Immunopathogenesis of hantavirus pulmonary syndrome and hemorrhagic fever with renal syndrome: Do CD8+ T cells trigger capillary leakage in viral hemorrhagic fevers?

This paper includes review of innovative methods of monitoring of activity of natural foci of epidemically important for Russian Federation such viral infections as hemorrhagic fever with renal syndrome (HFRS) and Crimean-Congo hemorrhagic fever (CCHF), and the analysis of probability to control such «exotic» infections, as Denge fever and severe fever with thrombocytopenia syndrome (SFTS).

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Viral hemorrhagic fevers or West Nile fever – surprise in the journey

Diagnostyka Laboratoryjna ◽

10.5604/01.3001.0009.3631 ◽

2016 ◽

Vol 52 (1) ◽

pp. 51-56

Author(s):

Jarosław Piszczyk

Keyword(s):

Circulatory System ◽

Hemorrhagic Fever ◽

Maculopapular Rash ◽

Physical Contact ◽

Hemorrhagic Diathesis ◽

West Nile Fever ◽

West Nile ◽

Hemorrhagic Fevers ◽

Ebola Hemorrhagic Fever ◽

Viral Hemorrhagic Fevers

Viral hemorrhagic fevers (VHFs) represent a group of similar clinical entities contagious constitutional diseases, caused by four different types of RNA viruses: Flaviviridae, Bunyaviridae, Arenaviridae i Filoviridae. These diseases proceed with high fever and damage of the circulatory system leading to homeostasis disorders, commonly accompanied by symptoms of hemorrhagic diathesis. VHFs are typically transmitted through infection vectors (mosquito) or through direct physical contact with infectious material. West Nile fever is the disease which is caused by West Nile virus from the Flaviviridae family. It begins flu-like symptoms, then it appears maculopapular rash and lymphadenopathy. At the most cases the symptoms retreat idiopathically. This disease can proceed as West Nile Neurological Disease in 1% of infected. The article presents three diseases, which can be present in tropical climate such as: Ebola hemorrhagic fever, dengue hemorrhagic fever, West Nile fever.

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Analysis of the Immune Response to Hantaan Virus Nucleocapsid Protein C-Terminal-Specific CD8+T Cells in Patients with Hemorrhagic Fever with Renal Syndrome

Viral Immunology ◽

10.1089/vim.2008.0097 ◽

2009 ◽

Vol 22 (4) ◽

pp. 253-260 ◽

Cited By ~ 9

Author(s):

Ping-Zhong Wang ◽

Chang-Xing Huang ◽

Ye Zhang ◽

Zhi-Dong Li ◽

Hai-Tao Yu ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Cd8 T Cells ◽

Nucleocapsid Protein ◽

Protein C ◽

Hemorrhagic Fever ◽

Hantaan Virus

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Contributions of mast cells and vasoactive products, leukotrienes and chymase, to dengue virus-induced vascular leakage

eLife ◽

10.7554/elife.00481 ◽

2013 ◽

Vol 2 ◽

Cited By ~ 88

Author(s):

Ashley L St John ◽

Abhay PS Rathore ◽

Bhuvanakantham Raghavan ◽

Mah-Lee Ng ◽

Soman N Abraham

Keyword(s):

Mast Cells ◽

Dengue Virus ◽

Hemorrhagic Fever ◽

Denv Infection ◽

Vascular Leakage ◽

Clinical Samples ◽

Specific Product ◽

Hemorrhagic Fevers ◽

Viral Hemorrhagic Fevers

Dengue Virus (DENV), a flavivirus spread by mosquito vectors, can cause vascular leakage and hemorrhaging. However, the processes that underlie increased vascular permeability and pathological plasma leakage during viral hemorrhagic fevers are largely unknown. Mast cells (MCs) are activated in vivo during DENV infection, and we show that this elevates systemic levels of their vasoactive products, including chymase, and promotes vascular leakage. Treatment of infected animals with MC-stabilizing drugs or a leukotriene receptor antagonist restores vascular integrity during experimental DENV infection. Validation of these findings using human clinical samples revealed a direct correlation between MC activation and DENV disease severity. In humans, the MC-specific product, chymase, is a predictive biomarker distinguishing dengue fever (DF) and dengue hemorrhagic fever (DHF). Additionally, our findings reveal MCs as potential therapeutic targets to prevent DENV-induced vasculopathy, suggesting MC-stabilizing drugs should be evaluated for their effectiveness in improving disease outcomes during viral hemorrhagic fevers.

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Viral Hemorrhagic Fevers (Ebola, Lassa, Hantavirus)

10.1093/med/9780199976805.003.0066 ◽

2016 ◽

Author(s):

Marcos Schechter

Keyword(s):

Laboratory Finding ◽

Antiviral Drug ◽

Hemorrhagic Fever ◽

The United States ◽

Hemorrhagic Fevers ◽

Bodily Fluids ◽

Organ Systems ◽

Viral Hemorrhagic Fevers ◽

High Concentrations ◽

Common Laboratory

Viral hemorrhagic fever (VHF) designates diseases caused by enveloped, single-stranded RNA viruses belonging to the families Ebola, Lassa, Hantavirus, and yellow fever. Unifying features include fever, capillary leak, and coagulation defects. These viruses can affect all organ systems; transmission occurs via contact with rodent excretions, either by ingestion or through mucosa or non-intact skin. Aerosolized rodent urine and saliva are also infectious. Person-to-person spread has been documented in Lassa and Machupo viruses, both by direct contact with bodily fluids and by airborne transmission. Thrombocytopenia is a common laboratory finding. Most acutely ill patients have high concentrations of virus in the blood as measured by polymerase chain reaction assay. Clinical differentiation between the various causes of VHF is difficult. Care is supportive. No antiviral drug, including ribavirin, has activity against these viruses. Most of these diseases do not occur naturally in the United States; however, some are considered viable for bioterrorism.

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The Glycoprotein of the Live-Attenuated Junin Virus Vaccine Strain Induces Endoplasmic Reticulum Stress and Forms Aggregates prior to Degradation in the Lysosome

Journal of Virology ◽

10.1128/jvi.01693-19 ◽

2020 ◽

Vol 94 (8) ◽

Author(s):

John T. Manning ◽

Nadya E. Yun ◽

Alexey V. Seregin ◽

Takaaki Koma ◽

Rachel A. Sattler ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Vaccine Strain ◽

Hemorrhagic Fever ◽

Wild Type ◽

Live Attenuated Vaccine ◽

Hemorrhagic Fevers ◽

Attenuated Vaccine ◽

Argentine Hemorrhagic Fever ◽

Viral Hemorrhagic Fevers ◽

Junín Virus

ABSTRACT Argentine hemorrhagic fever is a potentially lethal disease that is caused by Junin virus (JUNV). There are currently around 5 million individuals at risk of infection within regions of endemicity in Argentina. The live attenuated vaccine strain Candid #1 (Can) is approved for use in regions of endemicity and has substantially decreased the number of annual Argentine hemorrhagic fever (AHF) cases. The glycoprotein (GPC) gene is primarily responsible for attenuation of the Can strain, and we have shown that the absence of an N-linked glycosylation motif in the subunit G1 of the glycoprotein complex of Can, which is otherwise present in the wild-type pathogenic JUNV, causes GPC retention in the endoplasmic reticulum (ER). Here, we show that Can GPC aggregates in the ER of infected cells, forming incorrect cross-chain disulfide bonds, which results in impaired GPC processing into G1 and G2. The GPC fails to cleave into its G1 and G2 subunits and is targeted for degradation within lysosomes. Cells infected with the wild-type Romero (Rom) strain do not produce aggregates that are observed in Can infection, and the stress on the ER remains minimal. While the mutation of the N-linked glycosylation motif (T168A) is primarily responsible for the formation of aggregates, other mutations within G1 that occurred earlier in the passage history of the Can strain also contribute to aggregation of the GPC within the ER. IMPORTANCE The development of vaccines and therapeutics to combat viral hemorrhagic fevers remains a top priority within the Implementation Plan of the U.S. Department of Health and Human Services Public Health Emergency Medical Countermeasures Enterprise. The Can strain, derived from the pathogenic XJ strain of JUNV, has been demonstrated to be both safe and protective against AHF. While the vaccine strain is approved for use in regions of endemicity within Argentina, the mechanisms of Can attenuation have not been elucidated. A better understanding of the viral genetic determinants of attenuation will improve our understanding of the mechanisms contributing to disease pathogenesis and provide critical information for the rational design of live attenuated vaccine candidates for other viral hemorrhagic fevers.

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Persistent Infection with Ebola Virus under Conditions of Partial Immunity

Journal of Virology ◽

10.1128/jvi.78.2.958-967.2004 ◽

2004 ◽

Vol 78 (2) ◽

pp. 958-967 ◽

Cited By ~ 54

Author(s):

Manisha Gupta ◽

Siddhartha Mahanty ◽

Patricia Greer ◽

Jonathan S. Towner ◽

Wun-Ju Shieh ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Cd8 T Cells ◽

Persistent Infection ◽

Cd4 T Cells ◽

Viral Antigen ◽

Ebola Virus ◽

Hemorrhagic Fever ◽

Subcutaneous Infection ◽

Deficient Mice

ABSTRACT Ebola hemorrhagic fever in humans is associated with high mortality; however, some infected hosts clear the virus and recover. The mechanisms by which this occurs and the correlates of protective immunity are not well defined. Using a mouse model, we determined the role of the immune system in clearance of and protection against Ebola virus. All CD8 T-cell-deficient mice succumbed to subcutaneous infection and had high viral antigen titers in tissues, whereas mice deficient in B cells or CD4 T cells cleared infection and survived, suggesting that CD8 T cells, independent of CD4 T cells and antibodies, are critical to protection against subcutaneous Ebola virus infection. B-cell-deficient mice that survived the primary subcutaneous infection (vaccinated mice) transiently depleted or not depleted of CD4 T cells also survived lethal intraperitoneal rechallenge for ≥25 days. However, all vaccinated B-cell-deficient mice depleted of CD8 T cells had high viral antigen titers in tissues following intraperitoneal rechallenge and died within 6 days, suggesting that memory CD8 T cells by themselves can protect mice from early death. Surprisingly, vaccinated B-cell-deficient mice, after initially clearing the infection, were found to have viral antigens in tissues later (day 120 to 150 post-intraperitoneal infection). Furthermore, following intraperitoneal rechallenge, vaccinated B-cell-deficient mice that were transiently depleted of CD4 T cells had high levels of viral antigen in tissues earlier (days 50 to 70) than vaccinated undepleted mice. This demonstrates that under certain immunodeficiency conditions, Ebola virus can persist and that loss of primed CD4 T cells accelerates the course of persistent infections. These data show that CD8 T cells play an important role in protection against acute disease, while both CD4 T cells and antibodies are required for long-term protection, and they provide evidence of persistent infection by Ebola virus suggesting that under certain conditions of immunodeficiency a host can harbor virus for prolonged periods, potentially acting as a reservoir.

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Comparison of MagPix Assays and Enzyme-Linked Immunosorbent Assay for Detection of Hemorrhagic Fever Viruses

Journal of Clinical Microbiology ◽

10.1128/jcm.01693-16 ◽

2016 ◽

Vol 55 (1) ◽

pp. 68-78 ◽

Cited By ~ 21

Author(s):

Neal G. Satterly ◽

Matthew A. Voorhees ◽

Abbe D. Ames ◽

Randal J. Schoepp

Keyword(s):

Immunosorbent Assay ◽

Limit Of Detection ◽

Hemorrhagic Fever ◽

Antigen Detection ◽

Enzyme Linked Immunosorbent Assay ◽

Hemorrhagic Fevers ◽

Viral Hemorrhagic Fevers ◽

Medical Countermeasures ◽

Potential Use ◽

Excellent Reproducibility

ABSTRACT Viral hemorrhagic fevers, because of their high mortality rates, the lack of medical countermeasures, and their potential use as instruments of bioterrorism, pose a significant threat to the developed and the developing areas of the world. The key to preventing the spread of these diseases is early and accurate detection. For decades, the gold-standard immunoassay for hemorrhagic fever detection has been the enzyme-linked immunosorbent assay (ELISA); however, newer technologies are emerging with increased sensitivities. One such technology is the Luminex MagPix platform using xMAP microspheres. Here, we compare the MagPix platform with a traditional ELISA for IgM and antigen detection of infections from Lassa and Ebola viruses (LASV and EBOV, respectively). For IgM detection in nonhuman primate samples, the MagPix platform was 5 and 25 times more sensitive in detecting LASV and EBOV, respectively, compared to that with ELISA. For antigen detection in buffer, the MagPix platform was 25 and 2.5 times more sensitive in detecting lower levels of LASV and EBOV, respectively. In both IgM and antigen detection assays, the MagPix platform demonstrated excellent reproducibility at the lower limit of detection (LLOD). These findings demonstrate that the MagPix platform is a viable diagnostic replacement for the ELISA for viral hemorrhagic fevers.

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