To investigate the nationwide severe fever with thrombocytopenia syndrome virus (SFTSV) infection status, we isolated SFTSVs from severe fever with thrombocytopenia syndrome (SFTS)-suspected patients in 207 hospitals throughout South Korea between 2013 and April of 2017. A total of 116 SFTSVs were isolated from 3,137 SFTS-suspected patients with an overall 21.6% case fatality rate. Genetic characterization revealed that at least six genotypes of SFTSVs are co-circulating in South Korea with multiple reassortments among them. Of these, the genotype B-2 strains were the most prevalent (n = 48, 36.1%) followed by the A and F genotypes. Clinical and epidemiologic investigations revealed that genotype B strains were associated with the highest case-fatality rate (34.8%, 32/92), while genotype A caused only one fatality out of ten patients. Further, ferret infection studies demonstrated varied clinical manifestations and case mortality rates of different strains of SFTSV, which suggests this virus could exhibit genotype-dependent pathogenicity.Keywords: severe fever with thrombocytopenia syndrome virus (SFTSV), clinical manifestations, genotypes, pathogenesis
Seok-Min Yun, Su-Jin Park, Young-Il Kim, Sun-Whan Park, Min-Ah Yu, Hyeok-Il Kwon, Eun-Ha Kim, Kwang-Min Yu, Hye Won Jeong, Jungsang Ryou, Won-Ja Lee, Youngmee Jee, Joo-Yeon Lee, Young Ki Choi
Influenza is a highly contagious viral pathogen with more than 200,000 cases reported in the U.S. during the 2017-2018 season. Annual vaccination is recommended by the World Health Organization with the goal to reduce influenza severity and transmission. Currently available vaccines are ~60% effective and vaccine effectiveness varies from season to season, as well as between different influenza subtypes within a single season. Immunological imprinting from early life influenza infection can prominently shape the immune response to subsequent infections. Here, the impact of pre-existing B cell memory in the response to quadrivalent influenza vaccine was assessed using blood samples collected from healthy subjects (18 to 85 years old) prior to and 21-28 days following influenza vaccination. Influenza vaccination increased both HA-specific antibodies and memory B cells frequency. Despite no apparent differences in antigenicity between vaccine components, most individuals were biased towards one of the vaccine strains. Specifically, responses to H3N2 were reduced in magnitude relative to the other vaccine components. Overall, this study unveils a new mechanism underlying differential vaccine effectiveness against distinct influenza subtypes.
Rodrigo B. Abreu, Greg A. Kirchenbaum, Emily F. Clutter, Giuseppe A. Sautto, Ted M. Ross
Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 in the Kingdom of Saudi Arabia and has caused over 2400 cases and more than 800 deaths. Epidemiological studies identified diabetes as the primary comorbidity associated with severe and/or lethal MERS-CoV infection. Understanding how diabetes affects MERS is important due to the global burden of diabetes and pandemic potential of MERS-CoV. We used a model in which mice were made susceptible to MERS-CoV by expressing human DPP4 and type 2 diabetes was induced by administering a high fat diet. Upon infection with MERS-CoV, diabetic mice had a prolonged phase of severe disease and delayed recovery which was independent of virus titers. Histological analysis revealed that diabetic mice had delayed inflammation which was then prolonged through 21 dpi. Diabetic mice had fewer inflammatory monocyte/macrophages and CD4+ T cells which correlated with lower levels of Ccl2 and Cxcl10 expression. Diabetic mice also had lower levels of Tnfa, Il6, Il12b, and Arg1 expression and higher levels of Il17a expression. These data suggest that the increased disease severity observed in individuals with MERS and comorbid type 2 diabetes is likely due to a dysregulated immune response which results in more severe and prolonged lung pathology.
Kirsten A. Kulcsar, Christopher M. Coleman, Sarah E. Beck, Matthew B. Frieman
Filoviruses of the genus Ebolavirus include five species with marked differences in their ability to cause disease in humans. From the highly virulent Ebola virus to the seemingly nonpathogenic Reston virus, case-fatality rates can range between 0-90%. In order to understand the molecular basis of these differences it is imperative to establish disease models that recapitulate human disease as faithfully as possible. Non-human primates are the gold-standard models for filovirus pathogenesis, but comparative studies are skewed by the fact that Reston virus infection can be lethal for NHP. Here we have used HLA-A2 transgenic, NOD-scid-interleukin 2γ receptor knockout (NSG-A2) mice reconstituted with human hematopoiesis to compare Ebola virus and Reston virus pathogenesis in a human-like environment. While significantly less pathogenic than Ebola virus, Reston virus killed 20% of infected mice, a finding that was linked to exacerbated inflammation and viral replication in the liver. In addition, ‘humanized’ mice recapitulated the case-fatality ratios of different Ebolavirus species in humans. Our findings point out at humanized mice as a putative model to test the pathogenicity of newly discovered filoviruses, and warrants further investigations on Reston virus pathogenesis in humans.
Beatriz Escudero-Pérez, Paula Ruibal, Monika Rottstegge, Anja Lüdtke, Julia R. Port, Kristin Hartmann, Sergio Gómez-Medina, Juergen Müller-Guhl, Emily V. Nelson, Susanne Krasemann, Estefanía Rodríguez, César Muñoz-Fontela
Nipah virus (NiV) is an emerging zoonotic paramyxovirus that causes highly lethal henipavirus encephalitis in humans. Survivors develop various neurologic sequelae, including late-onset and relapsing encephalitis, several months up to several years following initial infection. However, the underlying pathology and disease mechanisms of persistent neurologic complications remain unknown. Here, we demonstrate persistent NiV infection in the brains of grivets that survived experimental exposure to NiV. Encephalitis affected the entire brains, with the majority of NiV detected in the neurons and microglia of the brainstems, cerebral cortices, and cerebella. We identified the vascular endothelium in the brain as an initial target of NiV infection during the acute phase of disease, indicating a primary path of entry for NiV into the brain. Notably, we were unable to detect NiV anywhere else except the brains in the examined survivors. Our findings indicate that late-onset and relapsing encephalitis of NiV in human survivors may be due to viral persistence in the brain and shed light on the pathogenesis of chronic henipavirus encephalitis.
Jun Liu, Kayla M. Coffin, Sara C. Johnston, April M. Babka, Todd M. Bell, Simon Y. Long, Anna N. Honko, Jens H. Kuhn, Xiankun Zeng
The activation and recruitment of NK cells to the site of viral infection are crucial for virus control. However, it remains largely unknown what controls the recruitment of the activated NK cells to the infection site. In a model of intraperitoneal infection with vaccinia virus (VV), we showed that poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage, is critical for NK cell recruitment to the site of infection and viral control in vivo. We further demonstrated that PARP-1 promotes the production of CCL2 and that the CCL2-CCR2 axis is essential for NK cell recruitment to the infection site. In addition, we demonstrated that peritoneal macrophages are the main producer of PARP-1–dependent CCL2 secretion. Mechanistically, PARP-1 functions as a regulator of NF-κB by promoting its nuclear translocation and binding to its response sequences in macrophages upon VV infection. Taken together, our results reveal a potentially previously unknown role for PARP-1–dependent CCL2 production in NK cell migration and viral control and may provide important insights into the design of effective NK cell–based therapies for viral infections and cancer.
Qiyang Shou, Huiying Fu, Xiaopei Huang, Yiping Yang
The recent Zika virus (ZIKV) epidemic in the Americas has revealed rare but serious manifestations of infection. ZIKV has emerged in regions endemic for dengue virus (DENV), a closely related mosquito-borne flavivirus. Cross-reactive antibodies confound studies of ZIKV epidemiology and pathogenesis. The immune responses to ZIKV may be different in people, depending on their DENV immune status. Here, we focus on the human B cell and antibody response to ZIKV as a primary flavivirus infection to define the properties of neutralizing and protective antibodies generated in the absence of preexisting immunity to DENV. The plasma antibody and memory B cell response is highly ZIKV type–specific, and ZIKV-neutralizing antibodies mainly target quaternary structure epitopes on the viral envelope. To map viral epitopes targeted by protective antibodies, we isolated 2 type-specific monoclonal antibodies (mAbs) from a ZIKV case. Both mAbs were strongly neutralizing in vitro and protective in vivo. The mAbs recognize distinct epitopes centered on domains I and II of the envelope protein. We also demonstrate that the epitopes of these mAbs define antigenic regions commonly targeted by plasma antibodies in individuals from endemic and nonendemic regions who have recovered from ZIKV infections.
Matthew H. Collins, Huy A. Tu, Ciara Gimblet-Ochieng, Guei-Jiun Alice Liou, Ramesh S. Jadi, Stefan W. Metz, Ashlie Thomas, Benjamin D. McElvany, Edgar Davidson, Benjamin J. Doranz, Yaoska Reyes, Natalie M. Bowman, Sylvia Becker-Dreps, Filemón Bucardo, Helen M. Lazear, Sean A. Diehl, Aravinda M. de Silva
Incidence of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) has been increasing dramatically. Although long-term survival rates for these patients are high, they often suffer from permanent radiotherapy-related morbidity. This has prompted the development of de-escalation clinical protocols to reduce morbidity. However, a subset of patients do not respond even to standard therapy and have poor outcomes. It is unclear how to properly identify and treat the high- and low-risk HPV+ OPSCC patients. Since HPV positivity drives radiotherapy sensitivity, we hypothesized that variations in HPV biology may cause differences in treatment response and outcome. By analyzing gene expression data, we identified variations in HPV-related molecules among HPV+ OPSCC. A subset of tumors presented a molecular profile distinct from that of typical HPV+ tumors and exhibited poor treatment response, indicating molecular and clinical similarities with HPV– tumors. These molecular changes were also observed in vitro and correlated with radiation sensitivity. Finally, we developed a prognostic biomarker signature for identification of this subgroup of HPV+ OPSCC and validated it in independent cohorts of oropharyngeal and cervical carcinomas. These findings could translate to improved patient stratification for treatment deintensification and new therapeutic approaches for treatment-resistant HPV-related cancer.
Frederico O. Gleber-Netto, Xiayu Rao, Theresa Guo, Yuanxin Xi, Meng Gao, Li Shen, Kelly Erikson, Nene N. Kalu, Shuling Ren, Guorong Xu, Kathleen M. Fisch, Keiko Akagi, Tanguy Seiwert, Maura Gillison, Mitchell J. Frederick, Faye M. Johnson, Jing Wang, Jeffrey N. Myers, Joseph Califano, Heath D. Skinner, Curtis R. Pickering
BACKGROUND. The West African Ebola virus epidemic from 2014–2016 highlighted the lack of knowledge about the pathogenicity of the virus and the factors responsible for outcome. A performant and rapid diagnosis is of crucial importance, as is overcoming the difficulty of providing high-quality patient management during such an extensive outbreak. Here, we propose to study the role of the immune mediators during Ebola virus disease and to define some molecules of importance in the outcome. METHODS. Plasma from Guinean patients sampled during the outbreak were analyzed using RT-qPCR, magnetic bead assay, ELISA, and high-quality statistical analyses. We also performed a transcriptomic analysis in leukocytes samples. Therefore, we deeply characterized the immune responses involved in Ebola virus disease. RESULTS. We evaluated the immune patterns depending on the outcome of the disease. Survivors presented an efficient and well-balanced immune response, whereas fatalities were characterized by an intense inflammatory response, overexpression of multiple cytokines, and a “chemokine storm.” The plasma concentration of most of the parameters tested increased until death. Statistical analyses also allowed us to define a panel of markers highly predictive of outcome. CONCLUSION. The immune response observed in fatalities was highly similar to that characterizing septic shock syndrome. Our results suggest that immune responses can play a major pathogenic role during severe Ebola virus infection and argue in favor of therapeutic approaches that act on both viral replication and the induction of shock syndrome. FUNDING. French Ministry of Foreign Affairs, the Agence Française de Développement, and the Institut Pasteur.
Stéphanie Reynard, Alexandra Journeaux, Emilie Gloaguen, Justine Schaeffer, Hugo Varet, Natalia Pietrosemoli, Mathieu Mateo, Nicolas Baillet, Cédric Laouenan, Hervé Raoul, Jimmy Mullaert, Sylvain Baize
It is not understood how the human T cell leukemia virus human T-lymphotropic virus-1 (HTLV-1), a retrovirus, regulates the in vivo balance between transcriptional latency and reactivation. The HTLV-1 proviral plus-strand is typically transcriptionally silent in freshly isolated peripheral blood mononuclear cells from infected individuals, but after short-term ex vivo culture, there is a strong, spontaneous burst of proviral plus-strand transcription. Here, we demonstrate that proviral reactivation in freshly isolated, naturally infected primary CD4+ T cells has 3 key attributes characteristic of an immediate-early gene. Plus-strand transcription is p38-MAPK dependent and is not inhibited by protein synthesis inhibitors. Ubiquitylation of histone H2A (H2AK119ub1), a signature of polycomb repressive complex-1 (PRC1), is enriched at the latent HTLV-1 provirus, and immediate-early proviral reactivation is associated with rapid deubiquitylation of H2A at the provirus. Inhibition of deubiquitylation by the deubiquitinase (DUB) inhibitor PR619 reverses H2AK119ub1 depletion and strongly inhibits plus-strand transcription. We conclude that the HTLV-1 proviral plus-strand is regulated with characteristics of a cellular immediate-early gene, with a PRC1-dependent bivalent promoter sensitive to p38-MAPK signaling. Finally, we compare the epigenetic signatures of p38-MAPK inhibition, DUB inhibition, and glucose deprivation at the HTLV-1 provirus, and we show that these pathways act as independent checkpoints regulating proviral reactivation from latency.
Anurag Kulkarni, Graham P. Taylor, Robert J. Klose, Christopher J. Schofield, Charles R.M. Bangham
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