Role of dendritic cells in antibody-dependent enhancement of dengue virus infection.

Dengue viruses (DV), composed of four distinct serotypes (DV1 to DV4), cause 50 to 100 million infections annually. Durable homotypic immunity follows infection but may predispose to severe subsequent heterotypic infections, a risk conferred in part by the immune response itself. Antibody-dependent enhancement (ADE), a process best described in vitro, is epidemiologically linked to complicated DV infections, especially in Southeast Asia. Here we report for the first time the ADE phenomenon in primary human dendritic cells (DC), early targets of DV infection, and human cell lines bearing Fc receptors. We show that ADE is inversely correlated with surface expression of DC-SIGN (DC-specific intercellular adhesion molecule-3-grabbing nonintegrin) and requires Fc gamma receptor IIa (FcgammaRIIa). Mature DC exhibited ADE, whereas immature DC, expressing higher levels of DC-SIGN and similar FcgammaRIIa levels, did not undergo ADE. ADE results in increased intracellular de novo DV protein synthesis, increased viral RNA production and release, and increased infectivity of the supernatants in mature DC. Interestingly, tumor necrosis factor alpha and interleukin-6 (IL-6), but not IL-10 and gamma interferon, were released in the presence of dengue patient sera but generally only at enhancement titers, suggesting a signaling component of ADE. FcgammaRIIa inhibition with monoclonal antibodies abrogated ADE and associated downstream consequences. DV versatility in entry routes (FcgammaRIIa or DC-SIGN) in mature DC broadens target options and suggests additional ways for DC to contribute to the pathogenesis of severe DV infection. Studying the cellular targets of DV infection and their susceptibility to ADE will aid our understanding of complex disease and contribute to the field of vaccine development.

The Epidemiology, Virology and Clinical Findings of Dengue Virus Infections in a Cohort of Indonesian Adults in Western Java.

BACKGROUND: Dengue has emerged as one of the most important infectious diseases in the last five decades. Evidence indicates the expansion of dengue virus endemic areas and consequently the exponential increase of dengue virus infections across the subtropics. The clinical manifestations of dengue virus infection include sudden fever, rash, headache, myalgia and in more serious cases, spontaneous bleeding. These manifestations occur in children as well as in adults. Defining the epidemiology of dengue in a given area is critical to understanding the disease and devising effective public health strategies. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report the results from a prospective cohort study of 4380 adults in West Java, Indonesia, from 2000-2004 and 2006-2009. A total of 2167 febrile episodes were documented and dengue virus infections were confirmed by RT-PCR or serology in 268 cases (12.4%). The proportion ranged from 7.6 to 41.8% each year. The overall incidence rate of symptomatic dengue virus infections was 17.3 cases/1,000 person years and between September 2006 and April 2008 asymptomatic infections were 2.6 times more frequent than symptomatic infections. According to the 1997 WHO classification guidelines, there were 210 dengue fever cases, 53 dengue hemorrhagic fever cases (including one dengue shock syndrome case) and five unclassified cases. Evidence for sequential dengue virus infections was seen in six subjects. All four dengue virus serotypes circulated most years. Inapparent dengue virus infections were predominantly associated with DENV-4 infections. CONCLUSIONS/SIGNIFICANCE: Dengue virus was responsible for a significant percentage of febrile illnesses in an adult population in West Java, Indonesia, and this percentage varied from year to year. The observed incidence rate during the study period was 43 times higher than the reported national or provincial rates during the same time period. A wide range of clinical severity was observed with most infections resulting in asymptomatic disease. The circulation of all four serotypes of dengue virus was observed in most years of the study.

Enhancing knowledge and awareness of dengue during a prospective study of dengue fever.

In 1992, the Indonesian CDC implemented strategies to control and prevent dengue fever (DF) by including community involvement to reduce larva breeding sites and a mass health education program. To contribute to this effort, we incorporated an educational component into a prospective study of DF conducted at two textile factories in Bandung. This education provided: a lecture on the signs and symptoms of dengue and ways to prevent the disease, posters in the health clinic at each factory and handouts given to each volunteer with an explanation of symptoms. Upon enrollment, each participant completed a questionnaire to gather demographic information. Additionally they were given a brief (non-standardized) test (PRE-test) of their dengue knowledge, which was verbally administered by the study physicians. Five questions (15 point system) were designed to assess the participant's ability to recognize and describe aspects of dengue in lay terms. The subject material included: the symptoms of acute DF, transmission of dengue virus, and basic steps for disease prevention. The same questionnaire was re-administered 18 months later (POST-test), and the results were compared. A total of 2,340 participants completed both the PRE- and POST-tests; there were 1,373 males and 967 females, median age 36 years (range 18-59). Only 0.3% of participants scored EXCELLENT (15-14 points) on the PRE-test whereas 8.4% scored EXCELLENT on the POST-test. Fewer participants scored VERY BAD (2-0 points) on the POST-test compared to the PRE-test (1.4% vs 4.0%). The average raw scores for the PRE- and POST-tests were 7.8 and 10.1, respectively. Improvement of individual scores correlated highly with educational level. No significant correlation was identified for gender, age, factory location or a diagnosis of dengue during the study. These findings demonstrate that our prospective study enhanced knowledge and awareness of dengue in the volunteers.