Reconstruction of 60 Years of Chikungunya Epidemiology in the Philippines Demonstrates Episodic and Focal Transmission

Proper understanding of the long-term epidemiology of chikungunya has been hampered by poor surveillance. Outbreak years are unpredictable and cases often misdiagnosed. Here we analyzed age-specific data from 2 serological studies (from 1973 and 2012) in Cebu, Philippines, to reconstruct both the annual probability of infection and population-level immunity over a 60-year period (1952-2012). We also explored whether seroconversions during 2012-2013 were spatially clustered. Our models identified 4 discrete outbreaks separated by an average delay of 17 years. On average, 23% (95% confidence interval [CI], 16%-37%) of the susceptible population was infected per outbreak, with \u3e 50% of the entire population remaining susceptible at any point. Participants who seroconverted during 2012-2013 were clustered at distances of \u3c 230 m, suggesting focal transmission. Large-scale outbreaks of chikungunya did not result in sustained multiyear transmission. Nevertheless, we estimate that \u3e 350,000 infections were missed by surveillance systems. Serological studies could supplement surveillance to provide important insights on pathogen circulation

Complete Genome Sequences of Zika Virus Strains Isolated from the Blood of Patients in Thailand in 2014 and the Philippines in 2012

Here, we present the complete genome sequences of two Zika virus (ZIKV) strains, Zika virus/Homo sapiens-tc/THA/2014/SV0127-14 and Zika virus/H. sapiens-tc/PHL/2012/CPC-0740, isolated from the blood of patients collected in Thailand, 2014, and the Philippines, 2012, respectively. Sequencing and phylogenetic analysis showed that both strains belong to the Asian lineage

Pathogenesis of migraine

Migraine is a common neurovascular disorder characterized by chronic episodic attacks of moderate to severe primary headache involving activation of trigeminal neurons. Despite its prevalence, the pathogenesis of migraine is not clearly understood. The pulsating nature of the headache suggests the involvement of the cranial vasculature in headache pathogenesis. However, current hypotheses emphasize the role of the trigeminal nociceptive system in the development of migraine, and other forms of primary headache. In these hypotheses, migraine pain is driven by the activation and sensitization of central trigeminal neurons driving the activation and sensitization of peripheral trigeminal neurons that innervate the meninges forming the trigeminocervical complex, which includes the caudal extension of trigeminal nucleus in the upper spinal cord. A better understanding of headache pathogenesis will pave the way for the development of more effective treatments

Upregulation of HLA-E by dengue and not Zika viruses

Introduction: The most severe form of dengue virus (DENV) illness, dengue haemorrhagic fever, is characterised by plasma leakage and increased vascular permeability. Objectives: Given the critical role that endothelial cells play in the pathogenesis of DENV, we wanted to determine whether infection with DENV altered the expression of MHC class I related genes including HLA-E. Results: In this study, we provide evidence that HLA-E but not MICA/B or HLA-G is upregulated by all four serotypes of DENV in an endothelial cell line human microvascular endothelial cells (HMEC)-1. In contrast, Zika virus (ZIKV), a related flavivirus, where plasma leakage is not a major manifestation of disease, did not upregulate HLA-E. We found modest levels of soluble HLA-E in supernatants from DENV but not ZIKV-infected cells. Coculture experiments found minimal activation of natural killer (NK) cells in the presence of both uninfected and infected HMEC-1 cells. HLA-E induced by DENV infection could not dampen the degranulation of activated NK cells by interacting with its ligand NKG2a. Conclusions: Our results suggest that while DENV infection induces HLA-E, the high MHC class I expression on uninfected and infected HMEC-1 cells may dominate the diverse signals generated between inhibitory and activating receptors on NK cells and ligands on target cells

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

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 ex-vivo and cultured ELISPOT assays to further evaluate the associations between DENV serotype-cross-reactive memory T cells and severity of secondary infection. Using ex-vivo 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

Protection from arthritis and myositis in a mouse model of acute chikungunya virus disease by bindarit, an inhibitor of monocyte chemotactic protein-1 synthesis

Chikungunya virus (CHIKV) is associated with outbreaks of infectious rheumatic disease in humans. Using a mouse model of CHIKV arthritis and myositis, we show that tumor necrosis factor-α, interferon-γ, and monocyte chemotactic protein 1 (MCP-1) were dramatically induced in tissues from infected mice. The same factors were detected in the serum of patients with CHIKV-induced polyarthralgia and polyarthritis, with MCP-1 levels being particularly elevated. Bindarit (MCP inhibitor) treatment ameliorated CHIKV disease in mice. Histological analysis of muscle and joint tissues showed a reduction in inflammatory infiltrate in infectedmice treated with bindarit. These results suggest that bindarit may be useful in treating CHIKV-induced arthritides in humans.Facultad de Ciencias Exacta

Protection from arthritis and myositis in a mouse model of acute chikungunya virus disease by bindarit, an inhibitor of monocyte chemotactic protein-1 synthesis

Chikungunya virus (CHIKV) is associated with outbreaks of infectious rheumatic disease in humans. Using a mouse model of CHIKV arthritis and myositis, we show that tumor necrosis factor-α, interferon-γ, and monocyte chemotactic protein 1 (MCP-1) were dramatically induced in tissues from infected mice. The same factors were detected in the serum of patients with CHIKV-induced polyarthralgia and polyarthritis, with MCP-1 levels being particularly elevated. Bindarit (MCP inhibitor) treatment ameliorated CHIKV disease in mice. Histological analysis of muscle and joint tissues showed a reduction in inflammatory infiltrate in infectedmice treated with bindarit. These results suggest that bindarit may be useful in treating CHIKV-induced arthritides in humans.Facultad de Ciencias Exacta