35.1 Examples of Viral Disease Flashcards
Influenza
flu virus
Influenza structure
- Enveloped
- Spikes (HA and NA)
- Helical nucleoprotein
- (-)ssRNA in 8 segments and 11 genes
Influenza epidemics
Mutations in haemagglutinin, neuraminidase; antigenic drift = seasonal epidemics
Influenza spread
Respiratory droplets
Influenza infects and why
Respiratory epithelial cells in the nasopharyngeal and oropharyngeal spaces - lots of sialic acid on cell surface
Main human influenza classes
A, B, C, D
Severe strains of influenza
H1N1, H3N2
Influenza Baltimore class
V (-ssRNA)
Influenza genetic makeup
Linear (-)ssRNA within viral ribonuclearproteins
Haemagglutinin
Influenza surface protein used to interact with alpha-2,6-sialic acid linkages and induce receptor-mediated endocytosis
Escape of influenza vRNPs to cytosol
Protonation of endosome and intraviral space by M2 channels leads to injection of fusion protein between virus and endosome membrane, allowing vRNPS to exit to cytoplasm and move to nucleus for replication
Influenza genome replication
Viral RNA-dependent RNA polymerases produce +ssRNA for formation of proteins, or as a template for more -ssRNA
Effect of dsRNA intermediates formed during influenza replication
Act as signal for host cell to produce and secrete IFN-alpha/beta to prevent spread
Influenza nucleoproteins
PA, PB1, PB2 (RNA-dependent RNA polymerase)
Neuraminidase
Cleave haemagglutinin-sialic acid linkages to allow escape of nascent virions
Baloxavir marboxil
Inhibitor of cap snatching to treat influenza infection
Favipiravir
Inhibitor of influenza RNA-dependent RNA polymerase
Oseltamivir, zanamivir, relenza
Neuraminidase inhibitor to treat influenza infection
Amantadine
M2 channel blocker
Influenza vaccine
Killed/live attenuated vaccine of 4 major A/B strains
SARS-CoV-2 infects
Mucosal epithelial cells
SARS spread
Aerosol droplets
Coronaviruses: structure, examples
Structure:
- Lipid envelope
- Helical capsid
- S1 and S2 spike proteins
- (+)ssRNA
E.g.s: Common cold, SARS, MERS
SARS-CoV-2 Baltimore class
IV (+ssRNA)
Coronavirus protenome/genome
27 proteins from 13 genes
Site of infection of coronavirus
Nasopharyngeal epithelium/type II alveolar cells
Mechanism of entry of coronavirus
TMPRSS2 (serine protease) used to cleave S1 domain of spike protein, exposing S2 fusion domain for binding with ACE2 and endocytosis
Endosome escape of coronavirus
pH decrease or cathepsin (protease) action alters binding affinity and enables membrane fusion
Coronavirus genome replication
RNA-dependent RNA polymerases used for subgenomic transcription of +ssRNA in vesicle
-produces dsRNA
-and a precursor of -ssRNA that acts as a template for further +ssRNA development
Cap snatching
Viral cleavage of host mRNA and incorporation of the 5’ 7-methyguanoside cap to enable translation
Roles of papain-like protease (PLpro)
Break down ISG15 to oppose type I interferon response and promote inflammation, leading to severe COVID-19
Immune evasion by SARS-CoV-2
PLpro to decrease interferons (IFNs)
Down-regulation of MCH-I on infected cells
COVID-19 pathophysiology
Severe pulmonary and cardiac inflammation and cytotoxicity, leading to surfactant disorders and myocardial scarring
Treatment of COVID-19
Fluids to prevent sepsis, oxygen support, pharmacology like dexamethasone
Pharmacological agents to treat SARS-CoV-2 infection
Remdesivir and dexamethasone
Dexamethasone MoA
Long-acting corticosteroid, decreases inflammation by down-regulating polymorphonuclear leukocytes and reversing increased capillary permeability
Remdesivir
Coronavirus RNA-dependent RNA polymerase inhibitor
SARS-CoV-2 vaccines
mRNA
Adenovirus vectored (ChAdOx1)
Polio infects
Grey matter in anterior horn of spinal cord and brain
Polio structure
- Icosahedral nucleocapsid shell
- (+)ssRNA
- No envelope until acquired from host
Poliomyelitis Baltimore class
IV (+ssRNA)
Polio infection symptoms
Mild (abortive), gastrointestinal (nausea, vomiting, pain), meningeal (can progress to motor neuron death and paralysis)
Prevalence of paralytic poliomyelitis
0.3% of cases
Major poliovirus proteins
RNA-dependent RNA-polymerase, proteases, VP surface proteins
Entry of poliovirus to host cells
Engage CD155 receptors on host epithelium and motor neurons for endocytosis
Replication of poliovirus genome
- RNA-dependent RNA polymerases replicate to form dsRNA and amplify +ssRNA levels in vesicle
- The single, genomic strand produced is then translated as mRNA and polypeptide cleaved by proteases to form functional units
Polio spread
Faecal-oral route
IRES
Internal ribosome entry site - 5’ region of poliovirus +ssRNA used to attach ribosomes and initiate translation
Enveloped viruses
Influenza, SARS-CoV-2, HIV, EBV, HBV
Non-enveloped viruses
Poliovirus, HPV
Polio pathogenesis
- Lysis of gut epithelial cells
- Paralysis of motor neurons
Poliovirus immune evasion
Resistance to acidity (survive stomach), rapid replication and virion maturation, antigenic variation
Polio treatment
Supportive care; analgesics
Poliomyelitis vaccine
Salk - Inactivated injectable
Sabin - Oral live attenuated
Risks of live attenuated polio vaccine
Risk of reversion in 3 per million, leading to vaccine-derived poliomyelitis (vdPM)
HIV infects
CD4+ T helper cells
HIV structure
- Nucleoprotein core (RT and RNA)
- Icosahedral with conical capsid
- Envelope
- Attachment proteins
- lentivirus
HIV envelope derived from what membrane
Plasma membrane of previously infected cell
HIV Baltimore class
VI (+ssRNA-RT)
HIV genome
2 single strands of identical RNA
3 open reading frame and 9 genes coding 16 proteins
HIV peptides (3)
- gag: capsid protein
- pol: reverse transcriptase
- env: envelope proteins (gp120 & gp41)
HIV structural proteins
Envelope - gp41, gp120. Capsid/matrix - p24, p17
Vif (viral infectivity factor)
APOBEC3G inhibitor; normally functions to interfere with viral replication in retroviruses
vpr (viral protein R)
Interferon (IFN) downregulator
Nef (negative regulatory factor)
MHC-I expression downregulator
Entry of HIV
gp120 binds CD4, then CCR5, allowing insertion of gp41 and endocytosis
Escape of HIV from endosome
Neutral pH endosome; gp41 distal tips inserted to lipid bilayer to reduce integrity and pull apart
HIV genome replication
- Reverse transcriptase produces ssDNA copy
- DNA-dependent DNA-polymerase of virus forms dsDNA
- Integrase inserts this to host genome for standard eukaryotic transcription
Transcription factor driving vDNA upregulation
NF-kB, following inflammatory activation of CD4 T-cell
Emergence of nascent HIV virions
Cell-free (within ECM), cell-to-cell (virological synapses)
How does antigenic variation of HIV occur? Consequences?
- Low-fidelity replication of proteins means that significant differences in antigen structure (env) occurs
- Evasion of adaptive immunity
Mechanism of HIV clearance
Chronic non-progressors produce produce broadly-acting antibodies to limit spread of virions and keep T-cell levels high
T-cell threshold for AIDS
<200 cells/ml
Issues with AIDS
- T-cell depletion impairs adaptive response activation
- Leads to inflammatory responses and MALT damage which can worsen T-cell depletion
HIV vaccine
None
HIV vaccine approaches
CTL - use cytoplasmic antigen to stimulate CTLs and reduce infection levels before depletion
Immunoglobulin - Produce antibodies against env
HIV symptoms
Flu-like illness initially
Viral load drop = asymptomatic until AIDS
Treatment of HIV
Antiretroviral therapy (ART)
Reverse transcriptase inhibitor
Zidovudine (AZT)
RT chain inhibitors
Nevirapine
Direct RT inhibitor
Saquinavir
HIV protease inhibitor
Raltegravir
HIV integrase inhibitor
Maraviroc
HIV; CCR5 antagonist (prevents HIV entry)
Hepatitis
Inflammation of the liver, usually caused by a viral infection
HBV= DNA virus
HCV= RNA virus
Difference between HBV and HCV
HBV = DNA virus
- Reverse transcriptase
- Can integrate genome
- Risk of hepatocellular cancer
HCV = RNA virus
Structure of Hepatitis B
- Enveloped
- dsDNA-RT
Hepatitis symptoms
Malaise, stool darkening, jaundice, paler urine
Long-term issues with hepatitis
Hypoalbuminaemia, clotting deficiency (decreased vitamin K reduction), metabolic disturbance
HAV Baltimore class
IV (+ssRNA)
HAV spread
Faecal-oral route
HBV Baltimore class
VII (dsDNA-RT)
Diagnostic marker for Hepatitis
Elevated ALT
Surface antigens of HBV
S/M/L HBsAg
Entry of HBV
L-HBsAg engages NTCPRs on hepatocytes for internalisation
HBV genome replication
Endosomal escape with viral uncoating, releasing dsDNA. dsDNA converted to dsRNA, and then to cccDNA (covalently closed circular DNA) retained in host nucleus outside of chromosomes
Issues with cccDNA
Highly stable, can be latent and can modulate DNA for neoplasia (HCC). Replicated with host cells
Treatment of HBV
RT inhibitors, IFN-a to stop spread
Tenofovir
HBV rt inhibitor
HBV nucleocapsid
Icosahedral
How long may HBV stay infectious on a surface for?
1 month
HBV spread
Bodily fluid transmission; chronic carrier status
HBV Vaccine
Recombinant subunit, delivering L-HBsAg
HCV Baltimore class
IV (+ssRNA-RT)
Hepatocellular carcinoma
Cirrhotic liver (associated with hepatitis B and with alcoholism)
HCV structure
Icosahedral, enveloped
HCV replication
virus enters cell, RNA genome is translated into polyprotein.
2 proteases processes the polyprotein.
genome replication follows where RNA - strand is made and copied into more + strands, replicating the genome.
HCV treatment
interferon and ribavirin
HCV vaccine
none
HBV/HCV pathogenesis
cell killing by cytotoxic T-cells
Mononucleosis
condition caused by the Epstein-Barr virus and characterized by an increase in mononuclear cells (monocytes and lymphocytes) in the blood along with enlarged lymph nodes (lymphadenopathy), fatigue, and sore throat (pharyngitis)
EBV infects
- Oropharynx
- Liver(hepatitis and hepatomegaly, elevated liver enzymes)
- B cells
EBV
Epstein-Barr virus (cause of mononucleosis and other disorders)
HHV4 (human herpesvirus 4) is also known as
EBV
EBV Baltimore class
I (dsDNA)
Prevalence of EBV infection
90% worldwide
Symptoms of EBV infection
Asymptomatic, can lead to mononucleosis (non-specific symptoms with lymph node swelling and extreme tiredness) or lymphomas
Entry of EBV to host cells (nasopharynx)
BMRF-2 with B1-integrins, gH with avB6-integrins, gL with avB8-integrins
Entry of EBV to host cells (B-lymphocytes)
gp350 with CD21, gp42 with MHC2
EBV genome replication
Nasopharyngeal epithelium:
- Linear DNA transcribed by host RNA polymerase II in nucleus
- Replicated by viral DNA polymerase
B cells:
- Once in nucleus, vDNA acts as episome
- Aka genetic material used as host genetic material
EBV structure
HHV4
- Enveloped
- dsDNA
- Tegument proteins around capsid
Latency of EBV - genomic changes
Forms circular, plasmid-like genome in nucleus
Cancers associated with EBV
Burkitt lymphoma, nasopharyngeal carcinoma
Nasopharyngeal carcinoma
Malignant tumour of nasopharyngeal epithelium associated with EBV
Burkitt’s lymphoma
Malignant cancer of B lymphocytes associated with EBV infection
Symptoms of EBV
Asymptomatic until leading to:
- Glandular fever/mononucleosis
- Cancers
Treatment of EBV
NSAIDs - ease swelling without potent immunosuppression that further activates the virus
EBV vaccine
None
Acyclovir
Herpes prodrug
HPV infects
Keratinocytes
Papilloma virus (HPV)
Warts, cervical cancer
HPV Baltimore class
I (dsDNA)
HPV transmission
Skin to skin contact (sexually transmitted)
Tissue tropism of HPV
Keratinocytes; basal layer of epithelium
HPV treatment
No treatment. Just manage issues that HPV can cause.
HPV structure
- No envelope
- Icosahedral
- dsDNA
HPV vaccine
Recombinant
A vaccine that can prevent cervical cancer, pre-cancerous genital lesions (or sores), and genital warts caused by genital HPV infection
HPV replication
Genome integrated to host; unregulated expression of viral transforming protein E6 and E7
Herpesviridae Baltimore class
I dsDNA
Herpesviridae structure
- Large
- Enveloped
- dsDNA
- Icosahedral capsid
- Tegument proteins around capsid
What are the human herpes viruses?
1= herpes simplex 1
2= herpes simplex 2
3= varicella zoster virus
4= epstein barr virus
5= cytomegalovirus
Symptoms of HHV-1
Painful, itchy skin lesions on the lips which last 7 to 10 days
Initial infections can be accompanied by flulike signs and symptoms
Cells targeted by HHV-1
Mucoepithelial cells above the waist
Transmission of HHV-1
Close contact
Entry of HHV-1 to cell
Receptor mediated endocytosis
Release of HHV-1 new virions
Lysis
Treatments of HHV-1
Antivirals
HHV-1 latency - where?
Trigeminal ganglion neurons
Symptoms of HHV-2
Painful blisters on genitals and in genital region
Labial and genital herpes
Release of new HHV-2 virions
Budding - membrane exocytosis
Latency of HHV-2 - where?
Sacral ganglion neurons
Symptoms of HHV-3
- Chicken pox rash begins on trunk, extends to limbs and head
- Fever
- Shingles (after latency)
HHV-3 infects what cells
Upper respiratory tract, travels in blood to skin, where rash occurs
HHV3 latency - where?
Dorsal root ganglia
Herpes viruses infect neurons to become latent - how?
Retrograde axonal flow into ganglia cells
In latently infected cells, what is the DNA of VZV associated with?
Located in nucleus, but not integrated into cellular DNA
Treatment of HHV-3
Paracetamol for fever in chickenpox
Antivirals effective for shingles
Cytomegalovirus
HHV-5
Symptoms of HH5-V
Asymptomatic/mononucleosis-like:
- Fever
- Sore throat
Symptoms of child whose mother became infected with HHV-5 during pregnancy
Long term intellectual disability and hearing loss
HHV-5 treatment
Antivirals
