Ebola Flashcards
What is the definition of an emerging virus?
virus is:
- newly appearing
- notably increasing incidence/geographic range
- potential of increase in near future
Ebolavirus
- discovered ne’er Ebola river (Congo, 1976)
- incubation 8-10 days (transmission after 4/5
- unspecific symptoms; first dry than wet
- Zoonosis
- virus forms filaments of various shapes
- constant diameter (80nm)
- (-)ssRNA in nucleocapsid
- lipid membrane envelope contains GP trimers (random)
Ebolavirus pathogenesis
- infects macrophages and DCs
- massive immune dysregulation -> cytokine storm
- systemic spread leads to massive organ dysfunction and tissue damage
How is EBV transmitted?
- infected animals
- body fluids
- contaminated objects/dead bodies
- sexual contact
-> zoonotic
outbreak in the DRC (18-20)
- 3481 cases, 2299 deaths -> case fatality rate: 66%
- not only rural areas
- active conflict area
EbolaV genome
- (-)ssRNA
- 5‘ methyl cap and 3‘ poly (A) tail
- transcriptional stutter at a centrally located poly-U domain results in membrane bound GP and secreted GP and decoy GP (70%)
What is the problem in EbolaV therapy development?
- only ~35,000 cases since 1976
- 28,610 in outbreak 2014-16
- hard to do clinical studies
- hard to get funding -> rare disease
Are there vaccines against EbolaV?
Yes
1. rVSV ZEBOV-GP (approved 19.12.19)
- recombinant, replication-competent vector vaccine
- GP of Zaire-EBV
- no cross protection
- Zabdeno-Mvabea
- approved for kids >1
- two dose regimen -> not suitable for outbreak
- first dose is adenovirus vector vaccine
- second dose is MVA (poxvirus) vector vaccine (8 weeks later)
- multivalent -> also other EBV species
Name possible drug targets for EbolaV
- entry
- transcription & replication
- assembly and maturation
Describe EbolaV cell entry
- EvolaV uses multiple receptors with low specificity
- virus internalisation via macropinocytosis
GP has two parts: GP1 for receptor-binding and GP2 for membrane fusion
- GP is cleaved in endosome
-> GP1 interacts with NPC-1, GP2 accessible -> endosome fusion
NPC -> disease with defective NPC-1 -> immune to EbolaV
Name EbolaV entry inhibitors
all only affect early infection stages -> better for prophylaxis
- Two-pore channel 2 inhibitor: inhibits EbolaV disease in mouse when given at day 0; targets host
- GP related entry inhibitors:
a) targets Cathepsin B cleavage of GP; targets host
b) destabilise GP -> no membrane fusion; bind to pocket in EbolaV GP - Cationic amphiphilic drugs (CAD): bind directly to NPC-1; FDA approved; conflicting data on efficiency in mouse model
Name RdRp inhibitors for EbolaV
- L-protein of EbolaV must interact with VP35 to be functional
- nucleoside analogues lead to chain termination
- remdesivir also active against other viruses
- BCX4430 targets only (-)RNA viruses
- lipid conjugation helps membran permeability (Brincidofovir)
How do GP related glycosylation inhibitors work
- sugars of GP must be trimmed properly for folding and maturation
- inhibition of host glycosidase leads to dysfunctional GP
- Imino sugars are competitive inhibitors of glycosidases
What impact has the inhibition of host kinases?
- the major matrix protein VP40 must be phosphorylated to be functional (genome/protein) transport
- kinase inhibition reduces virus budding
-Nilotinib & Imatinib
Name the approved EbolaV drugs and there mode of action
mAB 114 and REGN-EB3
mAB 114 is single human mAB specific for Zaire EbolaV; rescues 100% of rhesus m. when treated up to 5 days post-challenge
REGN-EB3 is combination of 3 human mAB specific for Zaire EbolaV; rescues 100% of rhesus m. when treated up to 5 days post-challenge
