Category: Publications

O’Driscoll M, Buddhari D, Huang AT, Waickman A, Kaewhirun S, Iamsirithaworn S, Khampaen D, Farmer A, Fernandez S, Rodriguez-Barraquer I, Srikiatkhachorn A, Thomas S, Endy T, Rothman AL, Anderson K, Cummings DAT, Salje H

Proc Natl Acad Sci U S A 2023 Oct;120(41):e2308221120

PMID: 37774093

Abstract

Infants less than 1 y of age experience high rates of dengue disease in dengue virus (DENV) endemic countries. This burden is commonly attributed to antibody-dependent enhancement (ADE), whereby concentrations of maternally derived DENV antibodies become subneutralizing, and infection-enhancing. Understanding antibody-related mechanisms of enhanced infant dengue disease risk represents a significant challenge due to the dynamic nature of antibodies and their imperfect measurement processes. Further, key uncertainties exist regarding the impact of long-term shifts in birth rates, population-level infection risks, and maternal ages on the DENV immune landscape of newborns and their subsequent risks of severe dengue disease in infancy. Here, we analyze DENV antibody data from two infant cohorts (N = 142 infants with 605 blood draws) and 40 y of infant dengue hospitalization data from Thailand. We use mathematical models to reconstruct maternally derived antibody dynamics, accounting for discretized measurement processes and limits of assay detection. We then explore possible antibody-related mechanisms of enhanced infant dengue disease risk and their ability to reconstruct the observed age distribution of hospitalized infant dengue cases. We find that ADE mechanisms are best able to reconstruct the observed data. Finally, we describe how the shifting epidemiology of dengue in Thailand, combined with declining birth rates, have decreased the absolute risk of infant dengue disease by 88% over a 40-y period while having minimal impact on the mean age of infant hospitalized dengue disease.

Ribeiro Dos Santos G, Buddhari D, Iamsirithaworn S, Khampaen D, Ponlawat A, Fansiri T, Farmer A, Fernandez S, Thomas S, Rodriguez Barraquer I, Srikiatkhachorn A, Huang AT, Cummings DAT, Endy T, Rothman AL, Salje H, Anderson KB

J Infect Dis 2022 Oct;226(8):1348-1356

PMID: 35512137

Abstract

BACKGROUND: Dengue virus (DENV) often circulates endemically. In such settings with high levels of transmission, it remains unclear whether there are risk factors that alter individual infection risk.

METHODS: We tested blood taken from individuals living in multigenerational households in Kamphaeng Phet province, Thailand for DENV antibodies (N = 2364, mean age 31 years). Seropositivity ranged from 45.4% among those 1-5 years old to 99.5% for those >30 years. Using spatially explicit catalytic models, we estimated that 11.8% of the susceptible population gets infected annually.

RESULTS: We found that 37.5% of the variance in seropositivity was explained by unmeasured household-level effects with only 4.2% explained by spatial differences between households. The serostatus of individuals from the same household remained significantly correlated even when separated by up to 15 years in age.

CONCLUSIONS: These findings show that despite highly endemic transmission, persistent differences in infection risk exist across households, the reasons for which remain unclear.

Udawatte DJ, Lang DM, Currier JR, Medin CL, Rothman AL

Front Cell Infect Microbiol 2022;12:926036

PMID: 36310878

Abstract

Dengue virus (DENV) infection is the most prevalent arthropod-borne virus disease and is endemic in more than 100 countries. Several DENV proteins have been shown to target crucial human host proteins to evade innate immune responses and establish a productive infection. Here we report that the DENV NS3 protein targets RIPK1 (Receptor Interacting Protein Kinase I), a central mediator of inflammation and cell death, and decreases intracellular RIPK1 levels during DENV infection. The interaction of NS3 with RIPK1 results in the inhibition of NF-κB activation in response to TNFR or TLR3 stimulation. Also, we observed that the effects of NS3 on RIPK1 were independent of NS3 protease activity. Our data demonstrate a novel mechanism by which DENV suppresses normal cellular functions to evade host innate immune responses.

Huang AT, Takahashi S, Salje H, Wang L, Garcia-Carreras B, Anderson K, Endy T, Thomas S, Rothman AL, Klungthong C, Jones AR, Fernandez S, Iamsirithaworn S, Doung-Ngern P, Rodriguez-Barraquer I, Cummings DAT

Proc Natl Acad Sci U S A 2022 May;119(20):e2115790119

PMID: 35533273

Abstract

SignificanceThe age of reported dengue hemorrhagic fever (DHF) cases, the severe form of dengue infections, has been increasing in Thailand for four decades. Factors underlying this shift remain poorly understood, challenging public health planning. Here, we found aging of the population and its effect on the hazard of transmission to be the dominant contributors, with temporal changes in surveillance practices playing a lesser role. With ongoing population aging, we expect a continuing shift of DHF toward older individuals, heightening the chance of clinical complications with comorbidities. With most other highly endemic countries facing similar shifts in age structure, the pattern is expected to appear elsewhere. Awareness is needed to improve diagnosis and treatment.

Fansiri T, Buddhari D, Pathawong N, Pongsiri A, Klungthong C, Iamsirithaworn S, Jones AR, Fernandez S, Srikiatkhachorn A, Rothman AL, Anderson KB, Thomas SJ, Endy TP, Ponlawat A

Pathogens 2021 Sep;10(10)

PMID: 34684183

Abstract

Individual houses with high risks of dengue virus (DENV) transmission might be a source of virus transmission within the neighborhood. We conducted an entomological risk assessment for DENV transmission at the household level, comprising family cohort members residing in the same location, to assess the risk for dengue virus transmitted by mosquito vectors. The studies were conducted in Kamphaeng Phet Province, Thailand, during 2016-2020. Entomological investigations were performed in 35 cohort families on day 1 and day 14 after receiving dengue case reports. DENV was found in 22 samples (4.9%) out of 451 tested samples. A significantly higher DENV infection rate was detected in vectors collected on day 1 (6.64%) compared to those collected on day 14 (1.82%). Annual vector surveillance was carried out in 732 houses, with 1002 traps catching 3653 females. The majority of the 13,228 water containers examined were made from plastic and clay, with used tires serving as a primary container, with 59.55% larval abundance. Larval indices, as indicators of dengue epidemics and to evaluate disease and vector control approaches, were calculated. As a result, high values of larval indices indicated the considerably high risk of dengue transmission in these communities.