Coronaviruses Flashcards
MERS-CoV structure & classification
Family: Coronaviridae
Genus: Betacoronavirus
3 clades: A&B in Gulf, C in Africa
Enveloped (+)ssRNA
Baltimore: IV
Reservoir: Camels & bats
MERS-CoV receptor & tropism
DPP4 (CD26)
Does NOT utilise ACE2 like SARS-CoV
DPP4 expressed on human bronchial endothelium & kidneys.
MERS case definition
- SARI + one of:
A. Travel to endemic area in 14 days prior
B. Close contact with confirmed case
C. HCW based in ITU regardless of travel
D. Part of epidemiological cluster - ILI + exposure to camels/camel environments/camel meat or milk or urine in preceding 14 days
Bahrain, Jordan, Iraq, Iran, SA, Kuwait, Oman, Qatar, UAE, Yemen, Kenya
MERS diagnostics
RT-PCR targeting N/E genes
Positive results referred to UKHSA Colindale by Cat B UN3373
Human betacornoviruses
SARS
SARS-CoV-2
MERS
OC41
HKU1
MERS incubation period
2-14 days
MERS therapeutics
No proven antivirals. Few under trial:
- lopinavir/ritonavir plus IFN-beta-1b for up to 14 days
- IFN+ Ribavirin
- Remdesivir
- Mabs
MERS mortality rate
35%
SARS-CoV-2 structure & classification
Family: Coronaviridae
Genus: Betacoronavirus (SARS&MERS included)
(+)ss RNA
Baltimore: IV
Medically important coronaviruses
- Alphacoronavirus genus: HCoV-229E
HCoV-NL63 - Betacoronavirus genus:
HCoV-OC43
HCoV-HKU1
SARS-CoV
SARS-CoV-2
MERS-CoV - Gamma and Delta - avian coronaviruses
C-19 receptor and pathogenesis, antiviral mechanism
Receptor: ACE2
binds to ACE2 through the receptor-binding domain of its spike protein
SARS-CoV-2 antivirals have targeted one of two important viral proteins:
● RNA-dependent RNA polymerase (RdRp) – This is an error-prone enzyme responsible for viral replication [16]. Remdesivir, molnupiravir, and mindeudesivir (a drug available in China) target the RdRp.
● 3CL protease – This is also called the main protease, and it cleaves the polyproteins encoded by the SARS-CoV-2 RNA. Ritonavir-boosted nirmatrelvir [17], ritonavir- boosted simnotrelvir, and ensitrelvir target this protease.
C-19 variants of interest
The Pango dynamic nomenclature is a commonly referenced and important system, in which each major lineage begins with a letter, followed by additional letters or numbers
- Wildtype
- Alpha B1.1.7 (N501Y mutation)
- Beta 1.351
- Gamma P.1
- Omicron 1.1.529 - increased transmissibility & tropism for nasopharyngeal cells. BA.1 to BA.5 lineages.
Prior infection with pre-Omicron variants provides poor long-term protection against subsequent Omicron infection; in one meta-analysis, it was estimated to reduce the risk by approximately 35 percent after 40 weeks. Infection with one Omicron sublineage also does not prevent reinfection with a second Omicron sublineage.
- FLiRT variants characterized by specific spike mutations-F to L at position 456 and R to T at position 346-enhancing their transmissibility and immune evasion capabilities. KP 1 to 3.
C-19 diagnostics
- RT-PCR: targets S, N, E, or RdRp genes
- NGS - Genexus
- LFT - S & N genes
- Serology
C-19 therapeutics in OP
Outpatient:
- Nirmatrelvir-ritonavir 300/100 mg x 5 days - a combination of oral protease inhibitors.
Nirmatrelvir blocks the activity of the SARS-CoV-2-3CL protease, an enzyme required for viral replication, and coadministration with ritonavir slows the metabolism of nirmatrelvir so it remains active in the body for longer and at higher concentrations.
- Molnupiravir 800mg BD x 5 days
Molnupiravir is metabolized to the cytidine nucleoside analog, NHC, which is further phosphorylated to the active ribonucleoside triphosphate (NHC-TP). NHC-TP is incorporated into SARS-CoV-2 RNA by viral RNA polymerase, resulting in errors in viral genome and subsequently inhibition of replication
- Remdesivir is administered as 200 mg IV on day 1, followed by 100 mg IV daily on days 2 and 3. The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp).
Unproven benefit:
- Simnotrelvir-ritonavir – Simnotrelvir-ritonavir is a combination of protease inhibitors that acts similarly to nirmatrelvir-ritonavir by inhibiting the protease enzyme that is required for viral replication.
- Ensitrelvir is an oral protease inhibitor that prevents SARS-CoV-2 replication.
C-19 therapeutics in IP
No O2 requirement: Remdesivir 200mg Od followed by 100mg OD x 3-5 days
O2 requirement: Dex + Remdesivir
High inflammatory markers: Todilizumab - IL6 inhibitor
Baricitinib - JAK inhibitor
