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Hantaan virus (HTNV) infection causes an epidemic of hemorrhagic fever with renal syndrome (HFRS) mainly in Asia. Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes known to play an important role in innate host defense during virus infection. However, their roles and phenotypes during HTNV infection have not yet been explored. We characterized CD8+MAIT cells from HFRS patients based on scRNA-seq data combined with flow cytometry data. We showed that HTNV infection caused the loss and activation of CD8+MAIT cells in the peripheral blood, which were correlated with disease severity. The production of granzyme B and IFN-γ from CD8+MAIT cells and the limitation of HTNV replication in endothelia cells indicated the anti-viral property of CD8+MAIT cells. In addition, in vitro infection of MAIT cells by HTNV or HTNV-exposed monocytes showed that the activation of MAIT cells was IL-18 mediated. In conclusion, this study identified, for the first time, gene expression profiles of MAIT cells, provided underlying molecular mechanisms for activation of MAIT cells during HTNV infection, and suggested a potential anti-viral role of MAIT cells in HFRS. HTNV infection caused the activation and deficiency of MAIT cells in the peripheral blood. The production of IFN-γ from MAIT cells can limit the replication of HTNV. The activation of MAIT cells was mediated by IL-18, which was sourced from monocytes infected by HTNV. [ABSTRACT FROM AUTHOR]

Hantaan virus (HTNV) infection causes an epidemic of hemorrhagic fever with renal syndrome (HFRS) mainly in Asia. It is well known that T cells mediated anti-viral immune response. Although previous studies showed that double positive T (DP T) cells, a little portion of T lymphocytes, were involved in adaptive immune response during virus infection, their kinetic changes and roles in HTNV infection have not yet been explored. In this study, we characterized DP T cells from HFRS patients based on flow cytometry data combined with scRNA-seq data. We showed that HTNV infection caused the upregulation of DP T cells in the peripheral blood, which were correlated with disease stage. The scRNA-seq data clustered DP T cells, unraveled their gene expression profile, and estimated the ordering of these cells. The production of granzyme B and CD107a from DP T cells and the abundant TCR distribution indicated the anti-viral property of DP T cells. In conclusion, this study identified, for the first time, an accumulation of DP T cells in the peripheral blood of HFRS patients and suggested these DP T cells belonging to CD8+T cells lineage. The DP T cells shared the similar characteristics with cytotoxic T cells (CTL) and exerted an anti-viral role in HFRS. [ABSTRACT FROM AUTHOR]

ABSTRACT Wind chill temperature ( WCT) describes the joint effect of wind velocity and air temperature on exposed body skin and could support policymakers in designing plans to reduce the risks of notably cold and windy weather. This study examined winter WCT over Northern Asia during 1973-2013 by analysing in situ station data. The winter WCT warming rate over the Tibetan Plateau ( TP) slowed during 1999-2013 (−0.04 °C decade−1) compared with that of during 1973-1998 (0.67 °C decade−1). The winter WCT warming hiatus has also been observed in the remainder of Northern Asia with trends of 1.11 °C decade−1 during 1973-1998 but −1.02 °C decade−1 during 1999-2013, except for the Far East ( FE) of Russia, where the winter WCT has continued to heat up during both the earlier period of 1973-1998 (0.54 °C decade−1) and the recent period of 1999-2013 (0.75 °C decade−1). The results indicate that the influence of temperature on winter WCT is greater than that of wind speed over Northern Asia. Atmospheric circulation changes associated with air temperature and wind speed were analysed to identify the causes for the warming hiatus of winter WCT over Northern Asia. The distributions of sea-level pressure and 500- hPa height anomalies during 1999-2013 transported cold air from the high latitudes to middle latitudes, resulting in low air temperature over Northern Asia except for the FE of Russia. Over the TP, the increase in wind speed offset the increase in air temperature during 1999-2013. For the FE, the southerly wind from the Western Pacific drove the temperature up during the 1999-2013 period through warm advection. [ABSTRACT FROM AUTHOR]

Background: Hantaan virus (HTNV) causes a severe lethal haemorrhagic fever with renal syndrome (HFRS) in humans. Despite a limited understanding of the pathogenesis of HFRS, the importance of the abundant production of pro-inflammatory cytokines has been widely recognized. Interleukin 33 (IL-33) has been demonstrated to play an important role in physiological and pathological immune responses. After binding to its receptor ST2L, IL-33 stimulates the Th2-type immune response and promotes cytokine production. Depending on the disease model, IL-33 either protects against infection or exacerbates inflammatory disease, but it is unknown how the IL-33/ST2 axis regulates the immune response during HTNV infection. Methodology/Principal Findings: Blood samples were collected from 23 hospitalized patients and 28 healthy controls. The levels of IL-33 and soluble ST2 (sST2) in plasma were quantified by ELISA, and the relationship between IL-33, sST2 and the disease severity was analyzed. The role of IL-33/sST2 axis in the production of pro-inflammatory cytokines was studied on HTNV-infected endothelial cells. The results showed that the plasma IL-33 and sST2 were significantly higher in patients than in healthy controls. Spearman analysis showed that elevated IL-33 and sST2 levels were positively correlated with white blood cell count and viral load, while negatively correlated with platelet count. Furthermore, we found that IL-33 enhanced the production of pro-inflammatory cytokines in HTNV-infected endothelial cells through NF-κB pathway and that this process was inhibited by the recombinant sST2. Conclusion/Significance: Our results indicate that the IL-33 acts as an initiator of the "cytokine storm" during HTNV infection, while sST2 can inhibit this process. Our findings could provide a promising immunotherapeutic target for the disease control. Author Summary: Hantaan virus (HTNV) causes human hemorrhagic fever with renal syndrome (HFRS) with a mortality rate of approximately 15% in Asia. At present, the primary treatment for HFRS is limited to critical care management and the use of anti-viral drugs, such as Ribavirin. However, the cytokine storm at the acute phase of HFRS, which is thought to contribute to the development of the disease, is still lacking an effective way to prevent. An alternative way to prevent the development of cytokine storm is of priority to overcome the problem. We found that IL-33 and sST2 levels were higher in the plasma of HFRS patients, especially in their acute phase. Although both of them were positively correlated with the severity of the diseases, they acted in different roles in the regulation of the immune response during HTNV infection. In vitro study showed that IL-33 acted as an initiator of the cytokine storm in HTNV-infected endothelial cells, while sST2 acted as an inhibitor of the process. For the first time, we defined the IL-33/ST2 axis as inflammatory regulators during HTNV infection. Our results may provide a novel therapeutic target of HTNV infections. [ABSTRACT FROM AUTHOR]

Background: Hantaan virus (HTNV) infection in humans is a serious public health concern in Asia. A potent T cell activation peptide vaccine from HTNV structure protein represents a promising immunotherapy for disease control. However, the T cell epitopes of the HTNV restricted by the HLA alleles and the role of epitope-specific T cell response after HTNV infection remain largely unexplored. Methodology/Principal Findings: Five well-conserved novel CD8+ T-cell epitopes of the HTNV nucleoprotein restricted by the most popular HLA alleles in Chinese Han population were defined with interferon-γ enzyme-linked immunospot assay in 37 patients infected with HTNV during hospitalization. Two epitopes aa129–aa137 and aa131–aa139 restricted by HLA-A2 and B35, respectively, were selected to evaluate the epitope-specific CD8+ T-cell response. HLA-peptide pentamer complex staining showed that the frequency of single epitope-specific CD8+ T cell could be detected in patients (95% confidence interval for aa129–aa137: 0.080%–0.208%; for aa131–aa139: 0.030%–0.094%). The frequency of epitope-specific pentamer+ CD8+ T-cell response was much higher in mild/moderate patients than in severe/critical ones at the acute stage of the disease. Moreover, the frequency of epitope-specific CD8+ T cells at acute stage was inversely associated with the peak level of serum creatinine and was positively associated with the nadir platelet counts during the hospitalization. The intracellular cytokine staining and the proliferation assay showed that the effective epitope-specific CD8+ T cells were characterized with the production of interferon-γ, expression of CD69 and the strong capacity of proliferation. Conclusion/Significance: The novel HLA class I restricted HTNV nucleoprotein epitopes-specific CD8+ T-cell responses would be closely related with the progression and the severity of the disease, which could provide the first step toward effective peptide vaccine development against HTNV infection in humans. Author Summary: Hantaan virus (HTNV), the prototype of the Hantavirus genus, is a rodent-borne pathogen that causes human hemorrhagic fever with renal syndrome (HFRS) with a mortality rate of approximately 15% in Asia. Since effective prevention is not available currently and the non-specific symptoms at the early stage of the disease always lead to the delay of visiting to hospital or misdiagnosis, alternative vaccinations against HTNV are of priority to overcome the problem. We defined five novel HTNV nucleoprotein CD8+ T-cell epitopes restricted by the most popular HLA alleles in Chinese Han population. For the first time, we quantitated the HTNV epitope-specific CD8+ T-cell frequency during HTNV infection and evaluated the correlations between the CD8+ T-cell response and the different outcomes of the HFRS severity. We also found that effective HTNV nucleoprotein epitope-specific CD8+ T-cell responses were characterized by the interferon-γ secretion with a strong capacity of activation and proliferation. Our results add weight to understanding the important role of epitope-specific CD8+ T-cell responses in the disease control after acute zoonotic HTNV infections in humans and provide a rationale foundation to speed up the process of peptide vaccine development. [ABSTRACT FROM AUTHOR]

Novel strains of influenza A viruses (IAVs) have emerged with high infectivity and/or pathogenicity in recent years, causing worldwide concern. T cells are correlated with protection in humans through cross-reactive immunity against heterosubtypes of IAV. However, the different hierarchical roles of IAV-derived epitopes with distinct levels of polymorphism in the cross-reactive T-cell responses against IAV remain elusive. In this study, immunodominant epitopes scattered throughout the entire proteome of 2009 pandemic influenza A H1N1 virus and seasonal IAVs were synthesized and divided into different pools depending on their conservation. The overall profile of the IAV-specific CD8(+) T-cell immunity was detected by utilizing these peptide pools and also individual peptides. A dominant role of the conserved peptide-specific T-cell immunity was illuminated within the anti-IAV responses, while the CD8(+) T-cell responses against the variable epitopes were lower than the conserved peptides. As previously demonstrated within a Caucasian population, we determined that GL9-specific T cells, which also utilize Vβ 17 TCR (BV19), play a pivotal role in IAV-specific T-cell immunity within an HLA-A2(+) Asian population. Our study objectively reveals the different predominant roles of T-cell epitopes among IAV-specific cross-reactive cellular immunity. This may guide the development of vaccines with cross-T-cell immunogenicity against heterosubtypes of IAV., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)