Neurological Manifestations of Hemorrhagic Fever with Renal Syndrome Caused by Puumala Virus: Review of 811 Cases

AbstractViruses from the taxonomic familyHantaviridaeare encountered as emerging pathogens causing two life-threatening human zoonoses: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) with case fatalities of up to 50%. Here we comprehensively investigated entry of the Old-World Hantavirus, Puumala virus (PUUV), into mammalian cells, showing that upon treatment with pharmacological inhibitors of macropinocytosis and clathrin-mediated endocytosis, PUUV infections are significantly reduced. We demonstrated that the inhibitors did not interfere with viral replication and that RNA interference, targeting cellular mediators of macropinocytosis, is able to decrease PUUV infection levels significantly. Moreover, we established lipophilic tracer staining of PUUV virus particles and showed co-localization of stained virions and markers of macropinocytic uptake. Cells treated with lysosomotrophic agents were shown to exhibit an increased resistance to infection, confirming previous data suggesting that a low pH-dependent step is involved in PUUV infection. Finally, we observed a significant increase in the fluid-phase uptake of cell infected with PUUV, indicative of a virus-triggered promotion of macropinocytosis.Author SummaryTheHantaviridaefamily comprises a very diverse group of virus species and is considered an emerging global public health threat. Human pathogenic hantaviruses are primarily rodent-borne. Zoonosis is common with more than 150,000 annually registered cases and a case fatality index of up to 50%. Individual hantavirus species differ significantly in terms of their pathogenicity, but also their cell biology and host-pathogen interactions. In this study, we focused on the most prevalent pathogenic hantavirus in Europe, Puumala virus (PUUV), and investigated the entry and internalization of PUUV virions into mammalian cells. We showed that both, clathrin-mediated endocytosis and macropinocytosis, are cellular pathways exploited by the virus to establish productive infections and demonstrated that pharmacological inhibition of macropinocytosis or its targeted knockdown using RNA interference significantly reduced viral infections. We also found indications for an increase of macropinocytic uptake upon PUUV infections, suggesting that the virus triggers specific cellular mechanisms in order to promote its own internalization and facilitate infections.

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Pulmonary-renal syndrome due to hemorrhagic fever with renal syndrome: an unusual manifestation of Puumala virus infection in France

Clinical Nephrology ◽

10.5414/cnp59297 ◽

2003 ◽

Vol 59 (04) ◽

pp. 297-300 ◽

Cited By ~ 15

Author(s):

D. Launay ◽

Ch. Thomas ◽

D. Fleury ◽

S. Roueff ◽

M.-L. Line ◽

...

Keyword(s):

Virus Infection ◽

Hemorrhagic Fever ◽

Puumala Virus ◽

Unusual Manifestation ◽

Puumala Virus Infection ◽

Pulmonary Renal Syndrome

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Molecular Diagnosis of Hemorrhagic Fever with Renal Syndrome Caused by Puumala Virus

Journal of Clinical Microbiology ◽

10.1128/jcm.00113-16 ◽

2016 ◽

Vol 54 (5) ◽

pp. 1335-1339 ◽

Cited By ~ 8

Author(s):

Nina Lagerqvist ◽

Åsa Hagström ◽

Malin Lundahl ◽

Elin Nilsson ◽

Mikael Juremalm ◽

...

Keyword(s):

Real Time ◽

Early Phase ◽

Genomic Sequence ◽

Winter Season ◽

Hemorrhagic Fever ◽

Diagnostic Methods ◽

Puumala Virus ◽

Rt Pcr ◽

Pcr Assay ◽

Routine Diagnosis

Rodent-borne hantaviruses cause two severe acute diseases: hemorrhagic fever with renal syndrome (HFRS) in Eurasia, and hantavirus pulmonary syndrome (HPS; also called hantavirus cardiopulmonary syndrome [HCPS]) in the Americas. Puumala virus (PUUV) is the most common causative agent of HFRS in Europe. Current routine diagnostic methods are based on serological analyses and can yield inconclusive results. Hantavirus-infected patients are viremic during the early phase of disease; therefore, detection of viral RNA genomes can be a valuable complement to existing serological methods. However, the high genomic sequence diversity of PUUV has hampered the development of molecular diagnostics, and currently no real-time reverse transcription-quantitative (RT)-PCR assay is available for routine diagnosis of HFRS. Here, we present a novel PUUV RT-PCR assay. The assay was validated for routine diagnosis of HFRS on samples collected in Sweden during the winter season from 2013 to 2014. The assay allowed detection of PUUV RNA in 98.7% of confirmed clinical HFRS samples collected within 8 days after symptomatic onset. In summary, this study shows that real-time RT-PCR can be a reliable alternative to serological tests during the early phase of HFRS.

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Monocyte subset redistribution from blood to kidneys in patients with Puumala virus caused hemorrhagic fever with renal syndrome

PLoS Pathogens ◽

10.1371/journal.ppat.1009400 ◽

2021 ◽

Vol 17 (3) ◽

pp. e1009400

Author(s):

Sindhu Vangeti ◽

Tomas Strandin ◽

Sang Liu ◽

Johanna Tauriainen ◽

Anne Räisänen-Sokolowski ◽

...

Keyword(s):

Endothelial Cells ◽

Chemokine Receptors ◽

Severe Disease ◽

Hemorrhagic Fever ◽

Puumala Virus ◽

Monocyte Subset ◽

Blood Monocytes ◽

Peripheral Tissues ◽

Hla Dr

Innate immune cells like monocytes patrol the vasculature and mucosal surfaces, recognize pathogens, rapidly redistribute to affected tissues and cause inflammation by secretion of cytokines. We previously showed that monocytes are reduced in blood but accumulate in the airways of patients with Puumala virus (PUUV) caused hemorrhagic fever with renal syndrome (HFRS). However, the dynamics of monocyte infiltration to the kidneys during HFRS, and its impact on disease severity are currently unknown. Here, we examined longitudinal peripheral blood samples and renal biopsies from HFRS patients and performed in vitro experiments to investigate the fate of monocytes during HFRS. During the early stages of HFRS, circulating CD14–CD16+ nonclassical monocytes (NCMs) that patrol the vasculature were reduced in most patients. Instead, CD14+CD16– classical (CMs) and CD14+CD16+ intermediate monocytes (IMs) were increased in blood, in particular in HFRS patients with more severe disease. Blood monocytes from patients with acute HFRS expressed higher levels of HLA-DR, the endothelial adhesion marker CD62L and the chemokine receptors CCR7 and CCR2, as compared to convalescence, suggesting monocyte activation and migration to peripheral tissues during acute HFRS. Supporting this hypothesis, increased numbers of HLA-DR+, CD14+, CD16+ and CD68+ cells were observed in the renal tissues of acute HFRS patients compared to controls. In vitro, blood CD16+ monocytes upregulated CD62L after direct exposure to PUUV whereas CD16– monocytes upregulated CCR7 after contact with PUUV-infected endothelial cells, suggesting differential mechanisms of activation and response between monocyte subsets. Together, our findings suggest that NCMs are reduced in blood, potentially via CD62L-mediated attachment to endothelial cells and monocytes are recruited to the kidneys during HFRS. Monocyte mobilization, activation and functional impairment together may influence the severity of disease in acute PUUV-HFRS.

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Macropinocytosis and Clathrin-Dependent Endocytosis Play Pivotal Roles for the Infectious Entry of Puumala Virus

Journal of Virology ◽

10.1128/jvi.00184-20 ◽

2020 ◽

Vol 94 (14) ◽

Author(s):

Sandy Bauherr ◽

Filip Larsberg ◽

Annett Petrich ◽

Hannah Sabeth Sperber ◽

Victoria Klose-Grzelka ◽

...

Keyword(s):

Rna Interference ◽

Cell Biology ◽

Mammalian Cells ◽

Case Fatality ◽

Hemorrhagic Fever ◽

Puumala Virus ◽

Virus Species ◽

Global Public Health ◽

Emerging Pathogens ◽

The Family

ABSTRACT Viruses from the family Hantaviridae are encountered as emerging pathogens causing two life-threatening human zoonoses: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS), with case fatality rates of up to 50%. Here, we comprehensively investigated entry of the Old World hantavirus Puumala virus (PUUV) into mammalian cells, showing that upon treatment with pharmacological inhibitors of macropinocytosis and clathrin-mediated endocytosis, PUUV infections are greatly reduced. We demonstrate that the inhibitors did not interfere with viral replication and that RNA interference, targeting cellular mediators of macropinocytosis, decreases PUUV infection levels significantly. Moreover, we established lipophilic tracer staining of PUUV particles and show colocalization of stained virions and markers of macropinosomes. Finally, we report a significant increase in the fluid-phase uptake of cells infected with PUUV, indicative of a virus-triggered promotion of macropinocytosis. IMPORTANCE The family Hantaviridae comprises a diverse group of virus species and is considered an emerging global public health threat. Individual hantavirus species differ considerably in terms of their pathogenicity but also in their cell biology and host-pathogen interactions. In this study, we focused on the most prevalent pathogenic hantavirus in Europe, Puumala virus (PUUV), and investigated the entry and internalization of PUUV into mammalian cells. We show that both clathrin-mediated endocytosis and macropinocytosis are cellular pathways exploited by the virus to establish productive infections and demonstrate that pharmacological inhibition of macropinocytosis or a targeted knockdown using RNA interference significantly reduced viral infections. We also found indications of an increase of macropinocytic uptake upon PUUV infection, suggesting that the virus triggers specific cellular mechanisms in order to stimulate its own internalization, thus facilitating infection.

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Dengue fever masquerading as hypokalemic paralysis: a case report

Italian Journal of Medicine ◽

10.4081/itjm.2017.767 ◽

2017 ◽

Vol 11 ◽

Author(s):

Rajesh Rajput ◽

Deepak Jain ◽

Ashima Mittal ◽

Anoop Kumar ◽

Vaibhav Pathak

Keyword(s):

Case Report ◽

Dengue Fever ◽

Dengue Hemorrhagic Fever ◽

Dengue Shock Syndrome ◽

Hemorrhagic Fever ◽

Neurological Manifestations ◽

Neurotropic Virus ◽

Tropical Countries ◽

Hypokalemic Paralysis ◽

Arboviral Disease

Dengue fever is a mosquito borne arboviral disease endemic in tropical countries. The spectrum of presentation of dengue fever ranges from classical flu like illness to dengue hemorrhagic fever and dengue shock syndrome. It is usually regarded as a non-neurotropic virus and neurological manifestations of dengue are rare and hypokalemic quadriparesis is even rarer. Here we present a case report of a patient who presented with hypokalemic quadriparesis due to dengue.

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Fluorescein iris angiography in the febrile phase of Puumala virus infection (hemorrhagic fever with renal syndrome)

Acta Ophthalmologica Scandinavica ◽

10.1034/j.1600-0420.1998.760425.x ◽

1998 ◽

Vol 76 (4) ◽

pp. 513-514

Author(s):

Tuomo Puustjärvi ◽

Matti Kontkanen ◽

Leo Repo ◽

Juhani Lähdevirta ◽

Maija Mäntyjärvi

Keyword(s):

Virus Infection ◽

Hemorrhagic Fever ◽

Puumala Virus ◽

Puumala Virus Infection

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Dengue: a new challenge for neurology

Neurology International ◽

10.4081/ni.2012.e15 ◽

2012 ◽

Vol 4 (3) ◽

pp. 15 ◽

Cited By ~ 24

Author(s):

Marzia Puccioni-Sohler ◽

Marco Orsini ◽

Cristiane N. Soares

Keyword(s):

Dengue Infection ◽

Hemorrhagic Fever ◽

Acute Disseminated Encephalomyelitis ◽

Neurological Complications ◽

Immunoglobulin M ◽

Neurological Manifestations ◽

Dengue Vaccine ◽

Autoimmune Reaction ◽

Viral Antigens ◽

The World

Dengue infection is a leading cause of illness and death in tropical and subtropical regions of the world. Forty percent of the world’s population currently lives in these areas. The clinical picture resulting from dengue infection can range from relatively minor to catastrophic hemorrhagic fever. Recently, reports have increased of neurological manifestations. Neuropathogenesis seems to be related to direct nervous system viral invasion, autoimmune reaction, metabolic and hemorrhagic disturbance. Neurological manifestations include encephalitis, encephalopathy, meningitis, Guillain-Barré syndrome, myelitis, acute disseminated encephalomyelitis, polyneuropathy, mononeuropathy, and cerebromeningeal hemorrhage. The development of neurological symptoms in patients with positive Immunoglobulin M (IgM) dengue serology suggests a means of diagnosing the neurological complications associated with dengue. Viral antigens, specific IgM antibodies, and the intrathecal synthesis of dengue antibodies have been successfully detected in cerebrospinal fluid. However, despite diagnostic advancements, the treatment of neurological dengue is problematic. The launch of a dengue vaccine is expected to be beneficial.

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