Pathogenesis Of Hemorrhagic Fever Research Articles

The role of immune mechanisms in the pathogenesis of hemorrhagic fever with renal syndrome

Hemorrhagic fever with renal syndrome (HFRS) is an acute natural focal disease of a viral nature. Its severity is determined by hemorrhagic phenomena, cytokine storm, kidney damage with the development of acute renal failure, and the possibility of death. HFRS is caused by viruses from the family Hantaviridae. Hantaviruses are characterized by the ability to infect endothelial and epithelial cells of the renal tubules, as well as innate immunity cells (neutrophils, monocytes, dendritic cells), which leads to both direct damage to the immune system and indirect through a violation of their functions. The review analyzes the immune mechanisms in HFRS and their role in the pathogenesis of this disease.

Cytokine profile of patients with severe hemorrhagic fever complicated with acute renal failure

Objective: to determine the cytokine profile in blood serum in patients with severe hemorrhagic fever complicated by acute renal failure. Materials and methods. The examined persons were divided into a control group – 46 people (healthy), a group of patients with an average course of the disease – 35 people, and a group of patients with severe severity, complicated by acute renal failure – 38 people. Blood was taken from the subjects for the study of cytokines. The determination of cytokines was carried out by enzyme immunoassay using test kits in accordance with the manufacturer’s instructions. Results. In patients with hemorrhagic fever, both with moderate and severe, there was an increase in interleukins IL-1β, IL-6, IL-10 compared with the control group. However, the values of these interleukins were significantly higher in patients with severe hemorrhagic fever complicated by acute renal failure compared with the group of patients with moderate severity. The values of IL-8, IFN-γ and SDF-1α changed only in patients with severe course. At the same time, there was an increase in the expression of IL-8 and a decrease in IFN-γ compared with the control group. IL-8 and IFN-γ did not change statistically in patients who had just been admitted to the hospital, as well as in patients with an average degree of the disease. A change in the SDF-1α chemokine also turned out to be specific for patients with a severe course of the disease: its values increased in comparison with the control group. No significant changes in SDF-1α were detected in patients who had just been admitted to the hospital, as well as in the group of patients with moderate severity of the disease. Conclusion. The results obtained indicate the diagnostic value of cytokine determination in severe hemorrhagic fever complicated by acute renal failure. Changes in the parameters of some cytokines, detected only in the profile of patients with severe severity, require further research to clarify their role in the pathogenesis of hemorrhagic fever, and also open up opportunities for considering them as biomarkers.

Research Progress on the Pathogenesis of Hemorrhagic Fever with Renal Syndrome

Abstract Hemorrhagic fever with renal syndrome (HFRS) is an acute natural focus epidemic disease characterized by fever, shock, hemorrhage and kidney injury caused by hantavirus infection. Hantavirus mainly infects human vascular endothelial cells, and induces extensive damage to small blood vessels and capillaries. Increased vascular permeability is the pathological basis for clinical manifestations of HFRS. Although domestic and foreign scholars have carried out many studies on the hantavirus pathogenesis, such as the immune pathological response induced by hantavirus, host genetics and apoptosis, thrombocytopenia, coagulation and fibrinolysis dysfunction, and the vascular endothelial damage, the pathogenesis of HFRS has not been fully elucidated and there is no effective drug yet. In-depth discussion of the molecular mechanism of HFRS and finding effective therapeutic drugs are still the research hotspots on the field of hantavirus/HFRS. This review will elaborate the research progress on the pathogenesis of HFRS in recent years.

Host response transcriptomic analysis of Crimean-Congo hemorrhagic fever pathogenesis in the cynomolgus macaque model

Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne RNA virus prevalent in Asia, Europe, and Africa, and can cause a hemorrhagic disease (CCHF) in humans with mortality rates as high as 60%. A general lack of both effective medical countermeasures and a comprehensive understanding of disease pathogenesis is partly driven by an historical lack of viable CCHF animal models. Recently, a cynomolgous macaque model of CCHF disease was developed. Here, we document the targeted transcriptomic response of non-human primates (NHP) to two different CCHFV strains; Afghan09-2990 and Kosova Hoti that both yielded a mild CCHF disease state. We utilized a targeted gene panel to elucidate the transcriptomic changes occurring in NHP whole blood during CCHFV infection; a first for any primate species. We show numerous upregulated genes starting at 1 day post-challenge through 14 days post-challenge. Early gene changes fell predominantly in the interferon stimulated gene family with later gene changes coinciding with an adaptive immune response to the virus. There are subtle differences between viral strains, namely duration of the differentially expressed gene response and biological pathways enriched. After recovery, NHPs showed no lasting transcriptomic changes at the end of sample collection.

Insights into the Pathogenesis of Viral Haemorrhagic Fever Based on Virus Tropism and Tissue Lesions of Natural Rift Valley Fever.

Rift Valley fever phlebovirus (RVFV) infects humans and a wide range of ungulates and historically has caused devastating epidemics in Africa and the Arabian Peninsula. Lesions of naturally infected cases of Rift Valley fever (RVF) have only been described in detail in sheep with a few reports concerning cattle and humans. The most frequently observed lesion in both ruminants and humans is randomly distributed necrosis, particularly in the liver. Lesions supportive of vascular endothelial injury are also present and include mild hydropericardium, hydrothorax and ascites; marked pulmonary congestion and oedema; lymph node congestion and oedema; and haemorrhages in many tissues. Although a complete understanding of RVF pathogenesis is still lacking, antigen-presenting cells in the skin are likely the early targets of the virus. Following suppression of type I IFN production and necrosis of dermal cells, RVFV spreads systemically, resulting in infection and necrosis of other cells in a variety of organs. Failure of both the innate and adaptive immune responses to control infection is exacerbated by apoptosis of lymphocytes. An excessive pro-inflammatory cytokine and chemokine response leads to microcirculatory dysfunction. Additionally, impairment of the coagulation system results in widespread haemorrhages. Fatal outcomes result from multiorgan failure, oedema in many organs (including the lungs and brain), hypotension, and circulatory shock. Here, we summarize current understanding of RVF cellular tropism as informed by lesions caused by natural infections. We specifically examine how extant knowledge informs current understanding regarding pathogenesis of the haemorrhagic fever form of RVF, identifying opportunities for future research.

Hemorrhagic fevers of viral nature. State of the problem and directions for creating effective means of prevention and treatment

Abstract. An attempt to summarize the data of available information materials on epidemiological aspects, the state and prospects of prevention and treatment of hemorrhagic fevers was. Hemorrhagic fevers of viral nature-zoonotic diseases caused by viruses containing ribonucleic acid are classified into 4 families: Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae. They are spread all over the world, and their pathogens are easily transmitted from person to person, thereby spreading quickly enough beyond the main focus of biological infection. That is why the causative agents of hemorrhagic fevers are regarded as highly contagious biological agents, and agents bioterrorism. Unfortunately, there are currently no effective means of specific prevention and treatment of these infections, and therapeutic measures are limited to the use of symptomatic means. In this regard, the search for substances with pronounced antiviral activity against pathogens of hemorrhagic fevers that can effectively protect against these infections, as well as prevent their occurrence and spread is one of the priority areas of research in modern Infectology, and with the involvement of modern achievements in the field of molecular Virology and genetic engineering. The data obtained in this regard allow a more in-depth understanding of the pathogenesis of hemorrhagic fevers, the mechanisms of interaction of the pathogen with the host at the cellular level, the mechanisms of intracellular replication of viruses, the formation of the hosts response to viral invasion and clinical manifestations of diseases.

Introduction of Vaccinomics to Develop Personalized Vaccines in Light of Changes in the Usage of Hantaan Virus Vaccine (Hantavax®) in Korea.

The Ministry of Food and Drug Safety of Korea made an official announcement in March 2018 that the total number of inoculations of Hantaan virus vaccine (Hantavax®) would change from 3 to 4. Some aspects of this decision remain controversial. Based on the characteristics of Hantaan virus (HTNV) and its role in the pathogenesis of hemorrhagic fever with renal syndrome, it might be difficult to develop an effective and safe HTNV vaccine through the isolate-inactivate-inject paradigm. With the development of high-throughput ‘omics’ technologies in the 21st century, vaccinomics has been introduced. While the goal of vaccinomics is to develop equations to describe and predict the immune response, it could also serve as a tool for developing new vaccine candidates and individualized approaches to vaccinology. Thus, the possibility of applying the innovative field of vaccinomics to develop a more effective and safer HTNV vaccine should be considered.

The Role of Innate and Adaptive Immune Response Lymphocytes in Pathogenesis of Hemorrhagic Fever with Renal Syndrome

The Role of Innate and Adaptive Immune Response Lymphocytes in Pathogenesis of Hemorrhagic Fever with Renal Syndrome

Human hemorrhagic Fever causing arenaviruses: molecular mechanisms contributing to virus virulence and disease pathogenesis.

Arenaviruses include multiple human pathogens ranging from the low-risk lymphocytic choriomeningitis virus (LCMV) to highly virulent hemorrhagic fever (HF) causing viruses such as Lassa (LASV), Junin (JUNV), Machupo (MACV), Lujo (LUJV), Sabia (SABV), Guanarito (GTOV), and Chapare (CHPV), for which there are limited preventative and therapeutic measures. Why some arenaviruses can cause virulent human infections while others cannot, even though they are isolated from the same rodent hosts, is an enigma. Recent studies have revealed several potential pathogenic mechanisms of arenaviruses, including factors that increase viral replication capacity and suppress host innate immunity, which leads to high viremia and generalized immune suppression as the hallmarks of severe and lethal arenaviral HF diseases. This review summarizes current knowledge of the roles of each of the four viral proteins and some known cellular factors in the pathogenesis of arenaviral HF as well as of some human primary cell-culture and animal models that lend themselves to studying arenavirus-induced HF disease pathogenesis. Knowledge gained from these studies can be applied towards the development of novel therapeutics and vaccines against these deadly human pathogens.

Soluble Scavenger Receptor CD163 Is Associated with Severe Acute Kidney Injury in Patients with Hantaan Virus Infection.

CD163, a hemoglobin scavenger receptor for haptoglobin-hemoglobin complexes, is expressed by monocytes/macrophages and is often shed as soluble CD163 (sCD163) in response to inflammatory stimuli. This scavenger receptor is reported to dampen the inflammatory response, and high plasma levels of sCD163, which are thought to reflect the total level of CD163 expression, may predict the severity of disease. To understand the role of sCD163 in the pathogenesis of hemorrhagic fever with renal syndrome (HFRS) better, the concentrations of sCD163 in plasma from 66 patients were quantified, and the relationships between sCD163 level and disease course, severity, and clinical parameters were analyzed. The level of plasma sCD163 in HFRS patients was elevated from fever onset and during the course of the disease, and it peaked in the oliguria stage at 874.5 (549.9-1138.0) ng/mL compared with controls at 192.8 (54.9-282.1) ng/mL. The correlations between plasma sCD163 and renal dysfunction suggest that sCD163 may play an important role in the development of acute renal failure in patients infected with Hantaan virus.

Differentially Expressed Genes of Human Microvascular Endothelial Cells in Response to Anti-Dengue Virus NS1 Antibodies by Suppression Subtractive Hybridization

It has been previously shown that anti-dengue virus (DENV) nonstructural protein NS1 antibodies could act as autoantibodies that direct against one or more of the host's own proteins, which has potential implications for dengue hemorrhagic fever pathogenesis. In the present study, we have employed suppression subtractive hybridization (SSH) to identify the differentially expressed genes from human microvascular endothelial cells (HMEC-1) in response to anti-dengue virus type 2 NS1 antibodies (anti-DENV2 NS1 Abs). A total of 35 clones from the SSH cDNA library were randomly selected for further analysis using bioinformatics tools after vector screening. After searching for sequence homology in NCBI GenBank database with BLASTN and BLASTX programs, 23 obtained sequences with significant matches (E-values <1×10(-4)) in the SSH library. The predicted genes in the subtracted library include immune response molecules (CD59 antigen preproprotein preproprotein, MURR1), signal transduction molecules (Nuclear casein kinase and cyclin-dependent kinase substrate 1), calcium-binding proteins (S100A6, Annexin A2 isoform 1/2), and cell-membrane component (Yip1 domain family). From these clones, 5 upregulated genes were selected for differential expression profiling by real-time RT-PCR to confirm their upregulated status. The results confirmed their differential upregulation, and thus verified the success of SSHs and the likely involvement of these genes in dengue pathogenesis.

Determination of urine tumor necrosis factor, IL-6, IL-8, and serum IL-6 in patients with hemorrhagic fever with renal syndrome

ObjectiveThe aim of this study was to explore the role of cytokines in the pathogenesis of hemorrhagic fever with renal syndrome (HFRS). MethodsDouble-antibody sandwich ELISA was used to determine serum interleukin (IL)-6, urine tumor necrosis factor (TNF), IL-6, and IL-8 levels in 56 patients with HFRS. ResultsSerum IL-6, urine TNF, IL-6, and IL-8 concentrations in HFRS patients were significantly higher than those in the control group (p<0.001). The concentrations increased at fever stage, then continued to increase during the hypotension stage and peaked at the oliguria stage. The concentrations of serum IL-6, urine TNF, IL-6, and IL-8 increased according to the severity of the disease, and differed greatly among different types of the disease. Serum IL-6 had remarkable relationships with serum specific antibodies. It was positively related to serum β2-microglobulin (β2-MG), blood ureanitrogen (BUN), and creatinine (Cr). Significant positive relationships were also found both between urine IL-6 and TNF, and between IL-6 and IL-8 (r=0.5768, p<0.05; r=0.3760, p<0.01). ConclusionTNF, IL-6, and IL-8 were activated during the course of the disease. IL-6 was associated with the immunopathological lesions caused by the hyperfunction of the humoral immune response. IL-6, IL-8 and TNF were involved in renal immune impairment. Determining them might, to a certain extent, be useful in predicting the prognosis and outcome of patients with HFRS.

Mouse Models for Filovirus Infections

The filoviruses marburg- and ebolaviruses can cause severe hemorrhagic fever (HF) in humans and nonhuman primates. Because many cases have occurred in geographical areas lacking a medical research infrastructure, most studies of the pathogenesis of filoviral HF, and all efforts to develop drugs and vaccines, have been carried out in biocontainment laboratories in non-endemic countries, using nonhuman primates (NHPs), guinea pigs and mice as animal models. NHPs appear to closely mirror filoviral HF in humans (based on limited clinical data), but only small numbers may be used in carefully regulated experiments; much research is therefore done in rodents. Because of their availability in large numbers and the existence of a wealth of reagents for biochemical and immunological testing, mice have become the preferred small animal model for filovirus research. Since the first experiments following the initial 1967 marburgvirus outbreak, wild-type or mouse-adapted viruses have been tested in immunocompetent or immunodeficient mice. In this paper, we review how these types of studies have been used to investigate the pathogenesis of filoviral disease, identify immune responses to infection and evaluate antiviral drugs and vaccines. We also discuss the strengths and weaknesses of murine models for filovirus research, and identify important questions for further study.

Hantaan Virus RNA Load in Patients Having Hemorrhagic Fever With Renal Syndrome: Correlation With Disease Severity

To investigate the role of viral load in the pathogenesis of hemorrhagic fever with renal syndrome, the Hantaan virus RNA load in plasma from 101 patients was quantified, and the relationships between viral load and disease course, severity, and level of specific humoral immunity were analyzed. The viral load, detectable in 79 patients, ranged from 3.43 to 7.33 log10 copies/mL of plasma. In the early stage of disease, patients in severe/critical group were found to have higher viral loads than those in the mild/moderate group (5.90 vs 5.03 log10 copies/mL; P = .001), suggesting an association between Hantaan virus load and disease severity.

Levels of HTNV-specific CD8+ T lymphocytes in PBMC from the patients with hemorrhagic fever with renal syndrome

The pathogenesis of hemorrhagic fever with renal syndrome (HFRS) has not been fully clarified. Cell-mediated immunity appears to play a crucial role in the immune pathogenesis of HFRS. To explore the relationship between Hantaan (HTNV)-specific CD8(+) T lymphocytes and the immune pathogenesis of HFRS, the levels of interferon γ (IFN-γ) secreted by HTNV-specific CD8(+) T lymphocytes were detected by flow cytometry in peripheral blood mononuclear cells. Levels of HTNV-specific CD8(+) T lymphocytes in patients with HFRS were associated with different phases of HFRS. In fever phase, it was significantly elevated. The levels of HTNV-specific CD8(+) T lymphocytes in PBMC of patients with HFRS were negatively correlated with the levels of blood urea nitrogen and creatinine in plasma. The results show that the HTNV-specific CD8(+) T lymphocyte levels correlate with disease phases. Therefore, dynamic observation of these levels in patients with HFRS can help to judge the status of HFRS disease and to clarify the immune pathogenesis of HFRS.

Dobrava Virus RNA Load in Patients Who Have Hemorrhagic Fever with Renal Syndrome

To asses the role of virus load in the pathogenesis of hemorrhagic fever with renal syndrome, the serum Dobrava virus RNA load in 46 patients was measured with a novel quantitative real-time reverse-transcriptase polymerase chain reaction assay and compared to the disease severity. The level of viremia, detected in 26 patients, ranged from 10(2)-10(8) copies/mL of serum. The patients with severe disease had, on average, higher viral RNA loads than patients with a milder course of disease (6.15 vs. 4.67 log(10) copies/mL; P = .053). These results suggest that the Dobrava virus load might be associated with the severity of disease.

Ethnicity and Difference in Dengue Virus-Specific Memory T Cell Responses in Cuban Individuals

The different risk factors associated with dengue hemorrhagic fever pathogenesis needs yet additional clarification. The exceptional epidemiological circumstances in Cuba allow their evaluation in a well-defined situation. In the present study the memory T cell response of 80 Cuban donors previously infected with dengue-1 and dengue-2 during the 1977 and 1981 epidemics, and belonging to different ethnic groups, was examined. White people showed, in contrast to black people, stronger and remarkably cross-reactive dengue virus-specific memory CD4(+) T lymphocyte proliferation and interferon-gamma release. The observed variation in T cell response according to ethnicity could be related to the immunopathogenesis of dengue hemorrhagic fever, and may partially explain the epidemiological evidence that black individuals are at lower risk for the most severe dengue clinical course compared with white individuals.

Implication of a retrovirus‐like glycoprotein peptide in the immunopathogenesis of Ebola and Marburg viruses

Ebola and Marburg viruses can cause hemorrhagic fever (HF) outbreaks with high mortality in primates. Whereas Marburg (MARV), Ebola Zaire (ZEBOV), and Ebola Sudan (SEBOV) viruses are pathogenic in humans, apes, and monkeys, Ebola Reston (REBOV) is pathogenic only in monkeys. Early immunosuppression may contribute to pathogenesis by facilitating viral replication. Lymphocyte depletion, intravascular apoptosis, and cytokine dysregulation are prominent in fatal cases. Here we functionally characterize a 17 amino acid domain in filoviral glycoproteins that resembles an immunosuppressive motif in retroviral envelope proteins. Activated human or rhesus peripheral blood mononuclear cells (PBMC) were exposed to inactivated ZEBOV or a panel of 17mer peptides representing all sequenced strains of filoviruses, then analyzed for CD4+ and CD8+ T cell activation, apoptosis, and cytokine expression. Exposure of human and rhesus PBMC to ZEBOV, SEBOV, or MARV peptides or inactivated ZEBOV resulted in decreased expression of activation markers on CD4 and CD8 cells; CD4 and CD8 cell apoptosis as early as 12 h postexposure; inhibition of CD4 and CD8 cell cycle progression; decreased interleukin (IL)-2, IFN-gamma, and IL12-p40 expression; and increased IL-10 expression. In contrast, only rhesus T cells were sensitive to REBOV peptides. These findings are consistent with the observation that REBOV is not pathogenic in humans and have implications for understanding the pathogenesis of filoviral HF.

A clinical study on CD178 positive T lymphocyte in hemorrhagic fever with renal syndrome

To further probe into the role of CD178 in the pathogenesis of hemorrhagic fever with renal syndrome (HFRS). The expression of CD178 and HLA-DR on T cell subsets in peripheral blood of patients with HFRS and their dynamic changes were detected by Flow cytometry. CD4+ CD178+ and CD8+ CD178+ T lymphocytes both in fever and polyuria phases were significantly higher than those in normal controls, while there was no significant difference between the both phases of HFRS (P > 0.05). CD178 expression on CD4+ HLA-DR+ and CD8+ HLA-DR+ T lymphocytes were significantly higher than those in normal controls (P < 0.05, P < 0.01, P < 0.001, P < 0.001), while there was no significant difference between CD4+ HLA-DR+ and CD8+ HLA-DR+ T lymphocytes (P > 0.05). CD178 was expressed on both CD4+ and CD8+ T cell subsets, but mainly on CD8+ T cell subsets both in early stage and in later stage in the pathogenesis of HFRS. Cytotoxic T lymphocyte (CTL) might kill target cells infected by hantavirus (HV) and eliminate HV via cell apoptosis mediated by CD178 in early stage of HFRS. In later stage of HFRS, CD178 might reduce antigen-specific T lymphocytes by activation induced cell death (AICD) and help to maintain the homeostasis of immune system.

The contribution of the endothelium to the development of coagulation disorders that characterize Ebola hemorrhagic fever in primates

Recently, there have been substantial developments in the understanding of Ebola hemorrhagic fever pathogenesis, but there are still major gaps. These infections occur in underdeveloped areas of the world, and much of our knowledge of naturally occurring disease is derived from sporadic outbreaks that occurred decades in the past. Recently conducted laboratory animal studies have provided insight into Ebola pathogenesis and may help guide clinical investigations of disease using contemporary methodologies that were not available previously. A better understanding of the relevant host and viral factors that influence clinical and virologic outcome will be critical to our ability to combat this aggressive pathogen. This article reviews the most relevant information relating to the postulated pathogenesis of this disease, focusing on the role of the endothelium in contributing to the coagulation disorders that characterize Ebola hemorrhagic fever in primates. Some of the remaining and key unanswered questions relating to the role of the vascular system in the pathogenesis of this disease, that need to be addressed in further research, are highlighted.