Dynamics of Dengue Disease Severity Determined by the Interplay Between Viral Genetics and Serotype-Specific Immunity

OhAinle, Molly; Balmaseda, Ángel; Macalalad, Alexander R.; Téllez, Yolanda; Zody, Michael C.; Saborío, Saira; Nunez, Andrea C.; Lennon, Niall J.; Birren, Bruce W.; Gordon, Aubree; Henn, Matthew R.; Harris, Eva

doi:10.1126/scitranslmed.3003084

Cited by 267 publications

(315 citation statements)

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“…However, the highest frequency of severe forms in DENV-2 infections was observed in Southeast Asia and in Latin America. 13,15,21,22,26 The DENV-2 was recently found to be significantly associated with DSS in several countries. 27 However, all serotypes could lead to severe forms and death 1 ; among the deaths observed during the study period, one notes that half were attributed to cardiovascular-associated disease, diabetes, sickle cell disease, or nosocomial infections contracted in intensive care.…”

Section: Discussionmentioning

confidence: 99%

“…A recent publication showed that secondary DENV-2 infections could result from more virulent clades than others, depending on the serotype of the primary infecting serotype, DENV-1 or DENV-3. 21 Under these conditions, the development dynamics of epidemics, the function of the implicated genotypes, and the intervals between the successive epidemics, 22 the immune and genetic status of the population, 23 and other environmental factors such as the population density, 24 the climate and density of mosquitoes of the Aedes genus, 25 could create specific situations in each endemic region and thus create many confounding factors. This could explain the differences in results shown in various publications on the theme of clinical presentation by serotype.…”

Section: Discussionmentioning

confidence: 99%

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Clinical Presentation of Dengue by Serotype and Year of Epidemic in Martinique

Thomas

Najioullah

Besnier

et al. 2014

The American Society of Tropical Medicine and Hygiene

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Abstract. During the last decade Martinique experienced four dengue epidemics, each characterized by the predominance of 1 or 2 serotypes. In this retrospective database analysis, we investigated the relationship between dengue serotype and disease severity. Data on dengue were collected from 715 patients (male/female ratio 0.87), 14 to 91 years of age (median 35 years) examined in the adult emergency department between 2005 and 2010. In this series, DENV-4 infections more frequently had a milder clinical presentation. The DENV-2 infections were most often secondary infections admitted at the critical phase of dengue illness with signs of plasma leakage. The DENV-1 infections were disabling, particularly in females, and most often led to disease of intermediate severity, without overt plasma leakage. These data were consistent with there being differences in virulence between serotypes, regardless of the host's immune status. However, secondary DENV-2 infections showed an increased risk of plasma leakage.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical Presentation of Dengue by Serotype and Year of Epidemic in Martinique

Thomas

Najioullah

Besnier

et al. 2014

The American Society of Tropical Medicine and Hygiene

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“…36,51,58 Notably, although other lineage/genotype replacement events associated with increased disease severity involved a period of lineage/genotype cocirculation, the southeast Asian/American lineage II viruses from our study were introduced into Loreto in the absence of any DENV-2 competitors. 59,60 It is clear that both host and viral factors can play a role in determining dengue disease severity. Our results indicate that the large number of severe dengue cases observed during the 2010 and 2011 Loreto outbreak was not associated with increased viral replication in human mo-DCs or dissemination in mosquitoes.…”

Section: Denv-2 Lineage II Peru Outbreakmentioning

confidence: 99%

“…27,61 Even more specifically, it has been shown that disease severity in the context of a given immunological background can be affected by the genotype/clade of the DENV-2 infecting virus. 59,62 In Iquitos, a single DENV serotype typically dominates, and historically, the introduction of new DENV serotypes has resulted in epidemics of DF. These epidemics in Iquitos have been well-documented and were marked by the introduction of American DENV-2 in 1995, DENV-3 in 2001, and DENV-4 in 2008.…”

Section: Denv-2 Lineage II Peru Outbreakmentioning

confidence: 99%

Lineage II of Southeast Asian/American DENV-2 is Associated with a Severe Dengue Outbreak in the Peruvian Amazon

Williams¹,

Mayer²,

Johnson³

et al. 2014

The American Society of Tropical Medicine and Hygiene

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Abstract. During 2010 and 2011, the Loreto region of Peru experienced a dengue outbreak of unprecedented magnitude and severity for the region. This outbreak coincided with the reappearance of dengue virus-2 (DENV-2) in Loreto after almost 8 years. Whole-genome sequence indicated that DENV-2 from the outbreak belonged to lineage II of the southeast Asian/American genotype and was most closely related to viruses circulating in Brazil during 2007 and 2008, whereas DENV-2 previously circulating in Loreto grouped with lineage I (DENV-2 strains circulating in South America since 1990). One amino acid substitution (NS5 A811V) in the 2010 and 2011 isolates resulted from positive selection. However, the 2010 and 2011 DENV-2 did not replicate to higher titers in monocyte-derived dendritic cells and did not infect or disseminate in a higher proportion of Aedes aegypti than DENV-2 isolates previously circulating in Loreto. These results suggest that factors other than enhanced viral replication played a role in the severity of this outbreak.

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“…The sequence of infecting DENV serotypes can modulate disease severity (20). Defining the sequence of infecting DENV serotypes is difficult, except in the context of cohort studies, where individuals are followed longitudinally over many years and have wellcharacterized sequential DENV infections.…”

Section: A Protective Role For Original Antigenic Sinmentioning

confidence: 99%

Original antigenic sin in dengue revisited

Zompì

Harris

2013

Proc. Natl. Acad. Sci. U.S.A.

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The four dengue virus serotypes (DENV-1 to -4) cause the most important arthropod-borne viral disease of humans, with ∼100 million cases each year and over 3 billion people at risk for infection (1). The immune response to DENV infection is complex, because it can be either protective or pathogenic. The "original antigenic sin" in secondary (2°) DENV infections is defined as the dominance of cross-reactive antibodies or T-cell responses to a first infecting DENV serotype (the "original antigen") over the current infecting serotype. In acute DENV infections, cross-reactive T-cell responses have been associated with more severe disease, consigning cross-reactive T-cell responses to a pathogenic role (2, 3). In this issue of PNAS, Weiskopf et al. (4) challenge the idea that cross-reactive T-cell responses are only associated with pathogenesis by demonstrating that although CD8 + T-cell responses were indeed skewed toward the first DENV infection, this did not result in impaired responses, either qualitatively or quantitatively. Furthermore, they found that higher magnitude T-cell responses were associated with HLA alleles that have been linked to reduced susceptibility to severe dengue. Thus, these results suggest that human cross-reactive T-cell responses can be associated with a robust and multifunctional response that can induce protection, as has been shown in dengue mouse models (5-7). Dengue epidemiology and immune responseDengue is endemic throughout the world's subtropical and tropical regions, especially in Asia and Latin America, and it is considered an emerging infectious disease threat in the United States and a category A pathogen. Increased urbanization, globalization, and travel, as well as climate change, all contribute to its uncontrolled expansion (8). The acute febrile illness dengue fever (DF) can progress to a potentially life-threatening vascular leakage syndrome, known as dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), the latter characterized by hypotension and circulatory failure, most often affecting children (9). There are ∼500,000 hospitalizations attributable to dengue each year, with case fatality rates as high as 10-20% without appropriate treatment (9). Dengue constitutes a substantial economic burden in endemic countries (10), which are mostly low-and middle-income countries. No specific treatment exists, and an incomplete understanding of the immune response has hindered vaccine development.Primary (1°) infection with any of the four DENV serotypes is believed to confer lifelong protection to the homologous serotype; however, 2°infection with a different DENV serotype is the major risk factor for severe disease (11). This may be attributable to cross-reactive T cells (3) or to "antibodydependent enhancement" (12), where crossreactive anti-DENV antibodies facilitate entry of DENV into constant fragment receptorbearing cells. However, the majority of 2°D ENV infections are asymptomatic or result in only mild disease. The immune mechanisms underlying protection against a het...

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Dynamics of Dengue Disease Severity Determined by the Interplay Between Viral Genetics and Serotype-Specific Immunity

Cited by 267 publications

References 93 publications

Clinical Presentation of Dengue by Serotype and Year of Epidemic in Martinique

Clinical Presentation of Dengue by Serotype and Year of Epidemic in Martinique

Lineage II of Southeast Asian/American DENV-2 is Associated with a Severe Dengue Outbreak in the Peruvian Amazon

Original antigenic sin in dengue revisited

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