct serotypes of dengue virus, serotypes DENV-1 through DEN-4.  Infection with one dengue serotype confers lifelong homotypic immunity and a brief period of partial heterotypic immunity (2 years), but each individual can eventually be infected by all 4 serotypes. Several serotypes can be in circulation during an epidemic.

The Aedes mosquito

  • Dengue viruses are transmitted by the bite of an infected female Aedes (subgenus Stegomyia) mosquito.  Both males and females require nectar for energy. Females require a blood meal as a source of appropriate protein for egg development. Globally, Aedes aegypti is the predominant highly efficient mosquito vector for dengue infection, but the Asian tiger mosquito, Aedes albopictus, and other Aedes species can also transmit dengue with varying degrees of efficiency
  • Aedes mosquito species have adapted well to human habitation, often breeding around dwellings in small amounts of stagnant water found in old tires or other small containers discarded by humans. Even a bottle cap filled with water can serve as to incubate and hatch Aedes eggs. Eggs can survive periods of drying and will hatch when exposed to water. Humans are the preferred hosts.
  • Female Aedes mosquitoes are daytime feeders. They inflict an innocuous bite, usually on the back of the neck and the ankles, and are easily disturbed during a blood meal, causing them to move on to finish a meal on another individual, making them efficient vectors. Not uncommonly, entire families develop infection within a 24- to 36-hour period, presumably from the bites of a single infected mosquito.
    Hosts for transmission
  • Humans serve as the primary reservoir for dengue. Certain nonhuman primates in Africa and Asia also serve as hosts but do not develop dengue hemorrhagic fever. Mosquitoes acquire the virus when they feed on a carrier of the virus. Persons with dengue viruses in their blood can transmit the viruses to the mosquito 1 day before the onset of the febrile period. The patient usually remains infectious for the subsequent 4-5 days (up to 12 days).
  • The mosquito can transmit dengue if it immediately bites another host. In addition, transmission occurs after 8-12 days of viral replication in the mosquito’s salivary glands (extrinsic incubation period). The virus does not adversely affect the mosquito. The mosquito remains infected for the remainder of its life. The life span of A aegypti is usually 21 days but ranges from 15 to 65 days. Vertical transmission of dengue virus in mosquitoes has been documented.  The eggs of Aedes mosquitoes withstand long periods of desiccation, reportedly as long as 1 year, but are killed by temperatures of less than 10°C. Rare cases of vertical dengue transmission have been reported. In addition, rare reports of human-to-human transmission via needle-stick injuries have been published.
  • Once inoculated into a human host, dengue has an incubation period of 3-14 days (average 4-7 days) while viral replication takes place in target dendritic cells. Infection of target cells, primarily those of the reticuloendothelial system, such as dendritic cells, macrophages, hepatocytes, and endothelial cells, ] result in the production of immune mediators that serve to shape the quantity, type, and duration of cellular and humoral immune response to both the initial and subsequent virus infections.
  • Dengue viral infections frequently are not apparent. In most cases, especially in children younger than 15 years, the patient is asymptomatic or has a mild undifferentiated febrile illness lasting 5-7 days. Classic dengue fever primarily occurs in nonimmune, nonindigenous adults and children and is typically self-limiting. Recovery is usually complete by 7-10 days. Severe dengue (dengue hemorrhagic fever/dengue shock syndrome) usually occur around the third to seventh day of illness during a second dengue infection in persons with preexisting actively or passively (maternally) acquired immunity to a heterologous dengue virus serotype.

Dengue fever

  • Dengue presents in a nonspecific manner similarly to that of many other viral and bacterial illnesses. Fever typically begins on the third day of illness and persists 5-7 days, abating with the cessation of viremia. Fever may reach 41C°. Occasionally, and more frequently in children, the fever abates for a day and recurs, a pattern that is termed a saddleback fever; however, this pattern is more commonly seen in dengue hemorrhagic fever.
  • Leukopenia, lymphopenia near the end of the febrile phase, and thrombocytopenia are common findings in dengue fever and are believed to be caused by direct destructive actions of the virus on bone marrow precursor cells. The resulting active viral replication and cellular destruction in the bone marrow are believed to cause the bone pain. Approximately one third of patients with dengue fever may have mild hemorrhagic symptoms, including petechiae, gingival bleeding, and a positive tourniquet test (>20 petechiae in an area of 2.5 X 2.5 cm). Dengue fever is rarely fatal.

Severe dengue (dengue hemorrhagic fever)

  • Severe dengue occurs less frequently than dengue fever but has a more dramatic clinical presentation. In most of Asia, where it first was described, severe dengue is primarily a disease of children. However, in the Americas, and more recently reported in Taiwan, severe dengue has an equal distribution in all ages.
  • Severe dengue typically begins with the initial manifestations of dengue fever. The acute febrile illness (temperatures ≤40°C), like that of dengue fever, lasts approximately 2-7 days. However, in persons with severe dengue, the fever reappears, giving a biphasic or saddleback fever curve.
  • Along with biphasic fever, patients with severe dengue have progressive thrombocytopenia, increasing hematocrit (20% absolute rise from baseline) and low albumin (signs of hemoconcentration preceding shock), more obvious hemorrhagic manifestations (>50% of patients have a positive tourniquet test), and progressive effusions (pleural or peritoneal). Lymphocytosis, often with atypical lymphocytes, commonly develops before defervescence or the onset of shock. Transaminase levels may be mildly elevated or present in the several thousands associated with hepatomegaly in those patients with acute hepatitis. Low fibrinogen and elevated fibrin split products are signs of disseminated intravascular coagulation. Severe metabolic acidosis and circulatory failure can occur.
  • The critical feature of severe dengue is plasma leakage. Plasma leakage is caused by increased capillary permeability and may manifest as hemoconcentration, as well as pleural effusion and ascites. Bleeding is caused by capillary fragility and thrombocytopenia and may manifest in various forms, ranging from petechial skin hemorrhages to life-threatening gastrointestinal bleeding.
  • Liver damage manifests as increases in levels of alanine aminotransferase and aspartate aminotransferase, low albumin levels, and deranged coagulation parameters (prothrombin time, partial thromboplastin time). [28, 29] In persons with fatal dengue hepatitis, infection was demonstrated in more than 90% of hepatocytes and Kupffer cells with minimal cytokine response (tumor necrosis factor [TNF]–alpha, interleukin [IL]–2). This is similar to that seen with fatal yellow fever and Ebola infections.
  • As the term implies, severe dengue shock is essentially dengue hemorrhagic fever with progression into circulatory failure, with ensuing hypotension, narrow pulse pressure (< 20 mm Hg), and, ultimately, shock and death if left untreated. Death may occur 8-24 hours after onset of signs of circulatory failure. The most common clinical findings in impending shock include hypothermia, abdominal pain, vomiting, and restlessness.

Secondary infection

  • The immunopathology of severe dengue remains incompletely understood. Most patients who develop severe dengue have had prior infection with one or more dengue serotypes. When an individual is infected with another serotype (ie, secondary infection) and produces low levels of nonneutralizing antibodies, these antibodies, directed against 1 of 2 surface proteins (precursor membrane protein and envelope protein), when bound by macrophage and monocyte Fc receptors, have been proposed to fail to neutralize virus and instead form an antigen-antibody complex.
  • This results in increased viral entry into macrophages bearing IgG receptors, allowing unchecked viral replication with higher viral titers and increased cytokine production and complement activation, a phenomenon called antibody-dependent enhancement.
  • The affected macrophages release vasoactive mediators that increase vascular permeability, leading to vascular leakage, hypovolemia, and shock. This mechanism, along with individual host and viral genome variations, plays an active role in pathogenesis. Infants born to mothers who have had dengue, as maternally derived dengue neutralizing IgGs wane, are also thought to be at risk for enhanced disease.
  • Some researchers suggest that T-cell immunopathology may play a role, with increased T-cell activation and apoptosis. Increased concentrations of interferon have been recorded 1-2 days following fever onset during symptomatic secondary dengue infections. [32] The activation of cytokines, including TNF-alpha, TNF receptors, soluble CD8, and soluble IL-2 receptors, has been correlated with disease severity.
  • Cuban studies have shown that stored serum sample analysis demonstrated progressive loss of cross-reactive neutralizing antibodies to DENV-2 as the interval since DENV-1 infection increased.  In addition, certain dengue strains, particularly those of DENV-2, have been proposed to be more virulent, in part because more epidemics of dengue hemorrhagic fever have been associated with DENV-2 than with the other serotypes.
  • DENV-2–activated platelets were phagocytized in large numbers when the platelet activation inhibitor prostacyclin was added.
  • Several recent studies have investigated the causes of thrombocytopenia in dengue. Laboratory and human studies have suggested a direct correlation between activation and depletion of platelets, with a sharp drop occurring on day 4 of fever. A high number of dengue virus genome copies have been found in these activated platelets. Increased binding of complement C3 and IgG have also been found on the surface of these platelets. In addition to platelet activation, dengue infection has been found to activate the intrinsic pathway of apoptosis, with increased surface phosphatidylserine exposure, mitochondrial depletion, and activation of caspase 3 and 9.

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