Hantavirus
Hantavirus
Hantavirus
History
Hantaviruses are rodent-borne viruses which may be transmitted to humans in aerosolized urine, feces, or saliva, and occasionally by bite. Hantaviruses often cause either hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS) Other hantaviruses are not known to be human pathogens.
Hantavirus in the US
Prior to the HPS outbreak, the only known hantaviruses were those that caused HFRS At least three other hantaviruses, New York Virus, Bayou Virus, and Black Creek Canal virus have since been confirmed to cause HPS in the U.S.
History of HFRS
While HPS has only been identified since 1993, HFRS has a much longer and complex history. HFRS may have been recognized in China as early as 1000 years ago. HFRS described in 1913 Russian records
History of HFRS
Outbreaks of HFRS in the 1930s: Russia (1932) Japanese troops in Manchuria (1934) Sweden (1934)
Characterization of HFRS
1934 -Japanese outbreak led to studies by Japanese physicians 1940- Japanese physicians compiled a clinical and pathological description of what was then called epidemic hemorrhagic fever. First to implicate mice in disease transmission. Physicians injected filtrates of tissue from Apodemus agrarius carrying the hantavirus Hantaan into human subjects.
History of HFRS
1939-Russian studies also implicated mice in disease transmission. 1961- Moscow outbreak affecting 113 of 186 workers linked to rodent shipment
Characterization of HFRS
1967-Russian scientists Yankovski and Povalishina provide more insight into disease. Incubation period up to 6 weeks Cycles of virus activity parallel population cycles of field mice Transmission of disease occurred via inhalation of dust contaminated by rodent excretions.
Family Bunyaviridae
5 genera, 250 species
Genus Bunyavirus Human disease LaCrosse encephalitis, others
Phlebovirus
Nairovirus Tospovirus
Hantavirus
Hantavirus Genus
Hantavirus Similarities
RNA viruses Lipid membrane Tri-segmented genome
Hantavirus Differences
Hantavirus transmitted through aerosolized rodent urine, feces and saliva. Others genera transmitted through arthropod vectors.
Transmission of Hantaviruses
Chronically infected rodent Horizontal transmission of infection by intraspecific aggressive behavior
Secondary aerosols, mucous membrane contact, and skin breaches are also sources of infection
Courtesy of CDC
Rodent Hosts
Virus Strain
Hantaan Dobrav Seoul a Thailand Prospect Hill Puumala Sin Nombre New York
Rodent Host
Apodemus agrarius
Apodemus flavicollis Rattus norvegicus
Murinae
Bandicota indicus
Microtus pennsylvanicus Clethrionomys glareolus Peromyscus maniculatus Peromyscus leucopus
Arvicolinae
Sigmodontinae
New York
Peromyscus leucopus
Muleshoe
Sigmodon hispidus
Prospect Hill
Microtus pennsylvanicus
Bloodland Lake
Isla Vista
Microtus californicus
Microtus ochrogaster
El Moro Canyon
Reithrodontomys megalotis
Calabazo
Zygodontomys brevicauda Sigmodon alstoni Oligoryzomys Rio Mamore fulvescens Oligoryzomys microtis
Rio Segundo
Reithrodontomys mexicanus
Choclo
Juquitiba
Maciel
Necromys benefactus
Hu39694
Oligoryzomys longicaudatus
Unknown Host
Bermejo
Oligoryzomys chacoensis
Lechiguanas
Oligoryzomys flavescens
Andes
Oligoryzomys longicaudatus
Pergamino
Courtesy of CDC
Akodon azarae
Brazil (168)
Paraguay (74)
Uruguay (23) Argentina (404)
Virion Properties
Spherical or oval-shaped. 80-120 nm diameter Unique grid-like surface pattern, with 7-8 nm projections Lipid bilayer envelope Granulofilamentous interior Survive 12 hours at 4C, high salt concentration and nonphysiological pH. Survives 1-3 days after drying. Exposure to lipid solvents and nonionic detergents destroys viral envelope
Structure
Structural Proteins
Membrane glycoproteins (G1 and G2) Polymerase (L)
Membrane Glycoproteins
G1: 64-67kDa G2: 54 kDa, highly conserved Integral membrane proteins G1-G2 heterodimers form 8 nm projections on virion surface Cysteine-rich Contain asparagine-linked sugar groups Important in cell entry and pathogenesis
Polymerase (L)
247 kDA RNA-dependent RNA polymerase (RdRp) Complexed with ribonucleocapsids in virion Endonuclease activity to cleave host mRNA Transcriptase activity for making cRNA and mRNA from vRNA Helicase activity to unwind vRNA during transcription
Genomic Organization
Tripartite negative sense genome Small (S) segment, 1.7-2.1kb, codes for N nucleocapsid protein Medium (M) segment, 3.6-3.7kb, codes for G1 and G2 glycoproteins Large (L) segment, 6.5 kb, codes for L polymerase protein
Coding Strategy
Panhandle Structure
Conserved repeated complementary sequences at 5 and 3 ends form panhandle structures
Transcription
Viral polymerase transcribes negative-strand vRNA to mRNA Polymerase acts as a endonuclease and cleaves host mRNAs 7-18 nt from the 5 cap The capped oligonucleotides act as primers required to initiate transcription After transcription is primed and the first repeat of the terminal sequence is transcribed, polymerase slips and realigns the nascent RNA, then continues transcription
Replication
Viral polymerase transcribes negativestrand vRNA to sense cRNA cRNA is used as template to make more negative-strand vRNA pppG is used to prime cRNA and vRNA synthesis Same prime and realign strategy
Attachment
Entry
Uncoating Transcription Replication Release
Assembly Translation
Attachment
Viral G1 and G2 glycoproteins interact with cell surface receptors Pathogenic hantaviruses bind 3 integrins Non-pathogenic hantaviruses bind 1 receptors
Entry
Primary Transcription
Transcription of negative sense vRNA to mRNA Viral polymerase (RdRp) transcribes nucleoprotein-coated vRNA Capped oligonucleotides from cells own mRNA are used to prime transcription Follows prime and realign model
Translation
L and S segment mRNA is translated on free ribosomes in cytoplasm M segment mRNA translated on ER-bound ribosomes G1 and G2 peptides produced from M mRNA are cleaved cotranslationally Separate signal sequences for G1 and G2 cause ER attachment and embed the peptides in ER membrane (Signal Hypothesis)
Translation
Genome Replication
vRNA is used as a template by viral polymerase to make sense strand cRNA cRNA is used as a template to make more negative strand vRNA More genetic material means more virions produced
Secondary Transcription
Extra vRNA synthesized during replication is used as template to make mRNA Since more template is present after vRNA is replicated, more mRNA can be transcribed, and more viral proteins can be made
Virion Assembly
Membrane-bound G1 and G2 peptides are transported to Golgi and carbohydrates are attached by N-linked glycosylation vRNA complexes with N nucleopcapsid protein, forms looped panhandle structure, and complexes with L polymerase
Virion Assembly
Integrins
Heterodimeric receptors composed of and subunits Present on endothelial cells, macrophages, and platelets cells affected by Hantavirus infection Normally involved in regulation of endothelial cell adhesion, platelet aggregation, Ca++ channel activation, and extracellular matrix interactions, including cell migration
3-Integrins
Required for infection by pathogenic Hantaviruses 1 integrins are used by non-pathogenic strains Attachment of G1/G2 proteins of viroid to integrin initiates endocytosis, but also activates the receptor Variation in virus G1/G2 protein may account for severity of disease
Immune Reaction
Immune system activated against Hantavirus epitopes Virus epitopes expressed on surface of host cells triggers cytotoxic T-cell attack on host tissues Symptoms are consistent with inflammatory response
HFRS
A group of clinically similar diseases that occur throughout Europe and Asia Includes several diseases that formerly had other names, including Korean hemorrhagic fever, epidemic hemorrhagic fever and nephropathia epidemica ~15% fatality
3-5 days Characterized by fever, chills Headache, severe myalgia (muscle pain), nausea Blurred vision, photophobia, eye pain caused by movement Flushing of face, V-area of the neck and back Petechiae (small red spots on skin) Abdominal pain and back pain. Thirst, edema, hemoconcentration, postural hypotension
Febrile Phase
Hypotensive phase
Hours to days Blood pressure decrease, hypovolemia (decreased blood volume), shock Worsening of bleeding manifestations: petechiae, epistaxis (nosebleed), gastrointestinal and intracranial bleeding Levels of urea and creatinine in blood rise, proteinuria (excessive protein in urine) Leukocytosis, thrombocytopenia (decreased # of platelets)
Oliguric Phase
3-7 days Marked by decreased urine production due to renal (kidney) dysfunction Hypervolemia (high blood volume) leading to hypertension Blood electrolyte imbalance Continuation of hemorrhagic symptoms Severe complications: cardiac failure pulmonary edema (swelling of lungs), and cerebral bleeding
Diuretic Phase
Several days to several weeks Beginning of recovery 3-6 liters of urine/ day; return to normal renal activity Anorexia, fatigue due to dehydration
Convalescent Phase
2-3 months Progressive improvement in glomerular filtration, renal blood flow, and urine concentrating ability
HPS
1993 four corners outbreak Cases found in almost all of the Americas ~50% fatality
Febrile Phase
3-5 days Fever, myalgia, malaise Other symptoms: headache, dizziness, anorexia, nausea, vomiting, and diarrhea.
Cardiopulmonary Phase
4-24 hours Presentation and rapid progression of shock and pulmonary edema (4-24h non-productive cough and tachypnea (shortness of breath) Hypovolemia due to progressive leakage of high protein fluid from blood to lung interstitium and alveoli Hypotension and oliguria Thrombocytopenia (often present in febrile phase as well) Death within 24-48 hours due to hypoxia (lack of oxygen) and/or myocardial failure
Diuretic Phase
Several days to several weeks Beginning of recovery Rapid clearance of pulmonary edema Resolution of fever and shock Anorexia, fatigue due to dehydration
Convalescent Phase
Up to 2 months Results in chronic decreased small-airway volume and diminished alveolar diffusing capacity
General Care
HFRS General treatment for renal failure Hydration Dialysis HPS General treatment for pulmonary pathology Administration of oxygen
ECMO
Ribavirin
Administered intravenously Shown to be effective against HFRS causing strains Not shown to be effective against HPS causing strains
Terrorism
Terrorism
A policy intended to strike with terror those against whom it is adopted; the employment of methods of intimidation; the fact of terrorizing or condition of being terrorized.
CDC classifications
Category A Highest priority organisms that can be easily disseminated or transmitted form person to person, results in high mortality rates and have the potential for major public health impact, might cause public panic and social disruption, and require special action for public health preparedness.
CDC Classifications
Category A Anthrax (bacillus anthracis) Botulism (clostridium botulinum) Plague (Yersinia pestis) Smallpox (variola major) Tularemia (Francisella tularensis) Viral hemorrhagic fevers
CDC Classifications
Category B Second highest priority organisms that are moderately easy to disseminate, results in moderate mortality rates, and require specific enhancements of CDC's diagnostic capacity and enhanced disease surveillance.
CDC Classifications
Category B Typhus fever Viral encephalitis Ricin toxin Food and water safety threats
CDC Classifications
Category C Third highest priority organisms that include emerging pathogens that could be engineered for mass dissemination in the future because of availability, ease of production and dissemination, and potential for high morbidity and mortality rates and major health impact.
CDC Classifications
Category C Nipah Virus Crimean-Congo Hemorrhagic Fever virus Yellow fever Multi-drug resistant TB Influenza Rabies
CDC Classifications
HFRS causing strains are Category A because of high infectivity and morbidity HPS causing strains are Category C because of low infectivity
Health Effects
High lethality No or ineffective treatment
Health Effects
Hemorrhagic Fever with Renal Syndrome Medium lethality Dramatic visual change in patients (psychological) Some success with antiviral treatments Hantavirus Pulmonary Syndrome High Lethality No effective treatment
Epidemiology
Medium incubation time in order to cause secondary infections Rodent vector Spread through aerosol HFRS causing strains known to transmit human to human Suspected human to human transmission of HPS causing strain in Argentina (Andes Virus)
Andes Virus
1996 outbreak in rural Argentina Spread to people whose only contact was a car ride Spread to several doctors caring for HPS patients Low rodent population in Argentina at the time (early spring)
Aerosolization
Virus only infectious for 1-3 days outside of a host because of a weak lipid envelope The number of particles needed to cause a human infection is not known
Cost Effectiveness
What resources would be required to successfully disseminate Hantavirus into a large population?
Cost Effectiveness
Preparation of virus using cell culture (difficult, need training and equipment) Aerosolization? Contaminated water? Creation of infected rodent population?
Psychological Effects
HFRS causes dramatic visual effects in patients HPS would be especially difficult to diagnose outside of its normal range Media coverage super flu hemorrhagic fever
Economic Impact
What effect would an outbreak of hantavirus have on the economy? Treatment Disruption of work Hysteria Even a small outbreak could cause a large disruption
Prevention
Vaccines Hygiene
Vaccines
E. Coli expressed truncated nucleocapsid as an immunogen Naked DNA Recombinant non-pathogenic virus Rodent brain-derived Cell culture derived Inactivated virus
Hygiene
Prevent aerosolization of virus from rodent excrement Dampen surfaces with detergent before cleaning General hygiene
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