Animal models: virology II Flashcards
What is the percentage of results obtained in mice models that are somehow translated to humans?
~ 8%
Why do we want fewer animals?
3E’s –> Ethics, Economics and Efficacy
What is needed to replace animal models? (3)
- Legislation
- Mindset
- Science
How can horizontal virus transmission between rodents occur? (3)
- Saliva
- Urine
- Faeces
What are Orthohantavirus transmission risk factors? (3)
- Virus in the environment
- Human infection
- Rodent infection
What are risk factors for orthohantaviruses to be in the environment? (3)
- Rodent density
- Host infection phase
- Temperature, moisture, UV-radiation
What are the risk factors for rodent infection? (9)
- Seasonality
- Age
- Sex
- Maternal antibodies
- Co-infections
- Resistance genes
- Rodent density
- Species diversity
- Habitat type
What are the risk factors for human infection? (5)
- Rodent density
- Occupation/recreation
- Environmental conditions
- Season
- Resistance genes
Why does each strain of Orthohantavirus have a specific rodent host?
Strains have co-evolved with specific rodent species
Why is there a clear geographical distribution of Orthohantavirus strains?
Strains have co-evolved with specific rodent species –> live in certain location
Rodents carrying Orthohantaviruses are mostly symptomatic/asymptomatic
Asymptomatic
What symptoms do Orthohantaviruses often cause?
Haemorrhagic fever with renal syndrome (HFRS)
Which Orthohantaviruses are found in rodents in Europe? (4)
- Puumala virus
- Dobrava virus
- Seoul virus
- Tula virus
On what factors is a Orthohantavirus infection diagnosis based?
Clinical signs and serology
Serological assays to confirm Orthohantavirus infection are based on?
Cross-reactive antigens
What are the three different clinical manifestations of Orthohantavirus infections?
- Haemorrhagic fever with renal syndrome (HFRS)
- Nephropathia epidemics (NE)
- Hantavirus cardiopulmonary syndrome (HCPS)
Which Orthohantavirus causes nephropathia epidemica (NE)?
Puumala virus
What are the structural proteins of Orthohantaviruses? (3)
- Membrane glycoproteins Gn and Gc
- Polymerase L
- Nucleocapsid N
How do Orthohantaviruses attach?
Interaction with Gn/Gc (cell surface receptors)
Which process is initiated by the attachment of Gn/Gc proteins to integrin?
Endocytosis
Which integrins are bound by pathogenic orthohantaviruses?
B3-integrins
Which integrins are bound by NON-pathogenic orthohantaviruses?
B1-receptors
Integrins are present on which cell types?
Endothelial cells, macrophages and platelets
Integrins are involved in…(3)
- Regulation of endothelial cell adhesion
- Platelet aggregation
- Extracellular matrix interactions
Which process plays a central role in the pathogenesis of Orthohantavirus infections?
Vascular barrier loss
Orthohantaviruses: what causes disruption of vascular integrity?
Binding of Orthohantavirus glycoproteins to B3-integrin
What encompasses the disruption of vascular integrity caused by Orthohantaviruses? (3)
- Capillaries more permeable
- Arteriole vasoconstriction & vasodilation disrupted
- Binding to platelet receptor affects clotting and platelet function
Why do different Orthohantaviruses have different pathogenesis?
Different viruses bind endothelium in different locations
Where do HFRS bind to the endothelium?
Lungs, kidneys, spleen
Where do HCPS bind to the endothelium?
Lungs, liver, heart, spleen
Which immune response is mounted in humans to combat Orthohantaviruses?
Virus epitopes expressed on surface of host cells –> CD8+ T cell attack on host tissue
Why does the immune response against Orthohantaviruses that is mounted in human not occur in rodents?
Downregulation by Tregs
Describe the kinetics of Orthohantavirus infection in rodents (2)
- After acute infection: virus disappears from blood
- As infection continues: long-lasting antibody response are produced
Why do rodents not get sick from hantavirus infection
Local increases of Tregs, and decreases of CD8+ T cells at primary sites of replication
What does the term ‘neuro-invasion’ mean?
The ability of a virus enter either the PNS or CNS
How is neuro-invasion described in the case of respiratory viruses?
The ability to travel from the respiratory tract to the CNS
What are the routes of virus spread into the CNS? (4)
- Peripheral nerves
- BB barrier
- Cranial nerves
- Blood-CSF barrier
Virus spread: which kind of transport is used via the peripheral nerves?
Retrogade transport
Virus spread: which kind of transport is used via the BB barrier?
Intracellular (Trojan Horse)
What does the term neurotropism mean?
The ability of a virus to infect and replicate in cells of the nervous system
What does the term neurovirulence mean?
The ability of a virus infection to cause lesions in the CNS that contribute to the development of clinical disease of the nervous system independently of its neuroinvasiveness or neurotropism
Which route of neuro-invasion occurs in SARS-CoV2 infection?
Mostly olfactory nerve
Describe the preferred neurotropism in SARS-CoV2 infection (2)
- Glomerular layer neural cells
- Cortical neurons
Describe the neurovirulence in SARS-CoV2 infection (4)
- Lasting immune activation -> cognitive impairments
- Loss of oligodendrocytes -> memory impairments
- Shrinkage of specific brain regions
- Increased risk for depression, anxiety, dementia, psychosis