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Background: Hemorrhagic fever with renal syndrome (HFRS), a life-threatening zoonosis caused by hantavirus, poses significant mortality risks and lacks specific treatments. This study aimed to delineate the transcriptomic alterations during the recovery phases of HFRS. Methods: RNA sequencing was employed to analyze the transcriptomic alterations in peripheral blood mononuclear cells from HFRS patients across the oliguric phase (OP), diuretic phase (DP), and convalescent phase (CP). Twelve differentially expressed genes (DEGs) were validated using quantitative real-time PCR in larger sample sets. Results: Our analysis revealed pronounced transcriptomic differences between DP and OP, with 38 DEGs showing consistent expression changes across all three phases. Notably, immune checkpoint genes like CD83 and NR4A1 demonstrated a monotonic increase, in contrast to a monotonic decrease observed in antiviral and immunomodulatory genes, including IFI27 and RNASE2. Furthermore, this research elucidates a sustained attenuation of immune responses across three phases, alongside an upregulation of pathways related to tissue repair and regeneration. Conclusion: Our research reveals the transcriptomic shifts during the recovery phases of HFRS, illuminating key genes and pathways that may serve as biomarkers for disease progression and recovery. [ABSTRACT FROM AUTHOR]

Background: Hemorrhagic fever with renal syndrome (HFRS) is a severe public health problem in Jiangxi province, China. Previous studies reported genetic variants of Orthohantavirus hantanense (Hantaan virus, HTNV) in rodents in this area. However, the relationship between HTNV variants and human infection needs to be confirmed. This study aimed to identify the HTNV variants in patients and to understand the clinical characteristics of HFRS caused by these variants. Methods: Samples were collected from hospitalized suspected cases of HFRS during the acute phase. HFRS cases were confirmed using quantitative real-time RT-PCR. Peripheral blood mononuclear cells (PBMC) from patients with HFRS were inoculated into Vero-E6 cells for viral isolation. The genomic sequences of HTNV from patients were obtained by amplicon-based next-generation sequencing. A retrospective analysis was conducted on the clinical characteristics of the patients. Results: HTNV RNA was detected in 53 of 183 suspected HFRS patients. Thirteen HTNVs were isolated from 32 PBMCs of HFRS cases. Whole genome sequences of 14 HTNVs were obtained, including 13 isolates in cell culture from 13 patients, and one from plasma of the fatal case which was not isolated successfully in cell culture. Genetic analysis revealed that the HTNV sequence from the 14 patients showed significant variations in nucleotide and amino acid to the HTNV strains found in other areas. Fever (100%, 53/53), thrombocytopenia (100%, 53/53), increased serum aspartate aminotransferase (100%, 53/53), and increased lactate dehydrogenase (96.2%, 51/53) were the most common characteristics. Severe acute kidney injury was observed in 13.2% (7/53) of cases. Clinical symptoms, such as pain, petechiae, and gastrointestinal or respiratory symptoms were uncommon. Conclusion: The HTNV genetic variants cause human infections in Jiangxi. The clinical symptoms of HFRS caused by the HTNV genetic variant during the acute phase are atypical. In addition to renal dysfunction, attention should be paid to the common liver injuries caused by these genetic variants. Author summary: HTNV causes severe HFRS in Eastern Asia. Previous studies reported genetic variants or new genotypes of HTNV in animals in South Korea and many parts of China. However, little is known about the clinical characteristics of patients infected by the HTNV variant, because it is difficult to isolate HTNV from patients, and few HTNV variants were confirmed from patients. In this study, we use PBMC from patient to coculture with Vero-E6 cells and a 28-day passage isolation protocol for vial isolation, 13 HTNVs were successfully isolated from patients with a recovery rate of over 40%. We also established an amplicon-based next-generation sequencing method for HTNV whole gene sequencing and whole genome sequences of HTNVs from 14 patients were obtained. Genetic analysis revealed that the complete sequences from the patients showed significant variations in nucleotide and amino acid to the HTNVs found in other areas. Viral isolation and whole genome sequencing confirm that the HTNV variant causes human infection in Jiangxi province. The clinical symptoms of HFRS caused by the HTNV genetic variant during the acute phase are atypical, and laboratory diagnoses are needed. These results provide useful guidance for orthohantaviruses isolation from clinical cases and are important for HFRS diagnosis in clinical practice. [ABSTRACT FROM AUTHOR]

Hemorrhagic fever with renal syndrome caused by hantaviruses has long been a serious public health issue in Yunnan Province. Hantaviruses exhibit a high extent of biodiversity in their natural hosts, particularly in mammalian hosts. This study was conducted to screen for hantaviruses in bats and rodents in Yunnan Province and elucidate their genetic characteristics and possible zoonotic disease risk. Hantaviruses were detected in 202 bats and 372 rodents with the positive rates 27.49% and 1.25% respectively. A novel lineage (named Lineage 10) of the Seoul virus (SEOV) from rodents and the geographic clustering of hantavirus in bats were identified using phylogenetic analyses of the full-length M- and S-segments. Our study suggest a high cross-species transmissibility of hantaviruses in bats and existence of a new lineage of SEOV in rodents differing significantly from other SEOVs. These results provide data to support the prevention and control of hantavirus-associated diseases in Yunnan Province. Author summary: Hantavirus is an important pathogen that can cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). HFRS has long been a serious public health problem in Yunnan Province. However, the molecular epidemiology and host characteristics of hantavirus in Yunnan Province are still unclear. Therefore, we screened hantaviruses in bats and rodents in selected areas of Yunnan from 2018 to 2022 and found the 10th SEOV lineage in rodents, as well as new geographic clusters of Xuan son virus (XSV) and novel hantavirus in bats. We proposed the possibility of the 10th SEOV lineage in rodents as an ancestral lineage and explained the related host-switching events in bat hantaviruses. These results provide data to reveal a greater risk of zoonotic disease and support the prevention and control of hantavirus-associated diseases and in Yunnan Province. [ABSTRACT FROM AUTHOR]

Objective: We here displayed the global research trends of meteorology and hemorrhagic fever with renal syndrome (HFRS) as a visual knowledge map by using bibliometrics and revealed the research directions, hotspots, trends, and frontiers in this field. Methods: Using Web of Science core collection as the data source and with CiteSpace and VOSviewer software, we collected and analyzed the annual number of papers, cooperative relationships (countries, institutions, authors, etc.), citations (literature citation, literature co-citation, literature publication, etc.), keywords (emergence, clustering, etc.) of meteorology, and HFRSrelated research data for the past 30 years, and drew a visual map. Results: In total, this study included 313 papers investigating the relationship between meteorology and HFRS. The first paper was published in 1992. Globally, United States had the largest number of publications in this field, and the Chinese Center for Disease Control and Prevention was the most influential institution conducting related research (20 articles published, and the mediation centrality was 0.24). Several small author cooperation clusters were formed; however, the number of papers published by the same scholar and the co-citation frequency were low. Cazelles Bernard (7 articles) published the highest number of articles in this field, and Gubler DJ was the author with the most co-citations (55 times). The most frequently cited journal was Emerging Infectious Diseases. In this field, the top three high-frequency keywords were "hemorrhagic fever," "transmission," and "temperature." According to keyword cluster analysis, the top three themes were dengue, dechlorane plus, and bank voles. The timeline spectrum exhibited that dengue clustering had a good temporal continuity. The trend analysis of emergent words revealed that the research on "temperature," "meteorological factors" and "Puumala hantavirus" has gradually appeared in recent years. Conclusion: This study represents the first comprehensive exploration of global trends, hotspots, frontiers, and developments in the relationship between meteorology and HFRS, utilizing CiteSpace and VOSviewer software. The findings of this study are crucial for elucidating the influence of climate change on disease transmission patterns and offering novel insights for forthcoming epidemiological research and public health interventions. [ABSTRACT FROM AUTHOR]

Hemorrhagic fever with renal syndrome (HFRS) and tick-borne encephalitis (TBE) are the most common viral diseases in Russia. HFRS is caused by six different types of hantaviruses: Hantaan, Amur, Seoul, Puumala, Kurkino, and Sochi, which are transmitted to humans through small mammals of the Muridae and Cricetidae families. TBE is caused by viruses belonging to five different phylogenetic subtypes. The similarities in the ecology of HFRS and TBE pathogens is presented here. Hantavirus-infected small mammals can transmit the virus to uninfected animals, and ticks can also transmit hantavirus to other ticks and mammals. Hantavirus transmission from ticks to humans is possible only hypothetically based on indirect data. Over the past 23 years, 164,582 cases of HFRS (4.9 per 105 people) and 71,579 cases of TBE (2.5 per 105 people) were registered in Russia. The mortality rate was 0.4% (668 cases) in HFRS and 1.6% deaths (1136 cases) in TBE. There were 4030 HFRS (2.5%) and 9414 TBE (13%) cases in children under 14 years old. HFRS and TBE cases were registered in 42 out of 85 Russian regions; in 18—only HFRS, in 13—only TBE, and 12 had no reported cases. The prospects of applying a combined vaccine for HFRS and TBE prevention are shown in this paper. [ABSTRACT FROM AUTHOR]

Aim s : Haemorrhagic fever with renal syndrome (HFRS) is a significant zoonotic disease transmitted by rodents. The distribution of HFRS in the European part of Russia has been studied quite well; however, much less is known about the endemic area in the Russian Far East. The mutual influence of the epidemic situation in the border regions and the possibility of cross‐border transmission of infection remain poorly understood. This study aims to identify the spatiotemporal hot spots of the incidence and the impact of environmental drivers on the HFRS distribution in the Russian Far East. Methods and Results: A two‐scale study design was performed. Kulldorf's spatial scan statistic was used to conduct spatiotemporal analysis at a regional scale from 2000 to 2020. In addition, an ecological niche model based on maximum entropy was applied to analyse the contribution of various factors and identify spatial favourability at the local scale. One spatiotemporal cluster that existed from 2002 to 2011 and located in the border area and one pure temporal cluster from 2004 to 2007 were revealed. The best suitability for orthohantavirus persistence was found along rivers, including those at the Chinese–Russian border, and was mainly explained by land cover, NDVI (as an indicator of vegetation density and greenness) and elevation. Conclusions: Despite the stable incidence in recent years in, targeted prevention strategies are still needed due to the high potential for HRFS distribution in the southeast of the Russian Far East. [ABSTRACT FROM AUTHOR]

Objective: To investigate the epidemic factors of hemorrhagic fever with renal syndrome (HFRS) and compare the S and M gene sequences of hantavirus (HV) between rodents and the infected cases. Methods: Detailed epidemiological investigations were conducted on the cases' working and living areas. Captured rodents were classified by night trapping method, and their lungs and blood were collected for virus carriage detection after aseptic dissection. Viral S and M fragments of HV RNA were amplified and sequenced from positive samples of cases and mice, and their homology was analyzed. Results: After reconstruction, the geographic and living environment changed significantly, altering rodent behaviors. The industrial park, characterized by high population density, poor living conditions, and frequent contact of rodent (feces) and humans, had a high rodent density and HV virus infection ratio. Four workers infected with HV were positive for anti-HV immunoglobulin G (IgG) and IgM. Among the positive samples, HV RNA was detected in all two cases, and four Rattus norvegicus specimens were Seoul type HV S3 subtype. The virus had the closest relationship with Rod/2012/QHD/4/Gc (Hebei, China) and RuianRn180 (Zhejiang, China), with the 100% homology of M gene segment. The homology of viral S gene segment exhibited the closest relationship with the Jiangxi isolated JiangxiXinjianRn-09–2011, ranging from 99.6% to 99.8%. Conclusion: The HV sequencing showed a strong epidemiological relationship between the cases and host rodents. Improving living environmental health conditions, administering HFRS vaccine, and reducing rodent density and human–rodent contact can mitigate the risk of HFRS. [ABSTRACT FROM AUTHOR]

Both Old World and New World hantaviruses are transmitted through rodents and can lead to hemorrhagic fever with renal syndrome or hantavirus cardiopulmonary syndrome in humans without the availability of specific therapeutics. The square-shaped surface spikes of hantaviruses consist of four Gn-Gc heterodimers that are pivotal for viral entry into host cells and serve as targets for the immune system. Previously, a human-derived neutralizing monoclonal antibody, AH100, demonstrated specific neutralization against the Old World hantavirus, Hantaan virus. However, the precise mode binding of this neutralizing monoclonal antibody remains unclear. In the present study, we determined the structure of the Hantaan virus Gn-AH100 antigenbinding fragment complex and identified its epitope. Crystallography revealed that AH100 targeted the epitopes on domain A and b-ribbon and E3-like domain. Epitope mapping onto a model of the higher order (Gn-Gc)4 spike revealed its localization between neighboring Gn protomers, distinguishing this epitope as a unique site compared to the previously reported monoclonal antibodies. This study provides crucial insights into the structural basis of hantavirus neutralizing antibody epitopes, thereby facilitating the development of therapeutic antibodies. IMPORTANCE Hantaan virus (HTNV) poses a significant threat to humans by causing hemorrhagic fever with renal syndrome with high mortality rates. In the absence of FDA-approved drugs or vaccines, it is urgent to develop specific therapeutics. Here, we elucidated the epitope of a human-derived neutralizing antibody, AH100, by determining the HTNV glycoprotein Gn-AH100 antigen-binding fragment (Fab) complex structure. Our findings revealed that the epitopes situated on the domain A and b-ribbon and E3-like domain of the HTNV Gn head. By modeling the complex structure in the viral lattice, we propose that AH100 neutralizes the virus by impeding conformational changes of Gn protomer, which is crucial for viral entry. Additionally, sequence analysis of all reported natural isolates indicated the absence of mutations in epitope residues, suggesting the potential neutralization ability of AH100 in diverse isolates. Therefore, our results provide novel insights into the epitope and the molecular basis of AH100 neutralization. [ABSTRACT FROM AUTHOR]

Hemorrhagic fever with renal syndrome (HFRS) and severe fever with thrombocytopenia syndrome (SFTS) are both endemic in rural areas and some characteristics are similar between HFRS and SFTS, which usually lead to misdiagnosis. In this study, we summarized and compared some characteristics of HFRS and SFTS which will provide scientific information for differential diagnosis. From 2011 to 2022, a total of 4336 HFRS cases and 737 SFTS cases were reported in Zhejiang Province. Compared to SFTS, there was a higher proportion of males among HFRS cases (72.46% [3142/4336] vs. 50.88% [375/737], p = 0.000). The median age of all 4336 HFRS cases was 49 (39, 59), while the median age of SFTS cases was 66 (57, 74). In addition, the involved counties of HFRS were more than SFTS, but the number of counties affected by SFTS increased from 2011 to 2022. The majority of SFTS cases occurred in summer (from May to July), but besides summer, HFRS cases also showed a peak in winter. Finally, our results showed that the case fatality rate of SFTS was significantly higher than that of HFRS. Although there were some similarities between HFRS and SFTS, our study found several differences between them, such as gender distribution, age distribution, and seasonal distribution, which will provide scientific information for differential diagnosis of HFRS and SFTS. Further studies should be carried out to explore the mechanism of these differences. [ABSTRACT FROM AUTHOR]

Hemorrhagic fever with renal syndrome (HFRS) induced by Eurasian pathogenic orthohantaviruses is characterized by acute kidney injury (AKI) with often massive proteinuria. The mechanisms of the organ-specific manifestation are not completely understood. To analyze the role of glomerular and tubular damage in kidney injury induced by HFRS, we measured specific markers in urine samples of patients with acute Puumala virus (PUUV) infection and determined their correlation with disease severity. Levels of α1-microglobulin (α1-MG) and kidney injury molecule 1 (KIM-1), which is expressed by injured tubular epithelial cells, were measured to detect tubular dysfunction and injury. Immunoglobulin G (IgG) and the podocyte specific protein nephrin served as markers for glomerular injury. All four markers were elevated on admission. Markers of glomerular injury, IgG and nephrin, correlated with markers of disease severity such as length of hospitalization, serum creatinine, and proteinuria. In contrast, tubular injury did not correlate with these severity markers. Our results demonstrate that hantavirus infection induces both glomerular and tubular injury early in the clinical course. However, the glomerular dysfunction and podocyte injury seem to contribute directly to disease severity and to play a more central role in HFRS pathogenicity than direct damage to tubular epithelial cells. [ABSTRACT FROM AUTHOR]

Hantaviruses cause the acute zoonotic diseases hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Infected patients show strong systemic inflammation and immune cell activation. NK cells are highly activated in HFRS, suggesting that also other innate lymphoid cells (ILCs) might be responding to infection. Here, we characterized peripheral ILC responses, and measured plasma levels of soluble factors and plasma viral load, in 17 Puumala virus (PUUV)-infected HFRS patients. This revealed an increased frequency of ILC2 in patients, in particular the ILC2 lineage-committed c-Kitlo ILC2 subset. Patients' ILCs showed an activated profile with increased proliferation and displayed altered expression of several homing markers. How ILCs are activated during viral infection is largely unknown. When analyzing PUUV-mediated activation of ILCs in vitro we observed that this was dependent on type I interferons, suggesting a role for type I interferons—produced in response to virus infection–in the activation of ILCs. Further, stimulation of naïve ILC2s with IFN-β affected ILC2 cytokine responses in vitro, causing decreased IL-5 and IL-13, and increased IL-10, CXCL10, and GM-CSF secretion. These results show that ILCs are activated in HFRS patients and suggest that the classical antiviral type I IFNs are involved in shaping ILC functions. Author summary: Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) are acute zoonotic diseases caused by orthohantaviruses. Hantavirus initially infect the lung and then spread systemically, primarily infecting endothelial cells. The innate lymphoid cell (ILC) family consists of ILC1, ILC2, ILC3, and natural killer (NK) cells. While NK cells are well studied in viral infections, less is known regarding the other ILCs. Hantavirus-infected patients show highly activated immune cells, including NK cells, indicating that also other innate lymphoid cells (ILCs) might be affected. We discovered that Puumala virus (PUUV)-infected HFRS patients show increased frequency of ILC2s in circulation, and that ILCs are activated with an altered homing receptor expression pattern. Little is known regarding how ILCs are activated during viral infection. When analyzing, in vitro, for mechanisms behind activation we observed a PUUV-induced type I IFN-dependent activation of ILCs and that IFN-β affects ILC2 cytokine responses. These findings suggest that ILC functions are affected by classical antiviral type I IFNs. [ABSTRACT FROM AUTHOR]

Hantaviruses are single-stranded RNA viruses belonging to the family Bunyaviridae that causes hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS) worldwide. Currently, there is no effective vaccination or therapy available for the treatment of hantavirus, hence there is a dire need for research to formulate therapeutics for the disease. Computational vaccine designing is currently a highly accurate, time and cost-effective approach for designing effective vaccines against different diseases. In the current study, we shortlisted highly antigenic proteins i.e., envelope, and nucleoprotein from the proteome of hantavirus and subjected to the selection of highly antigenic epitopes to design of next-generation multi-epitope vaccine constructs. A highly antigenic and stable adjuvant was attached to the immune epitopes (T-cell, B-cell, and HTL) to design Env-Vac, NP-Vac, and Com-Vac constructs, which exhibit stronger antigenic, non-allergenic, and favorable physiochemical properties. Moreover, the 3D structures were predicted and docking analysis revealed robust interactions with the human Toll-like receptor 3 (TLR3) to initiate the immune cascade. The total free energy calculated for Env-Vac, NP-Vac, and Com-Vac was -50.02 kcal/mol, -24.13 kcal/mol, and -62.30 kcal/mol, respectively. In silico cloning, results demonstrated a CAI value for the Env-Vac, NP-Vac, and Com-Vac of 0.957, 0.954, and 0.956, respectively, while their corresponding GC contents were 65.1%, 64.0%, and 63.6%. In addition, the immune simulation results from three doses of shots released significant levels of IgG, IgM, interleukins, and cytokines, as well as antigen clearance over time, after receiving the vaccine and two booster doses. Our vaccines against Hantavirus were found to be highly immunogenic, inducing a robust immune response that demands experimental validation for clinical usage. [ABSTRACT FROM AUTHOR]

Central China has been reported to be one of the most important endemic areas of zoonotic infection by spotted fever group rickettsiae (SFGR), severe fever with thrombocytopenia syndrome virus (SFTSV) and hantaan virus (HTNV). Due to similar clinical symptoms, it is challenging to make a definite diagnosis rapidly and accurately in the absence of microbiological tests. In the present study, an all-in-one real-time PCR assay was developed for the simultaneous detection of nucleic acids from SFGR, SFTSV and HTNV. Three linear standard curves for determining SFGR-ompA, SFTSV-L and HTNV-L were obtained within the range of 101−106 copies/μL, with the PCR amplification efficiencies ranging from 93.46% to 96.88% and the regression coefficients R2 of >0.99. The detection limit was 1.108 copies/μL for SFGR-ompA, 1.075 copies/μL for SFTSV-L and 1.006 copies/μL for HTNV-L, respectively. Both the within-run and within-laboratory coefficients of variation on the cycle threshold (Ct) values were within the range of 0.53%-2.15%. It was also found there was no statistical difference in the Ct values between single template and multiple templates (PSFGR-ompA = 0.186, PSFTSV-L = 0.612, PHTNV-L = 0.298). The sensitivity, specificity, positive and negative predictive value were all 100% for determining SFGR-ompA and SFTSV-L, 97%, 100%, 100% and 99.6% for HTNV-L, respectively. Therefore, the all-in-one real-time PCR assay appears to be a reliable, sensitive, rapid, high-throughput and low cost-effective method to diagnose the zoonotic infection by SFGR, SFTSV and HTNV. Author summary: Spotted fever (SF), severe fever with thrombocytopenia syndrome (SFTS), and hemorrhagic fever with renal syndrome (HFRS) sporadically have outbreaks in central China. Due to the similarities in clinical symptoms and the absence of reliable diagnostic methods for the detection these pathogens simultaneously, clinical diagnosis and treatment frequently result in misdiagnosis or missed diagnosis. Thus, the development of a fast and accurate diagnostic method is crucial for prevention and precise treatment. In this study, we designed an all-in-one real-time PCR assay to differentiate spotted fever group rickettsiae (SFGR), severe fever with thrombocytopenia syndrome virus (SFTSV) and hantaan virus (HTNV). The ompA gene of SFGR, as well as the segment L of SFTSV and HTNV, were used as targets to design primers and probes for amplification. Through the verification of nucleic acid and clinical sample detection, the sensitivity of this detection method exceeded 97%, and its specificity was 100%. This new assay could be applied in epidemiology and clinical diagnosis, to control new outbreaks, reduce diagnostic and identification time, and improve test efficiency. [ABSTRACT FROM AUTHOR]

Puumala orthohantavirus-caused hemorrhagic fever with renal syndrome (PUUVHFRS) is characterized by strong neutrophil activation. Neutrophils are the most abundant immune cell type in the circulation and are specially equipped to rapidly respond to infections. They are more heterogenous than previously appreciated, with specific neutrophil subsets recently implicated in inflammation and immunosuppression. Furthermore, neutrophils can be divided based on their density to either low-density granulocytes (LDGs) or "normal density" polymorphonuclear cell (PMN) fractions. In the current study we aimed to identify and characterize the different neutrophil subsets in the circulation of PUUV-HFRS patients. PMNs exhibited an activation of antiviral pathways, while circulating LDGs were increased in frequency following acute PUUV-HFRS. Furthermore, cell surface marker expression analysis revealed that PUUV-associated LDGs are primarily immature and most likely reflect an increased neutrophil production from the bone marrow. Interestingly, both the frequency of LDGs and the presence of a "left shift" in blood associated with the extent of thrombocytopenia, one of the hallmarks of severe HFRS, suggesting that maturing neutrophils could play a role in disease pathogenesis. These results imply that elevated circulating LDGs might be a general finding in acute viral infections. However, in contrast to the COVID-19 associated LDGs described previously, the secretome of PUUV LDGs did not show significant immunosuppressive ability, which suggests inherent biological differences in the LDG responses that can be dependent on the causative virus or differing infection kinetics. [ABSTRACT FROM AUTHOR]

Puumala orthohantavirus (PUUV) is an emerging zoonotic virus endemic to Europe and Russia that causes nephropathia epidemica, a mild form of hemorrhagic fever with renal syndrome (HFRS). There are limited options for treatment and diagnosis of orthohantavirus infection, making the search for potential immunogenic candidates crucial. In the present work, various bioinformatics tools were employed to design conserved immunogenic peptides containing multiple epitopes of PUUV nucleocapsid protein. Eleven conserved peptides (90% conservancy) of the PUUV nucleocapsid protein were identified. Three conserved peptides containing multiple T and B cell epitopes were selected using a consensus epitope prediction algorithm. Molecular docking using the HPEP dock server demonstrated strong binding interactions between the epitopes and HLA molecules (ten alleles for each class I and II HLA). Moreover, an analysis of population coverage using the IEDB database revealed that the identified peptides have over 90% average population coverage across six continents. Molecular docking and simulation analysis reveal a stable interaction with peptide constructs of chosen immunogenic peptides and Toll-like receptor-4. These computational analyses demonstrate selected peptides' immunogenic potential, which needs to be validated in different experimental systems. [ABSTRACT FROM AUTHOR]

Introduction: Hantavirus, a zoonotic pathogen, causes severe syndromes like hemorrhagic fever with renal syndrome (HFRS), sometimes fatal in humans. Considering the importance of detecting the hantavirus antigen, the construction of an immunosensor is essential. The structural and functional characteristics of camelid nanobodies (VHHs) encourage their application in the areas of nanobiotechnology, therapeutics, diagnostics, and basic research. Therefore, this study aimed to standardize stable bioconjugates using gold nanoparticles (AuNPs) and VHHs, in order to develop immunobiosensors for the diagnosis of hantavirus infection. Methods: Immobilized metal affinity chromatography (IMAC) was performed to obtain purified recombinant anti-hantavirus nucleocapsid nanobodies (anti-prNΔ85 VHH), while AuNPs were synthesized for bioconjugation. UV-visible spectrophotometry and transmission electron microscopy (TEM) analysis were employed to characterize AuNPs. Results: The bioconjugation stability parameters (VHH-AuNPs), analyzed by spectrophotometry, showed that the ideal pH value and VHH concentration were obtained at 7.4 and 50 μg/mL, respectively, after addition of 1 M NaCl, which induces AuNP aggregation. TEM performed before and after bioconjugation showed uniform, homogeneous, well-dispersed, and spherical AuNPs with an average diameter of ~ 14 ± 0.57 nm. Furthermore, high-resolution images revealed a thin white halo on the surface of the AuNPs, indicating the coating of the AuNPs with protein. A biosensor simulation test (dot blot-like [DB-like]) was performed in stationary phase to verify the binding and detection limits of the recombinant nucleocapsid protein from the Araucária hantavirus strain (prN∆85). Discussion: Using AuNPs/VHH bioconjugates, a specific interaction was detected between 5 and 10 min of reaction in a dose-dependent manner. It was observed that this test was sensitive enough to detect prNΔ85 at concentrations up to 25 ng/μL. Considering that nanostructured biological systems such as antibodies conjugated with AuNPs are useful tools for the development of chemical and biological sensors, the stability of the bioconjugate indicates proficiency in detecting antigens. The experimental results obtained will be used in a future immunospot assay or lateral flow immunochromatography analysis for hantavirus detection. [ABSTRACT FROM AUTHOR]

Severe fever with thrombocytopenia syndrome (SFTS) virus and hantavirus are categorized under the Bunyavirales order. The severe disease progression in both SFTS and hemorrhagic fever with renal syndrome (HFRS) is associated with cytokine storms. This study aimed to explore the differences in cytokine profiles and immune responses between the two diseases. A cross-sectional, single-center study involved 100 participants, comprising 46 SFTS patients, 48 HFRS patients, and 6 healthy controls. The study employed the Luminex cytokine detection platform to measure 48 cytokines. The differences in cytokine profiles and immune characteristics between the two diseases were further analyzed using multiple linear regression, principal component analysis, and random forest method. Among the 48 cytokines tested, 30 showed elevated levels in SFTS and/or HFRS compared to the healthy control group. Furthermore, there were 19 cytokines that exhibited significant differences between SFTS and HFRS. Random forest analysis suggested that TRAIL and CTACK were predictive of SFTS, while IL2Ralpha, MIG, IL-8, IFNalpha2, HGF, SCF, MCP-3, and PDGFBB were more common with HFRS. It was further verified by the receiver operating characteristic with area under the curve >0.8 and P-values <0.05, except for TRAIL. Significant differences were observed in the cytokine profiles of SFTS and HFRS, with TRAIL, IL2Ralpha, MIG, and IL-8 being the top 4 cytokines that most clearly distinguished the two diseases. IMPORTANCE SFTS and HFRS differ in terms of cytokine immune characteristics. TRAIL, IL-2Ralpha, MIG, and IL-8 were the top 4 that differed markedly between SFTS and HFRS. [ABSTRACT FROM AUTHOR]

Introduction. Vaccination could be the most effective means of preventing hemorrhagic fever with renal syndrome (HFRS), which is one of the leading zoonoses and a major cause of natural disease in humans. Therefore, research to develop an effective vaccine and the search for new non-toxic and effective adjuvants that can enhance and prolong the immune response, reduce the antigen concentration and reduce the frequency of dose administration is an urgent task. The aim of the study was to determine the dependence of the immunogenic activity of an experimental hantavirus vaccine based on Puumala virus (HV) on the antigen dose both in native form and in combination with carbohydrate adjuvants. Materials and methods. The immunoadjuvant effect of Ac3-LPS S. sonnei and S. flexneri 1B and emulsions of nanoemulsified squalene Sepivac SWE (SWE) as part of HV at the optimal and minimal doses was investigated by induction of neutralising antibodies after 3-fold immunisation (day 0, 14, 182) of guinea pigs (Cavia porcellus). Differences in the immunogenic activity of HV were assessed in the neutralisation reaction by 50% suppression of focal units in Vero E6 cell cultures. Results. A statistically significant increase in neutralising antibodies levels was observed after immunization both with HV at the optimal dose and for its combination with adjuvants. Ac3-LPS S. sonnei and SWE showed the most pronounced immunoadjuvant effect at concentrations of 50 and 100 μg/dose, respectively. The immunoadjuvant effect of the combination of the hantavirus vaccine with Ac3-LPS S. sonnei and SWE contributed to both an enhanced immune response and its duration. The tenfold reduction of the antigen dose in the presence of SWE allows optimization of the immune response to the vaccine. Conclusion. The results of this study show the prospects of using Ac3-LPS S. sonnei and Sepivac SWE in the vaccine for the prevention of HFRS.

Introduction. Hemorrhagic fever with renal syndrome (HFRS) is the most common zoonotic human viral disease in the Russian Federation. More than 98% of the HFRS cases are caused by Puumala orthohantavirus (PUU). Effective serological tests are required for laboratory diagnosis of HFRS. Objective. Construction of an enzyme immunoassay (ELISA) test system for detection of specific antibodies using standard antigen in the form of highly purified inactivated PUU virus as immunosorbent. Materials and methods. Preparation of PUU virus antigen, designing the ELISA for detection of specific antibodies, developing parameters of the ELISA system, parallel titration of HFRS patients sera by fluorescent antibody technique (FAT) and the new ELISA. Results and discussion. For the first time, ELISA based on purified inactivated PUU virus as standard antigen directly absorbed onto immunoplate was developed. Parallel titration of 50 samples from HFRS patients blood sera using FAT and the developed ELISA showed high sensitivity and specificity of this ELISA, with 100% concordance of testing results and significant level of correlation between the titers of specific antibodies in the two assays. Conclusion. The ELISA based on purified inactivated PUU virus as an immunosorbent can be effectively used for HFRS serological diagnosis and for mass seroepidemiological studies.

The aim of the work was to study the species diversity of pathogenic and non-pathogenic hantaviruses circulating in populations of small mammals in the Republic of Bashkortostan using molecular-genetic methods.Materials and methods. Individual samples from small mammals were tested by the nested PCR using genus-specific primers that amplify the L segment of hantaviruses. The resulting PCR products were sequenced by the Sanger’s method from internal nested PCR primers. For samples containing Puumala virus, fragments of the S, M, and L segments of the viral genome were sequenced using Sanger’s method. The construction of phylogenetic trees was carried out using the MEGA X software.Results and discussion. Out of 300 examined samples of small mammals collected on the territory of the Republic of Bashkortostan in 2023, 14 samples have been found positive for the presence of hantavirus RNA: Seewis (8), Tula (3), Puumala (3). The circulation of the non-pathogenic hantavirus Seewis and the opportunistic hantavirus Tula has been established for the first time in the Republic of Bashkortostan. The circulation of the Seewis hantavirus has been confirmed in populations of the common shrew (Sorex araneus) and the pygmy shrew (S. minutus); the Tula hantavirus – in populations of the common vole (Microtus arvalis). Results of phylogenetic analysis substantiate the reassortment origin of one of the genetic variants of the Puumala hantavirus on the territory of the Republic of Bashkortostan. The prerequisites for the formation of combined natural foci of hantaviruses Puumala, Seewis, and Tula on the territory of the Republic of Bashkortostan are discussed.

Relevance. Hemorrhagic fever with renal syndrome (HFRS) is a natural focal viral infection with a high probability of severe course, the possibility of death, a long recovery period after infection, low effectiveness of therapy and vaccine prevention. In the Russian Federation, HFRS is most often caused by the Puumala orthohantavirus. The aim of the study — to evaluate the immunophenotypic composition of lymphocytes and cytokine profile in the blood of patients with hemorrhagic feverwith renal syndrome in comparison with acute respiratory viral infections and with the prospect of developing immunological criteria for early diagnosis of HFRS. Matherials and Methods. There were examined the blood of 24 patients with a verified diagnosis of HFRS who were hospitalized in the infectious diseases department of the Samara Medical University Clinics and admitted in the first days of the disease, 18 patients with acute respiratory viral infections of established etiology, as well as 15 healthy people. Results and Discussion. Analysis of the results of lymphocyte phenotyping and cytokine levels in the blood revealed that the percentage of B lymphocytes in the blood was 12.6 %, cytotoxic CD8+ T lymphocytes expressing the activating lectin receptor NKG2D (CD3+CD8+CD314+), 25 %, regulatory T cells with CD3+CD4+FoxP3+ phenotypes 7.8 % and CD3+CD8+FoxP3+ 9.5 %, as well as IL-6 24 pg/ml, TNFß 55 pg/ml, IL-10 11.3 pg/ml with high diagnostic significance, judging by the results of ROC analysis, indicates in favor of GLPS, but not ARVI. Conclusion. The results obtained can be used as criteria for early immunodiagnosis of HFRS. The development of a new hypothesis on the mechanism of CD8+ immunological memory formation may contribute to the discovery of new potential targets for HFRS immunotherapy and the creation of new principles for the production of vaccine preparations for the prevention of this disease.

Wang Yi,1,2 Weikai Wang,3 Hua Zhang,2 Ying Wang,2 Yong Zhou,2 Zhangyan Guo,2 Jingmei Li,2 Le Ma,2 Dan Yao,2 Taining Zhang,3 Yanqiang Du,2 Li Liu1 1Department of Neonatology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2Pediatric Intensive Care Unit, the Affiliated Children’s Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 3Pediatric intensive care unit, Gansu Provincial Maternity and Child Health Hospital, Gansu Provincial Central Hospital, Lanzhou, Gansu, People’s Republic of ChinaCorrespondence: Li Liu, Department of Neonatology, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta West Road, Yanta District, Xi’an, Shaanxi, 710003, People’s Republic of China, Email liuli918@sohu.com Yanqiang Du, Department of pediatric intensive care unit, the Affiliated Children’s Hospital of Xi’an Jiaotong University, No. 69, Xiju Lane, Lianhu District, Xi’an, Shaanxi, 710003, People’s Republic of China, Email duyanqiang_xaetyy@163.comBackground: In Asia, Hanta virus (HTNV) results in severe hemorrhagic fever with renal syndrome (HFRS). The efficacy of sivelestat in treating children with HTNV-induced HFRS remains unclear.Methods: An ambispective cohort study was performed on children diagnosed with HFRS and hospitalized at the Children’s Hospital Affiliated to Xi’an Jiaotong University from August 2018 to 2023. Patients who received neutrophil elastin-inhibitor infusion between August 2019 and August 2023 were assigned to the sivelestat group, while patients who did not were assigned to the control group. The independent sample t test was used for inter-group analysis. The Chi-square test and Fisher’s exact probability test were used for categorical variables. Spearman correlation test was used to evaluate the correlation between two sets of continuous variables. Kaplan-Meier survival curve and Log -Rank test was used to evaluate the difference in cumulative probability of survival between the two groups.Results: No significant differences were observed between the two groups in gender, age, contact history, body mass index, HFRS severity, clinical indexes at admission. Compared to the control group, the sivelestat group exhibited a significant decrease in the interleukin-8 level at 48 h (28.5± 3 vs 34.5± 3.5) and 72 h (21.3± 4.5 vs 31.5± 5.6) (P< 0.05), as well as the ICAM-1 level at 48 h (553± 122 vs 784± 187) and 72 h (452± 130 vs 623± 85) (P< 0.05). The concentration of VCAM-1 in the sivelestat group exhibited a consistent downward trend. Moreover, the level of VCAM-1 was significantly lower than that in the control group at 24 h (1760± 289 vs 2180± 445), 48 h (1450± 441 vs 1890± 267), and 72 h (1149± 338 vs 1500± 396) (P< 0.05). Kaplan-Meier curve analysis revealed a statistically significant difference in the cumulative probability of survival between two groups (P = 0.041). In the secondary outcomes, the sivelestat group demonstrated a decrease in the utilization rate of mechanical ventilation and continuous renal replacement therapy (CRRT).Conclusion: Sivelestat may suppress neutrophil-mediated inflammatory response to reduce endothelial and organ damage, and improve clinical outcomes in children with severe hemorrhagic fever and renal syndrome.Keywords: Sivelestat, hemorrhagic fever with renal syndrome, vascular endothelial injury, inflammatory response, cohort study, children

Xinran Yang,1,&ast; Chenglin Yu,2,&ast; Yixin Chen,1 Bin Nian,3 Min Chai,1 Dilimulat Maimaiti,4 Dahai Xu,1 Xiuxian Zang1 1Department of Emergency Medicine, The First Hospital of Jilin University, Changchun, Jilin, 130000, People’s Republic of China; 2Department of Emergency Medicine, Yanbian University Hospital, Yanji, Jilin, 133000, People’s Republic of China; 3Department of Ultrasonography, Yanbian University Hospital, Yanji, Jilin, 133000, People’s Republic of China; 4Department of Emergency Medicine, Seventh Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830054, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dahai Xu; Xiuxian Zang, Department of Emergency Medicine, The First Hospital of Jilin University, No. 1 Xinmin Street, Chaoyang District, Changchun, Jilin, 130000, People’s Republic of China, Tel +86-15043032548 ; +86-13596097922, Email xudahai0319@jlu.edu.cn; zangxx@jlu.edu.cnAbstract: Hemorrhagic fever with renal syndrome (HFRS), a naturally occurring epidemic disease, is primarily caused by hantaviruses. It frequently involves the lungs and is characterized by symptoms such as fever, hemorrhage, and renal failure. However, the occurrence of acute pancreatitis (AP) in HFRS patients can be neglected, and high intraocular pressure (IOP) is exceedingly uncommon. In this report, we discuss the case of a 30-year-old male who presented with fever, nausea, vomiting, and abdominal pain. Physical examination revealed extremity petechiae rashes and elevated IOP. Laboratory tests indicated coagulopathy and renal failure. A computed tomography scan confirmed AP. Further testing revealed a positive anti-hantavirus IgM antibody. The patient received supportive care, fluid hydration, hemofiltration, mannitol, brinzolamide, and brimonidine to reduce IOP. Three days post-admission, the patient developed shortness of breath and chest pain. Subsequent chest computed tomography revealed pulmonary edema and bilateral pleural effusion. Treatment included oxygen supply, respiratory support, and thoracentesis, with continued hemofiltration. The patient recovered, regaining normal pulmonary and renal functions and normalized IOP. This case underscores the importance of comprehensive evaluations and vigilant monitoring in HFRS patients, particularly measuring IOP in those with visual complaints, to save lives and reduce morbidity.Keywords: hemorrhagic fever with renal syndrome, acute pancreatitis, high intraocular pressure, pulmonary edema

Abstract Hemorrhagic fever with renal syndrome (HFRS) poses a major threat in Shandong. This study aimed to investigate the long- and short-term asymmetric effects of meteorological factors on HFRS and establish an early forecasting system using autoregressive distributed lag (ARDL) and nonlinear ARDL (NARDL) models. Between 2004 and 2019, HFRS exhibited a declining trend (average annual percentage change = − 9.568%, 95% CI − 16.165 to − 2.451%) with a bimodal seasonality. A long-term asymmetric influence of aggregate precipitation (AP) (Wald long-run asymmetry [WLR] = − 2.697, P = 0.008) and aggregate sunshine hours (ASH) (WLR = 2.561, P = 0.011) on HFRS was observed. Additionally, a short-term asymmetric impact of AP (Wald short-run symmetry [WSR] = − 2.419, P = 0.017), ASH (WSR = 2.075, P = 0.04), mean wind velocity (MWV) (WSR = − 4.594, P

Abstract Background Hemorrhagic fever with renal syndrome (HFRS) signals a recurring risk in Eurasia in recent years owing to its continued rise in case notifications and the extension of geographical distribution. This study was undertaken to investigate the spatiotemporal drivers and incidence heterogeneity of HFRS transmission in Shandong Province. Methods The epidemiological data for HFRS, meteorological data and socioeconomic data were obtained from China Information System for Disease Control and Prevention, China Meteorological Data Sharing Service System, and Shandong Statistical Yearbook, respectively. The spatial-temporal multicomponent model was employed to analyze the values of spatial-temporal components and the heterogeneity of HFRS transmission across distinct regions. Results The total effect values of the autoregressive, epidemic, and endemic components were 0.451, 0.187, and 0.033, respectively, exhibiting significant heterogeneity across various cities. This suggested a pivotal role of the autoregressive component in propelling HFRS transmission in Shandong Province. The epidemic component of Qingdao, Weifang, Yantai, Weihai, and Jining declined sharply at the onset of 2020. The random effect identified distinct incidence levels associated with Qingdao and Weifang, signifying regional variations in HFRS occurrence. Conclusions The autoregressive component emerged as a significant driver in the transmission of HFRS in Shandong Province. Targeted preventive measures should be strategically implemented across various regions, taking into account the predominant component influencing the epidemic.

The paper describes the epidemiological situation in the countries of the world in terms of the incidence of Hantavirus diseases. The results of an epidemiological analysis of the incidence of hemorrhagic fever with renal syndrome (HFRS) in the Russian Federation in 2023 by federal districts are presented and a forecast for 2024 is made. In 2023, 5 093 cases of HFRS were registered in the Russian Federation (3.47 per 100 thousand population). The incidence was reported in 7 out of 8 federal districts of the country. The age structure was dominated by people in the 30–59 age category (65.7 %); 247 cases of the disease were noted among children under 17 years of age. The proportion of the male population was 70.3 %. 63.2 % of the total number of cases was registered among the urban residents. The mortality rate was at the level of 0.49 % – 25 lethal outcomes. Analysis of the data has revealed a decrease in the incidence of HFRS in Russia by 27.2 % as compared to the previous year. However, the data from epizootiological monitoring and the results of laboratory research of field material indicate a continuing tense situation in the country as a whole. In a number of regions, a high risk of complications of the epidemiological situation is predicted (mainly, in the constituent entities of the Volga and Central Federal Districts). Moderate risks of developing local complications of the epidemiological situation at the level of long-term average morbidity are expected to be realized in the entities of the Northwestern, Ural and Far Eastern Federal Districts. Sporadic cases of the disease in the territory of the Southern Federal District are not excluded. The aggravation of the situation on HFRS in the territory of the North-Caucasian and Siberian Federal Districts is not anticipated in 2024.

Objective To explore the optimal prediction model for hantavirus hemorrhagic fever with renal syndrome (HFRS) in Hubei province, and to provide a basis for establishing a monitoring and early warning model for HFRS. Methods Using monthly surveillance data of HFRS incidence in Hubei province from 2005 to 2021, eight single time series models based on exponential smoothing (ETS), seasonal autoregressive integrated moving average (SARIMA) with and without regression variables, a state space model with Box 一 Cox transformation, ARMA errors, trend, and seasonal components (TBATS), a time series neural network model (NNETAR) with and without regression variables, a linear regression time series model (TSLM), and a cubic spline prediction model (SPLINEF) were used to build 162 models through 1 -4 model combinations. The mean absolute percentage error (MAPE) was used as an evaluation index to evaluate the fitting and prediction performance of the models. The comprehensive fitting and prediction performance were evaluated by calculating the mean MAPE of fitting and prediction. Results The TSLM model and its combined models had a comprehensive MAPE of more than 100%. Among the other 98 models, the optimal fitting models for single, two, three, and four - model combinations were SPLINEF (IL 98%), SARIMA - SPLINEF (15. 14%), SARIMA - NNETAR - REG - SPLINEF (16.06%), and SARIMA - TBAT - NNETAR 一 REG 一 SPLINEF (17. 75%), respectively. The optimal prediction models for single, two, three, and four - model combinations were SARIMA - REG (34.48%), SARIMA - REG - TBATS (22.77%), SARIMA - TBATS - SPLINEF (23.84%), and SARIMA - SARIMA - REG - TBATS - SPLINEF (22.31%), respectively. The optimal fitting and prediction models for single, two, three, and four 一 model combinations were SPLINEF (24.75%), SARIMA 一 SPLINEF (22. 55%), SARIMA - TBATS - SPLINEF (20. 92%), and SARIMA - SARIMA - REG - TBATS - SPLINEF (20.75%), respectively. Conclusion Based on the number of models, fitting and prediction accuracy, SARIMA 一 TBATS - SPLINEF is considered the optimal prediction model and can be used for monitoring and early warning of HF RS in Hubei. [ABSTRACT FROM AUTHOR]

Background: Renal Syndrome Hemorrhagic Fever (HFRS) continues to pose a significant public health threat to the well-being of the population. Given that the spread of HFRS is susceptible to meteorological factors, we aim to probe into the meteorological drivers of HFRS. Thus, novel techniques that can discern time-delayed non-linear relationships from nonlinear dynamical systems are compulsory. Methods: We analyze the epidemiological features of HFRS in Weifang City, 2011–2020, via the employment of the Empirical Dynamic Modeling (EDM) method. Our analysis delves into the intricate web of time-delayed non-linear associations between meteorological factors and HFRS. Additionally, we investigate the repercussions of minor perturbations in meteorological variables on future HFRS incidence. Results: A total of 2515 HFRS cases were reported in Weifang from 2011 to 2020. The average weekly incidence was 4.81, and the average weekly incidence was 0.52 per 1,000,000. The propagation of HFRS is significantly impacted by the mean weekly temperature, relative humidity, cumulative rainfall, and wind speed, and the ρCCM converges to 0.55,0.48,0.38 and 0.39, respectively. The graphical representation of the relationship between temperature (lagged by 2 weeks) and the incidence of HFRS exhibits an inverted U-shaped curve, whereby the incidence of HFRS culminates as the temperature reaches 10 °C. Moreover, temperature, relative humidity, cumulative rainfall, and wind speed exhibit a positive correlation with HFRS incidence, with a time lag of 4–6 months. Conclusions: Our discoveries suggest that meteorological factors can drive the transmission of HFRS both at a macroscopic and microscopic scale. Prospective alterations in meteorological conditions, for instance, elevations in temperature, relative humidity, and precipitation will instigate an upsurge in the incidence of HFRS after 4–6 months, and thus, timely public health measures should be taken to mitigate these changes. Author summary: Renal Syndrome Hemorrhagic Fever (HFRS) is a serious disease caused by the Hantavirus and transmitted by rodents. Meteorological factors, such as temperature, humidity, precipitation, and wind speed, can influence the occurrence, spread, and outbreak of HFRS. However, the relationship between climate change and its impact on the disease is complex, and more research is needed to provide a strong scientific basis for the development of adaptation strategies. This study employs a novel technique called Empirical Dynamic Modeling (EDM) to investigate the time-delayed non-linear relationships between meteorological factors and HFRS outbreaks in Weifang. The results show that meteorological factors can drive the transmission of HFRS both at a macroscopic and microscopic scale. The relationship between temperature (lagged by 2 weeks) and HFRS incidence exhibits an inverted U-shaped curve, with the highest incidence occurring at 10 °C. Changes in meteorological conditions, such as increases in temperature, relative humidity, and precipitation, can lead to an upsurge in the incidence of HFRS after 4–6 months. The findings of this study are crucial for public health officials and policymakers to take timely measures to mitigate the impact of climate change on the spread of HFRS. [ABSTRACT FROM AUTHOR]

High incidences of haemorrhagic fever with renal syndrome (HFRS) have been reported in the southern Republic of Korea (ROK). A distinct southern genotype of Orthohantavirus hantanense (HTNV) was identified in Apodemus agrarius chejuensis on Jeju Island. However, its association with HFRS cases in southern ROK remains elusive. We investigated the potential of the southern HTNV genotype as an etiological agent of HFRS. Samples from 22 patients with HFRS and 193 small mammals were collected in the southern ROK. The clinical characteristics of patients infected with the southern HTNV genotype were analysed. Amplicon-based MinION sequencing was employed for southern HTNV from patients and rodents, facilitating subsequent analyses involving phylogenetics and genetic reassortment. High-throughput sequencing of HTNV exhibited higher coverage with a cycle of threshold value below 32, acquiring nearly whole-genome sequences from six patients with HFRS and seven A. agrarius samples. The phylogenetic pattern of patient-derived HTNV demonstrated genetic clustering with HTNV from Apodemus species on Jeju Island and the southern Korean peninsula, revealing genetic reassortment in a single clinical sample between the M and S segments. These findings imply that the southern HTNV genotype has the potential to induce HFRS in humans. The phylogenetic inference demonstrates the diverse and dynamic characteristics of the southern HTNV tripartite genomes. Therefore, this study highlights the significance of active surveillance and amplicon sequencing for detecting orthohantavirus infections. It also raises awareness and caution for physicians regarding the emergence of a southern HTNV genotype as a cause of HFRS in the ROK. [ABSTRACT FROM AUTHOR]

Pathogenic Eurasian hantaviruses cause hemorrhagic fever with renal syndrome (HFRS), which is characterized by acute kidney injury. The clinical course shows a broad range of severity and is influenced by direct and immune‐mediated effects. The neutrophil‐to‐lymphocyte ratio (NLR) is a marker of systemic inflammation and predicts severity and outcome in various diseases. Therefore, we examined the role of NLR in HFRS caused by hantavirus Puumala (PUUV) and its association with disease severity and kidney injury. We detected elevated NLR levels on admission (NLRadm: median 3.82, range 1.75−7.59), which increased during acute HFRS. Maximum NLR levels (NLRmax: median 4.19, range 1.75−13.16) were 2.38‐fold higher compared to the reference NLR level of 1.76 in the general population. NLR levels on admission correlate with markers of severity (length of hospital stay, serum creatinine) but not with other markers of severity (leukocytes, platelets, C‐reactive protein, lactate dehydrogenase, serum albumin, proteinuria). Interestingly, levels of nephrin, which is a specific marker of podocyte damage in kidney injury, are highest on admission and correlate with NLRmax, but not with NLRadm. Together, we observed a correlation between systemic inflammation and the severity of HFRS, but our results also revealed that podocyte damage precedes these inflammatory processes. [ABSTRACT FROM AUTHOR]

Hantaan virus (HTNV) infection can cause hemorrhagic fever with renal syndrome (HFRS) in humans, and currently, there are no long‐standing protective vaccines or specific antivirals available. Guanylate‐binding protein 1 (GBP1) is an interferon‐stimulated gene that defends against various pathogen infections. However, the function of GBP1 in HTNV infection remains unknown. Here, we describe how GBP1 prevents HTNV infection by obstructing virus entry. We found that HTNV infection induced GBP1 expression and that overexpression of GBP1 inhibited HTNV infection, while knockout of GBP1 had the opposite effect. Interestingly, GBP1 did not affect interferon (IFN) signaling during HTNV infection. Instead, GBP1 prevented HTNV from entering cells through clathrin‐mediated endocytosis (CME). We also discovered that GBP1 specifically interacted with actin but not dynamin 2 (DNM2) and made it difficult for DNM2 to be recruited by actin, which may account for the suppression of CME during HTNV infection. These findings establish an antiviral role for GBP1 in inhibiting HTNV infection and help us better understand how GBP1 regulates HTNV entry and could potentially aid in developing treatments for this virus. [ABSTRACT FROM AUTHOR]

Background: Seoul virus (SEOV) is an orthohantavirus primarily carried by rats. In humans, it may cause hemorrhagic fever with renal syndrome (HFRS). Its incidence is likely underestimated and given the expansion of urban areas, a better knowledge of SEOV circulation in rat populations is called for. Beyond the need to improve human case detection, we need to deepen our comprehension of the ecological, epidemiological, and evolutionary processes involved in the transmission of SEOV. Methodology / Principal findings: We performed a comprehensive serological and molecular characterization of SEOV in Rattus norvegicus in a popular urban park within a large city (Lyon, France) to provide essential information to design surveillance strategies regarding SEOV. We sampled rats within the urban park of 'La Tête d'Or' in Lyon city from 2020 to 2022. We combined rat population genetics, immunofluorescence assays, SEOV high-throughput sequencing (S, M, and L segments), and phylogenetic analyses. We found low structuring of wild rat populations within Lyon city. Only one sampling site within the park (building created in 2021) showed high genetic differentiation and deserves further attention. We confirmed the circulation of SEOV in rats from the park with high seroprevalence (17.2%) and high genetic similarity with the strain previously described in 2011 in Lyon city. Conclusion/Significance: This study confirms the continuous circulation of SEOV in a popular urban park where the risk for SEOV transmission to humans is present. Implementing a surveillance of this virus could provide an efficient early warning system and help prepare risk-based interventions. As we reveal high gene flow between rat populations from the park and the rest of the city, we advocate for SEOV surveillance to be conducted at the scale of the entire city. Author summary: Seoul virus is a zoonotic pathogen primarily carried by rats, and it can cause a serious illness called hemorrhagic fever with renal syndrome in humans. Research into the zoonotic risk associated with this virus is limited although human cases are detected worldwide. We investigated the circulation of SEOV and its genetic evolution in rats from a French urban park, where the virus was detected first in 2010–2012 and a strain characterized in 2011. We have studied 87 wild brown rats distributed non homogeneously all over the park and found that 17.2% of those animals had orthohantavirus-reactive antibodies. Furthermore, the molecular analyses of the virus showed amino acid exchanges over the past decade in this area. This study highlights the potential zoonotic risk posed by SEOV in a popular urban park, where humans are likely to come into contact with wild rats or their excretions. To mitigate this zoonotic risk, targeted surveillance of this virus in rat populations would be beneficial. Additionally, prevention strategies should be designed and communicated with all personnel working in the park. [ABSTRACT FROM AUTHOR]

Hypopituitarism is a relatively rare complication of hemorrhagic fever with renal syndrome. However, almost all available reported cases were total anterior pituitary hypofunction, isolated growth-hormone deficiency, or isolated gonadotropin deficiency. Here, we firstly describe a patient with partial hypopituitarism with ACTH deficiency as the main manifestation as a complication of hemorrhagic fever with renal syndrome. [ABSTRACT FROM AUTHOR]

Objective To investigate the role of neutrophil activation in the pathogenesis of hemorrhagic fever with renal syndrome (HFRS) . Methods Serum levels of neutrophil activation products, including myeloperoxidase (MPO), human neutrophil elastase (HNE), and neutrophil extracellular traps (NETs), were measured in 21 patients with HFRS and 18 healthy controls. Differences in expression levels were compared between the observed group and control group, as well as between the mild/medium and severe/critical subgroups. Results In the severe/critical subgroup, neutrophil count, blood urea nitrogen, and serum creatinine (Scr) levels were significantly higher, while platelet count (PLT) was significantly lower compared to the mild/medium subgroup (all P＜0.05) . Serum levels of MPO, HNE, and NETs in the observed group were significantly higher than those in the control group (all P＜0.05) . Compared to the mild/medium subgroup, patients in the severe/critical subgroup had significantly higher serum levels of NETs, with statistical significance (P＜0.05) . Serum HNE levels in HFRS were positively correlated with Scr (r=0.472, P＜0.05) . Conclusion Neutrophil activation may be associated with the severity of HFRS, and inhibition of NETs formation may be a potential therapeutic target for future HFRS treatment. [ABSTRACT FROM AUTHOR]

While the pathology of acute hemorrhagic fever with renal syndrome (HFRS) has been widely researched, details on the chronic HFRS sequelae remain mainly unexplored. In this study, we analyzed the clinical and laboratory characteristics of 30 convalescent HFRS patients 14 years after the disease contraction, mainly emphasizing several endothelial dysfunction parameters. Convalescent HFRS patients exhibited significantly higher serum levels of erythrocyte sedimentation rate, von Willebrand factor, uric acid, C-reactive protein and immunoglobulin A when compared to healthy individuals. Furthermore, 24 h urine analyses revealed significantly lower sodium and potassium urine levels, as well as significantly higher proteinuria, microalbumin levels and β2-microglobulin levels when compared to healthy individuals. First morning urine analysis revealed significantly higher levels of hematuria in convalescent HFRS patients. None of the additional analyzed endothelium dysfunction markers were significantly different in post-HFRS patients and healthy individuals, including serum and urine P-selectin, E-selectin, soluble intercellular adhesion molecule 1, vascular intercellular adhesion molecule 1 (sVCAM-1) and vascular endothelial growth factor (VEGF). However, binary logistic regression revealed a weak association of serum sVCAM-1 and urine VEGF levels with HFRS contraction. Generally, our findings suggest mild chronic inflammation and renal dysfunction levels in convalescent HFRS patients 14 years after the disease contraction. [ABSTRACT FROM AUTHOR]

Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease widespread in Europe and Asia. HFRS is caused by negative-sensed single-stranded RNA orthohantaviruses transmitted to humans through inhaling aerosolized excreta of infected rodents. Symptoms of HFRS include acute kidney injury, thrombocytopenia, hemorrhages, and hypotension. The immune response raised against viral antigens plays an important role in the pathogenesis of HFRS. Inhibitory co-receptors are essential in regulating immune responses, mitigating immunopathogenesis, and reducing tissue damage. Our research showed an increased soluble form of inhibitory co-receptors TIM-3, LAG-3, and PD-1 in HFRS patients associated with disease severity. Our study aimed to investigate the impact of HFRS on the concentrations of soluble forms of inhibitory receptors TIM-3, LAG-3, and PD-1 in the patient's serum and the potential correlation with key clinical parameters. Our study aimed to investigate the impact of HFRS on the concentrations of soluble forms of inhibitory receptors TIM-3, LAG-3, and PD-1 in the patient's serum and their possible association with relevant clinical parameters. Using multiplex immunoassay, we found elevated levels of TIM-3, LAG-3, and PD-1 proteins in the serum of HFRS patients. Furthermore, increased levels were associated with creatinine, urea, lactate dehydrogenase concentrations, and platelet count. These findings suggest that these proteins play a role in regulating the immune response and disease progression. [ABSTRACT FROM AUTHOR]

Background Numerous studies have revealed age-related inequalities in colorectal cancer care. Increasing levels of frailty in an ageing population may be contributing to this, but quantifying frailty in population-based studies is challenging. Objective To assess the feasibility, validity and reliability of the Hospital Frailty Risk Score (HFRS), the Secondary Care Administrative Records Frailty (SCARF) index and the frailty syndromes (FS) measures in a national colorectal cancer cohort. Design Retrospective population-based study using 136,008 patients with colorectal cancer treated within the English National Health Service. Methods Each measure was generated in the dataset to assess their feasibility. The diagnostic codes used in each measure were compared with those in the Charlson Comorbidity Index (CCI). Validity was assessed using the prevalence of frailty and relationship with 1-year survival. The Brier score and the c-statistic were used to assess performance and discriminative ability of models with included each measure. Results All measures demonstrated feasibility, validity and reliability. Diagnostic codes used in SCARF and CCI have considerable overlap. Prevalence of frailty determined by each differed; SCARF allocating 55.4% of the population to the lowest risk group compared with 85.1% (HFRS) and 81.2% (FS). HFRS and FS demonstrated the greatest difference in 1-year overall survival between those with the lowest and highest measured levels of frailty. Differences in model performance were marginal. Conclusions HFRS, SCARF and FS all have value in quantifying frailty in routine administrative health care datasets. The most suitable measure will depend on the context and requirements of each individual epidemiological study. [ABSTRACT FROM AUTHOR]

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with a high mortality rate. Differentiating between SFTS and hemorrhagic fever with renal syndrome (HFRS) is difficult and inefficient. Retrospective analysis of the medical records of individuals with SFTS and HFRS was performed. Clinical and laboratory data were compared, and a diagnostic model was developed based on multivariate logistic regression analyzes. Receiver operating characteristic curve analysis was used to evaluate the diagnostic model. Among the 189 patients, 113 with SFTS and 76 with HFRS were enrolled. Univariate analysis revealed that more than 20 variables were significantly associated with SFTS. Multivariate logistic regression analysis revealed that gender, especially female gender (odds ratio [OR]: 4.299; 95% confidence interval [CI]: 1.163–15.887; p = 0.029), age ≥65 years (OR: 16.386; 95% CI: 3.043–88.245; p = 0.001), neurological symptoms (OR: 12.312; 95% CI: 1.638–92.530; p = 0.015), leukopenia (<4.0 × 109/L) (OR: 17.355; 95% CI: 3.920–76.839; p < 0.001), and normal Cr (OR: 97.678; 95% CI: 15.483–616.226; p < 0.001) were significantly associated with SFTS but not with HFRS. The area under the curve of the differential diagnostic model was 0.960 (95% CI: 0.936–0.984), which was significantly better than that of each single factor. In addition, the model exhibited very excellent sensitivity and specificity (92.9% and 85.5%, respectively). In cases where HFRS and SFTS are endemic, a diagnostic model based on five parameters, such as gender, age ≥65 years, neurological symptoms, leukopenia and normal Cr, will facilitate the differential diagnosis of SFTS and HFRS in medical institutions, especially in primary care settings. [ABSTRACT FROM AUTHOR]

Hemorrhagic fever with renal syndrome (HFRS) poses a major threat in Shandong. This study aimed to investigate the long- and short-term asymmetric effects of meteorological factors on HFRS and establish an early forecasting system using autoregressive distributed lag (ARDL) and nonlinear ARDL (NARDL) models. Between 2004 and 2019, HFRS exhibited a declining trend (average annual percentage change = − 9.568%, 95% CI − 16.165 to − 2.451%) with a bimodal seasonality. A long-term asymmetric influence of aggregate precipitation (AP) (Wald long-run asymmetry [WLR] = − 2.697, P = 0.008) and aggregate sunshine hours (ASH) (WLR = 2.561, P = 0.011) on HFRS was observed. Additionally, a short-term asymmetric impact of AP (Wald short-run symmetry [WSR] = − 2.419, P = 0.017), ASH (WSR = 2.075, P = 0.04), mean wind velocity (MWV) (WSR = − 4.594, P < 0.001), and mean relative humidity (MRH) (WSR = − 2.515, P = 0.013) on HFRS was identified. Also, HFRS demonstrated notable variations in response to positive and negative changes in ∆MRH(−), ∆AP(+), ∆MWV(+), and ∆ASH(−) at 0–2 month delays over the short term. In terms of forecasting, the NARDL model demonstrated lower error rates compared to ARDL. Meteorological parameters have substantial long- and short-term asymmetric and/or symmetric impacts on HFRS. Merging NARDL model with meteorological factors can enhance early warning systems and support proactive measures to mitigate the disease's impact. [ABSTRACT FROM AUTHOR]

Introduction: Hemorrhagic fever with renal syndrome (HFRS) is an acute infectious disease comprising five stages: fever, hypotension, oliguria, diuresis (polyuria), and convalescence. Increased vascular permeability, coagulopathy, and renal injury are typical clinical features of HFRS, which has a case fatality rate of 1--15%. Despite this, a comprehensive meta-analyses of the clinical characteristics of patients who died from HFRS is lacking. Methods: Eleven Chinese- and English-language research databases were searched, including the China National Knowledge Infrastructure Database, Wanfang Database, SinoMed, VIP Database, PubMed, Embase, Scopus, Cochrane Library, Web of Science, Proquest, and Ovid, up to October 5, 2023. The search focused on clinical features of patients who died from HFRS. The extracted data were analyzed using STATA 14.0. Results: A total of 37 articles on 140,295 patients with laboratory--confirmed HFRS were included. Categorizing patients into those who died and those who survived, it was found that patients who died were older and more likely to smoke, have hypertension, and have diabetes. Significant differences were also observed in the clinical manifestations of multiple organ dysfunction syndrome, shock, occurrence of overlapping disease courses, cerebral edema, cerebral hemorrhage, toxic encephalopathy, convulsions, arrhythmias, heart failure, dyspnea, acute respiratory distress syndrome, pulmonary infection, liver damage, gastrointestinal bleeding, acute kidney injury, and urine protein levels. Compared to patients who survived, those who died were more likely to demonstrate elevated leukocyte count; decreased platelet count; increased lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase levels; prolonged activated partial thromboplastin time and prothrombin time; and low albumin and chloride levels and were more likely to use continuous renal therapy. Interestingly, patients who died received less dialysis and had shorter average length of hospital stay than those who survived. Conclusion: Older patients and those with histories of smoking, hypertension, diabetes, central nervous system damage, heart damage, liver damage, kidney damage, or multiorgan dysfunction were at a high risk of death. The results can be used to assess patients' clinical presentations and assist with prognostication. Systematic review registration: https://www.crd.york.ac.uk/prospero/, (CRD42023454553). [ABSTRACT FROM AUTHOR]

Background: Hemorrhagic fever with renal syndrome (HFRS) signals a recurring risk in Eurasia in recent years owing to its continued rise in case notifications and the extension of geographical distribution. This study was undertaken to investigate the spatiotemporal drivers and incidence heterogeneity of HFRS transmission in Shandong Province. Methods: The epidemiological data for HFRS, meteorological data and socioeconomic data were obtained from China Information System for Disease Control and Prevention, China Meteorological Data Sharing Service System, and Shandong Statistical Yearbook, respectively. The spatial-temporal multicomponent model was employed to analyze the values of spatial-temporal components and the heterogeneity of HFRS transmission across distinct regions. Results: The total effect values of the autoregressive, epidemic, and endemic components were 0.451, 0.187, and 0.033, respectively, exhibiting significant heterogeneity across various cities. This suggested a pivotal role of the autoregressive component in propelling HFRS transmission in Shandong Province. The epidemic component of Qingdao, Weifang, Yantai, Weihai, and Jining declined sharply at the onset of 2020. The random effect identified distinct incidence levels associated with Qingdao and Weifang, signifying regional variations in HFRS occurrence. Conclusions: The autoregressive component emerged as a significant driver in the transmission of HFRS in Shandong Province. Targeted preventive measures should be strategically implemented across various regions, taking into account the predominant component influencing the epidemic. [ABSTRACT FROM AUTHOR]

Puumala orthohantavirus-caused hemorrhagic fever with renal syndrome (PUUV-HFRS) is characterized by strong neutrophil activation. Neutrophils are the most abundant immune cell type in the circulation and are specially equipped to rapidly respond to infections. They are more heterogenous than previously appreciated, with specific neutrophil subsets recently implicated in inflammation and immunosuppression. Furthermore, neutrophils can be divided based on their density to either low-density granulocytes (LDGs) or “normal density” polymorphonuclear cell (PMN) fractions. In the current study we aimed to identify and characterize the different neutrophil subsets in the circulation of PUUV-HFRS patients. PMNs exhibited an activation of antiviral pathways, while circulating LDGs were increased in frequency following acute PUUV-HFRS. Furthermore, cell surface marker expression analysis revealed that PUUV-associated LDGs are primarily immature and most likely reflect an increased neutrophil production from the bone marrow. Interestingly, both the frequency of LDGs and the presence of a “left shift” in blood associated with the extent of thrombocytopenia, one of the hallmarks of severe HFRS, suggesting that maturing neutrophils could play a role in disease pathogenesis. These results imply that elevated circulating LDGs might be a general finding in acute viral infections. However, in contrast to the COVID-19 associated LDGs described previously, the secretome of PUUV LDGs did not show significant immunosuppressive ability, which suggests inherent biological differences in the LDG responses that can be dependent on the causative virus or differing infection kinetics.

This article discusses the role of GBP1, an interferon-inducible GTPase, in inhibiting Hantaan virus (HTNV) entry by restricting clathrin-mediated endocytosis. Hantaviruses are known to cause severe viral hemorrhagic diseases in humans and are primarily carried by rodents. The study found that GBP1 inhibits HTNV infection by decreasing viral RNA synthesis and inhibiting viral entry. The authors also discovered that GBP1 interacts with actin and inhibits clathrin-mediated endocytosis, which is the primary entry mechanism for HTNV. These findings have implications for understanding virus-host interactions and developing antiviral therapeutics. [Extracted from the article]

Objective: to study the level of the immune layer of the population to pathogens of natural focal infectious diseases in order to establish the epidemic activity of natural foci of particularly dangerous infectious diseases in the Rostov region.Materials and methods: blood serums of healthy donors living in the administrative territories of the region were collected in the period from 2020 to 2022. Specific antibodies in blood sera were determined by the ELISA method. Serum specific IgG class immunoglobulins were used as a serological marker of the transmitted infection.Results: IgG to the Crimean hemorrhagic fever virus was not detected in 2020. In 2021, the share of seropositive results was 0.7%, in 2022 — 2.0%. The proportion of IgG to West Nile virus in 2020 was 8.7%, in 2021 — 9.9%, in 2022 — 12.4%. Serological testing revealed an immune layer to ixodic tick–borne borreliosis in 2020–2022: 3.1%, 2.6% and 2.0%, respectively. Antibodies to hantaviruses, pathogens of hemorrhagic fever with renal syndrome in the blood of residents of the region in 2020 were found in 7.0% of samples, in 2021 — 4.5%, in 2022 — 7.1%. The share of positive samples in the study for Ku fever in 2022 was 2.3%. Conclusion: Seropositive samples were detected for all studied natural focal infections. The greatest variety of natural focal infections confirmed by serological monitoring data was detected in cities (Rostov-on-Don, Taganrog, Zernograd, Kamensk-Shakhtinsky) and districts of RO (Salsky, Neklinovsky, Remontnensky).Conclusion. The results of the serological monitoring made it possible to identify the circulation of pathogens of KGL, LZN, ICB, Ku fever, hantaviruses in the territory of two districts of the region. The detection of specific antibodies in the blood sera of healthy donors indicates the epidemic activity of natural foci. Also, a comprehensive study of healthy donors expanded the understanding of the area of the most relevant natural focal infections such as (KGL, LZN, ICB), and less frequently registered at present (HFRS and Ku fever).

Abstract Background Hantaan virus (HTNV), Seoul virus (SEOV) and Puumala virus (PUUV) are major serotypes of the Hantavirus, which can cause hemorrhagic fever with renal syndrome (HFRS). The pathophysiology of HFRS in humans is complex and the determinants associated with mortality, especially the coagulation and fibrinolysis disorders, are still not been fully elucidated. Severe patients usually manifest multiple complications except for acute kidney injury (AKI). The aim of this study was to observe the levels of peripheral blood routine, biochemical and coagulation parameters during the early stage, so as to find independent risk factors closely related to the prognosis, which may provide theoretical basis for targeted treatment and evaluation. Methods A total of 395 HFRS patients from December 2015 to December 2018 were retrospectively enrolled. According to prognosis, they were divided into a survival group (n = 368) and a death group (n = 27). The peripheral blood routine, biochemical and coagulation parameters were compared between the two groups on admission. The relationship between the parameters mentioned above and prognosis was analyzed, and the dynamic changes of the coagulation and fibrinolysis parameters during the first week after admission were further observed. Results In addition to AKI, liver injury was also common among the enrolled patients. Patients in the death group manifested higher levels of white blood cell counts (WBC) on admission. 27.30% (107/392) of the patients enrolled presented with disseminated intravascular coagulation (DIC) on admission and DIC is more common in the death group; The death patients manifested longer prothrombin time (PT) and activated partial thromboplastin time (APTT), higher D-dimer and fibrinogen degradation product (FDP), and lower levels of platelets (PLT) and fibrinogen (Fib) compared with those of the survival patients. The proportion of D-dimer and FDP abnormalities are higher than PT, APTT and Fib. Prolonged PT, low level of Fib and elevated total bilirubin (TBIL) on admission were considered as independent risk factors for prognosis (death). Conclusions Detection of PT, Fib and TBIL on admission is necessary, which might be benefit to early predicting prognosis. It is also important to pay attention to the dynamic coagulation disorders and hyperfibrinolysis during the early stage in the severe HFRS patients.

Seoul orthohantavirus (SEOV) is a rat-borne zoonotic virus that is transmitted via inhalation of aerosolized infectious excreta, and can cause hemorrhagic fever with renal syndrome (HFRS) in humans worldwide. In rats, SEOV predominantly exists as a persistent infection in the absence of overt clinical signs. Lack of disease in rats is attributed to downregulation of pro-inflammatory and upregulation of regulatory host responses. As lung microvascular endothelial cells (LMECs) represent a primary target of infection in both human and rats, infections in these cells provide a unique opportunity to study the central role of LMECs in the dichotomy between pathogenicity in both species. In this study, host responses to SEOV infection in primary human and rat LMECs were directly compared on a transcriptional level. As infection of rat LMECs was more efficient than human LMECs, the majority of anti-viral defense responses were observed earlier in rat LMECs. Most prominently, SEOV-induced processes in both species included responses to cytokine stimulus, negative regulation of innate immune responses, responses to type I and II interferons, regulation of pattern recognition receptor signaling and MHC-I signaling. However, over time, in the rat LMECs, responses shifted from an anti-viral state towards a more immunotolerant state displayed by a PD-L1, B2M-, JAK2-focused interaction network aiding in negative regulation of cytotoxic CD8-positive T cell activation. This suggests a novel mechanism by which species-specific orthohantavirus-induced endothelium and T cell crosstalk may play a crucial role in the development of acute disease in humans and persistence in rodents. Author summary: Seoul orthohantavirus is a rat-borne zoonotic virus that can cause hemorrhagic fever with renal syndrome in humans worldwide while it generally leads to persistent infection in absence of clinical signs in the natural reservoir host, the Norway rat. It is believed that persistent infection in reservoir hosts is due to downregulation of pro-inflammatory immune responses and upregulation of regulatory responses, while in humans excessive immune responses contribute to disease. Endothelial cells in the lungs are of particular interest as they represent a primary target during Seoul orthohantavirus infection in both species. So far, it remains incompletely understood how the responses of these cells to Seoul orthohantavirus contribute to the development of disease in humans and the prevention of such in rats. In this study, we compared the host responses of human and rat lung endothelial cells to Seoul orthohantavirus infection and found that anti-viral responses from both species are comparable, but differ in timing. Additionally, we identified a novel protein interaction network during later phases of acute infection in rat cells, which may play a crucial role in the development of disease in humans and persistence in rodents. [ABSTRACT FROM AUTHOR]