Category: Publications

Friberg H, Beaumier CM, Park S, Pazoles P, Endy TP, Mathew A, Currier JR, Jarman RG, Anderson KB, Hatch S, Thomas SJ, Rothman AL

PLoS Negl Trop Dis 2018 Dec;12(12):e0006975

PMID: 30557313

Abstract

BACKGROUND: Hyperendemic circulation of all four types of dengue virus (DENV-1-4) has expanded globally, fueling concern for increased incidence of severe dengue. While the majority of DENV infections are subclinical, epidemiologic studies suggest that type-cross-reactive immunity can influence disease outcome in subsequent infections. The mechanisms controlling these differential clinical outcomes remain poorly defined.

METHODOLOGY/PRINCIPAL FINDINGS: Blood samples were collected from a cohort of school-aged Thai children who subsequently experienced a subclinical DENV infection or developed dengue illness. PBMC collected prior to infection were stimulated in vitro with DENV and the secretion of 30 cytokines was measured using a multiplexed, bead-based array. Significant differences were found in cytokine production based on both the type of DENV used for stimulation and the occurrence of clinical illness. Secretion of IL-15 and MCP-1 was significantly higher by PBMC of subjects who later developed symptomatic DENV infection. In addition, IL-6 was produced by PBMC from all subjects who subsequently developed symptomatic infection, versus 59% of subjects who had subclinical infection. Secretion of IL-12, IL-2R, MIP-1α, RANTES, GM-CSF, and TNFα was significantly lower by PBMC from subjects with symptomatic infection.

CONCLUSIONS/SIGNIFICANCE: These data demonstrate significant differences in pre-existing immune responses to DENV associated with the clinical outcome of subsequent infection. The finding of higher levels of some cytokines in subjects with symptomatic infection and higher levels of other cytokines in subjects with subclinical infection supports the existence of both protective and pathologic immune profiles. Clinical-immunological correlations identified in the context of natural DENV infection may be useful for evaluating immune responses to dengue vaccines.

Rattanamahaphoom J, Leaungwutiwong P, Limkittikul K, Kosoltanapiwat N, Srikaitkhachorn A

Asian Pac. J. Allergy Immunol. 2017 Sep;35(3):171-178

PMID: 27996292

Abstract

BACKGROUND: The pathogenic mechanisms underlying the increased vascular permeability in dengue hemorrhagic fever (DHF) are not well understood. Enhanced cellular immune activation, especially activation of serotype-cross reactive T cells, has been implicated in plasma leakage in DHF. Changes in several biological markers and mediators including cytokines, chemokines, angiogenic factors and their receptors have been shown to correlate with disease severity. A decline in plasma levels of a soluble form of vascular endothelial growth factor receptor 2 (VEGFR2), a receptor of vascular endothelial growth factor (VEGF), has been associated with plasma leakage in dengue patients.

OBJECTIVE: We aimed to investigate the effect of dengue virus (DV)-specific CD8⁺ T cells on the expression of VEGFR2 on endothelial cells.

METHODS: An in vitro model was developed in which dengue virus-specific CD8⁺ T cells generated from peripheral blood mononuclear cells (PBMCs) of DHF patients were co-cultured with antigen-presenting cells, human umbilical vein endothelial cells (HUVECs) and activated with DV non-structural protein 3 (NS3) peptides. The expression of VEGFR2 by endothelial cells was measured.

RESULTS: DV-specific CD8⁺ T cells were serotype cross-reactive. Activation of DV-specific CD8⁺ T cells resulted in down-regulation of soluble VEGFR2 production and an up-regulation of cell-associated VEGFR2.

CONCLUSIONS: Our findings indicate that activation of DV-specific T cell is associated with modulation of VEGFR2 expression that may contribute to increased VEGF responsiveness and vascular permeability.

Haltaufderhyde K, Srikiatkhachorn A, Green S, Macareo L, Park S, Kalayanarooj S, Rothman AL, Mathew A

J. Infect. Dis. 2018 Oct;218(10):1675-1685

PMID: 29917084

Abstract

Background: Follicular helper T cells (TFH) are specialized CD4 T cells required for B-cell help and antibody production.

Methods: Given the postulated role of immune activation in dengue disease, we measured the expansion and activation of TFH in the circulation (peripheral TFH [pTFH]) collected from Thai children with laboratory-confirmed acute dengue virus (DENV) infection.

Results: We found significant expansion and activation of pTFH subsets during acute infection with the highest frequencies of activated pTFH (PD1hi pTFH and PD1+CD38+ pTFH) detected during the critical phase of illness. Numbers of activated pTFH were higher in patients with secondary compared with primary infections and in patients with more severe disease. We also found a positive correlation between the frequencies of activated pTFH and the frequencies of plasmablasts.

Conclusions: To our knowledge, this is the first ex vivo analysis of pTFH activation during acute DENV infection. Overall, our study supports the model that pTFH contribute to disease evolution during the critical stage of illness.

Kang JY, Aldstadt J

Int J Geogr Inf Sci 2019;33(1):193-213

PMID: 31695574

Abstract

Spatially explicit agent-based models (ABMs) have been widely utilized to simulate the dynamics of spatial processes that involve the interactions of individual agents. The assumptions embedded in the ABMs may be responsible for uncertainty in the model outcomes. To ensure the reliability of the outcomes in terms of their space-time patterns, model validation should be performed. In this paper, we propose the use of multiple scale spatio-temporal patterns for validating spatially explicit ABMs. We evaluated several specifications of vector-borne disease transmission models by comparing space-time patterns of model outcomes to observations at multiple scales via the sum of root mean square error (RMSE) measurement. The results indicate that specifications of the spatial configurations of residential area and immunity status of individual humans are of importance to reproduce observed patterns of dengue outbreaks at multiple space-time scales. Our approach to using multiple scale spatio-temporal patterns can help not only to understand the dynamic associations between model specifications and model outcomes, but also to validate spatially explicit ABMs.

Park S, Srikiatkhachorn A, Kalayanarooj S, Macareo L, Green S, Friedman JF, Rothman AL

PLoS Negl Trop Dis 2018 Oct;12(10):e0006799

PMID: 30273334

Abstract

BACKGROUND: Early recognition of dengue, particularly patients at risk for plasma leakage, is important to clinical management. The objective of this study was to build predictive models for dengue, dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS) using structural equation modelling (SEM), a statistical method that evaluates mechanistic pathways.

METHODS/FINDINGS: We performed SEM using data from 257 Thai children enrolled within 72 h of febrile illness onset, 156 with dengue and 101 with non-dengue febrile illnesses. Models for dengue, DHF, and DSS were developed based on data obtained three and one day(s) prior to fever resolution (fever days -3 and -1, respectively). Models were validated using data from 897 subjects who were not used for model development. Predictors for dengue and DSS included age, tourniquet test, aspartate aminotransferase, and white blood cell, % lymphocytes, and platelet counts. Predictors for DHF included age, aspartate aminotransferase, hematocrit, tourniquet test, and white blood cell and platelet counts. The models showed good predictive performances in the validation set, with area under the receiver operating characteristic curves (AUC) at fever day -3 of 0.84, 0.67, and 0.70 for prediction of dengue, DHF, and DSS, respectively. Predictive performance was comparable using data based on the timing relative to enrollment or illness onset, and improved closer to the critical phase (AUC 0.73 to 0.94, 0.61 to 0.93, and 0.70 to 0.96 for dengue, DHF, and DSS, respectively).

CONCLUSIONS: Predictive models developed using SEM have potential use in guiding clinical management of suspected dengue prior to the critical phase of illness.