Category: Publications

Sánchez-Vargas LA, Kounlavouth S, Smith ML, Anderson KB, Srikiatkhachorn A, Ellison DW, Currier JR, Endy TP, Mathew A, Rothman AL

Front Immunol 2019;10:1359

PMID: 31263466

Abstract

Prior exposure to dengue virus (DENV) has a profound impact on the outcome of infection, which varies according to the interval between infections. Antibodies secreted by B cells and cytokines secreted by T cells are thought to contribute both to protective immunity against DENV and the pathogenesis of dengue disease. We analyzed peripheral blood mononuclear cells (PBMC) collected from Thai children over a 5-year prospective cohort study to define the dynamics of DENV-specific memory B and T cell responses and the impact of symptomatic or subclinical DENV infections. To measure B cell responses, PBMC were stimulated with IL-2 plus R848 and culture supernatants were tested for DENV-binding antibodies by ELISA. To measure T cell responses, PBMC were stimulated in dual-color ELISPOT assays with overlapping peptide pools of structural and non-structural proteins from the four DENV types. B cell responses were low to one or more DENV types prior to symptomatic infection and increased with reactivity to all four types after infection. Subjects who had a subclinical infection or who did not experience a DENV infection during the study period showed strong memory B cell responses to all four DENV types. T cell responses to DENV peptides demonstrated a cytokine hierarchy of IFN-γ > IL-2 > IFN-γ/IL-2. T cell responses were low or absent prior to secondary infections. The trends in T cell responses to DENV peptides over 3 year post-infection were highly variable, but subjects who had experienced a secondary DENV1 infection showed higher cytokine responses compared to subjects who had experienced a secondary DENV2 or subclinical infection. The longitudinal nature of our study demonstrates persistent memory B cell responses over years and a lasting but variable impact of secondary DENV infection on DENV-specific T cell responses.

Sánchez-Vargas LA, Mathew A

Future Virol 2019 Mar;14(3):161-169

PMID: 31073324

Abstract

Follicular helper T cells (T) are a predominant subset of CD4 T cells specialized in providing help to B cells in germinal centers and necessary to generate T cell-dependent antibody responses. Peripheral T (pT) are the counterpart of T found in the circulation, which resemble T in many aspects of their phenotype and function. The CD4 pT subset has received a lot of interest recently because they are easy to access and have the potential to serve as a biomarker for long-lasting humoral immunity. This review will discuss recent findings of pT in human acute viral diseases with a focus on dengue infection.

Kang JY, Aldstadt J

Comput Environ Urban Syst 2019 May;75:170-183

PMID: 31728075

Abstract

Sensitivity analysis (SA) in spatially explicit agent-based models (ABMs) has emerged to address some of the challenges associated with model specification and parameterization. For spatially explicit ABMs, the comparison of spatial or spatio-temporal patterns has been advocated to evaluate models. Nevertheless, less attention has been paid to understanding the extent to which parameter values in ABMs are responsible for mismatch between model outcomes and observations. In this paper, we propose the use of multiple scale space-time patterns in variance-based global sensitivity analysis (GSA). A vector-borne disease transmission model was used as the case study. Input factors used in GSA include one related to the environment (introduction rates), two related to interactions between agents and environment (level of herd immunity, mosquito population density), and one that defines agent state transition (mosquito extrinsic incubation period). The results show parameters related to interactions between agents and the environment have great impact on the ability of a model to reproduce observed patterns, although the magnitudes of such impacts vary by space-time scales. Additionally, the results highlight the time-dependent sensitivity to parameter values in spatially explicit ABMs. The GSA performed in this study helps in identifying the input factors that need to be carefully parameterized in the model to implement ABMs that well reproduce observed patterns at multiple space-time scales.

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.