DHF Project

Category: Publications

  • Dengue virus downregulates TNFR1- and TLR3-stimulated NF-κB activation by targeting RIPK1

    in

    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.

  • Assessing the role of multiple mechanisms increasing the age of dengue cases in Thailand

    in

    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.

  • Entomological Risk Assessment for Dengue Virus Transmission during 2016-2020 in Kamphaeng Phet, Thailand

    in

    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.

  • Viral Suppression of RIPK1-Mediated Signaling

    in

    Udawatte DJ, Rothman AL

    mBio 2021 Aug;12(4):e0172321

    PMID: 34372694

    Abstract

    Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) has emerged as a key upstream regulator of cell death and inflammation. RIPK1-mediated signaling governs the outcome of signaling pathways initiated by tumor necrosis factor receptor 1 (TNFR1), Toll-like receptor 3 (TLR3), TLR4, retinoic acid-inducible gene 1 (RIG-I)/melanoma differentiation-associated protein 5 (MDA-5), and Z-binding protein 1 (ZBP1) by signaling for NF-κB activation, mitogen-associated protein kinase (MAPK) and interferon regulatory factor 3/7 (IRF3/7) phosphorylation, and cell death via apoptosis and necroptosis. Both cell death and inflammatory responses play a major role in controlling virus infections. Therefore, viruses have evolved multifaceted mechanisms to exploit host immune responses by targeting RIPK1. This review focuses on the current understanding of RIPK1-mediated inflammatory and cell death pathways and multiple mechanisms by which viruses manipulate these pathways by targeting RIPK1. We also discuss gaps in our knowledge regarding RIPK1-mediated signaling pathways and highlight potential avenues for future research.

  • Longitudinal Analysis of Dengue Virus-Specific Memory T Cell Responses and Their Association With Clinical Outcome in Subsequent DENV Infection

    in

    Sanchez-Vargas LA, Anderson KB, Srikiatkhachorn A, Currier JR, Friberg H, Endy TP, Fernandez S, Mathew A, Rothman AL

    Front Immunol 2021;12:710300

    PMID: 34394112

    Abstract

    Memory T cells resulting from primary dengue virus (DENV) infection are hypothesized to influence the clinical outcome of subsequent DENV infection. However, the few studies involving prospectively collected blood samples have found weak and inconsistent associations with outcome and variable temporal trends in DENV-specific memory T cell responses between subjects. This study used both and cultured ELISPOT assays to further evaluate the associations between DENV serotype-cross-reactive memory T cells and severity of secondary infection. Using ELISPOT assays, frequencies of memory T cells secreting IFN-γ in response to DENV structural and non-structural peptide pools were low in PBMC from multiple time points prior to symptomatic secondary DENV infection and showed a variable response to infection. There were no differences in responses between subjects who were not hospitalized (NH, n=6) and those who were hospitalized with dengue hemorrhagic fever (hDHF, n=4). In contrast, responses in cultured ELISPOT assays were more reliably detectable prior to secondary infection and showed more consistent increases after infection. Responses in cultured ELISPOT assays were higher in individuals with hDHF (n=8) compared to NH (n=9) individuals before the secondary infection, with no difference between these groups after infection. These data demonstrate an association of pre-existing DENV-specific memory responses with the severity of illness in subsequent DENV infection, and suggest that frequencies of DENV-reactive T cells measured after short-term culture may be of particular importance for assessing the risk for more severe dengue disease.