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GMS6121 - Infectious Diseases > Exam 1 > Flashcards

Exam 1 Flashcards

1
Q

virus definition

A

obligate intracellular parasites
all viruses have a NUCLEIC ACID GENOME (DNA or RNA, ss or ds) and a CAPSID
(protein coat encoded by virus)
about 1/2 have envelope

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2
Q

what key features do viruses lack?

A
  1. enzymes that produce basic chemical building blocks
  2. enzyme systems that generate usable energy
  3. enyzmes / tRNAs / ribosomes that direct protein synthesis
  4. membranes that concentrate and localize key molecules
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3
Q

virion

A

a single, complete, infectious virus particle

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4
Q

nucleocapsid definition

A

genome (DNA or RNA) + capsid protein

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5
Q

naked capsid virus

A

nucleocapsid only, no membrane

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6
Q

enveloped virus

A

nucleocapsid + lipid membrane and glycoproteins

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7
Q

sensitivity of naked vs enveloped viruses

A

Enveloped are more sensitive to most insults (ie drying, heat, detergents, acid), can be disinfected with ethanol
Naked capsids needs bleach

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8
Q

pros and cons of naked capsids

A

Pros: 1. Retain infectivity on drying, 2. Survive well on environmental surfaces, 3. Spread easily via fomites, 4. Can survive the acidic environment of the gastrointestinal tract
Cons: 1. Must kill host cells for release of mature virus particles (can cause self limiting infection) 2. Humoral (Ab) imm resp may be sufficient to neutralize infection

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9
Q

fomite

A

inanimate object that can cause spread of pathogens (door handles, shared cup, elevator buttons, utensils, etc)

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10
Q

enveloped virus pros and cons

A

Pros: 1. Do not need to kill cells in order to spread 2. May require both humoral (Ab) and cellular (T cell) imm responses to kill off the virus ‘factories’
Cons: 1. Can not survive in the gastrointestinal tract, 2. Must stay wet during transmission, 3. Transmission in large droplets and secretions

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11
Q

general capsid properties

A

symmetrical
simple (1-3 proteins)
icosahedral or helical
less proteins = less genes = smaller genome size = capsid can be smaller to fit genome
Self assembly, no E needed to form capsid

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12
Q

simplest icosahedral capsids composition

A

3 protein complex to form 1 triangle, then 20 triangles self assemble in into icosahedral (60 identical proteins)
remember that enveloped viruses have BOTH capsids and membranes

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13
Q

5:3:2 rule

A

5 is vertex, 3 is center of triangle, 2 is the fold between base of 2 triangles

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14
Q

helical capsid composition

A

Made of single proteins
Symmetrical helix around single axis
OPEN no closed like icosahedron
remember that enveloped viruses have BOTH capsids and membranes

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15
Q

bacteriophage capsids

A

Hybrid – icosahedral head and helical tails
Tail attaches to bacterium

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16
Q

purpose of virus genome

A

caries virus genes
genes code for all viral proteins

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17
Q

required viral protein functions

A

virus genome replication
formation of capsid
virion assembly

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18
Q

optional viral protein functions

A

evasion of intracellular defense systems
evasion of extracellular imm resp

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19
Q

DNA vs RNA genome transcription / translation

A

DNA > mRNA > protein
vs
RNA > protein

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20
Q

what does the Baltimore classification system use to group viruses

A

genome structure, plus reverse transcriptase

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21
Q

Baltimore classification in order I to VII

A

dsDNA
ssDNA
dsRNA
pos sense RNA
neg sense RNA
retroviruses (RT)
ss/dsDNA (RT)

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22
Q

general stages of virus lifecycle

A
  1. binding, 2. entry and uncoating, 3. early gene expression, 4. replication of genome, 5. late gene expression, 6. assembly of virions, 7. exit
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23
Q

key factors of binding

A

Specific protein on virus particle (capsid or membrane)
Specific protein on cell surface
“lock and key” = virus receptor
virus can also bind things other than its receptor (ie co-receptors or proteins on surface that allow them to aggregate)

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24
Q

dsDNA genome replication

A

regular dsDNA replication
use host machinery

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25
Q

ssDNA genome replication

A

ssDNA > dsDNA > ssDNA gets packaged
Use host cell DNA Pol to make dsDNA
Virions can have sense OR antisense strand bc first step is making other strand of the virus

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26
Q

pos sense RNA genome replication

A

pos RNA > neg RNA > pos RNA
facilitated by Rdrp
pos strand can immediately make proteins (act as mRNA) to make Rdrp (early gene)
Rdrp makes neg RNA, which acts as template for pos

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27
Q

neg sense RNA genome replication

A

neg RNA > EITHER mRNA or pos RNA
mRNA > proteins
pos RNA > template for neg RNA genome
RDRP IS PACKAGED INSIDE OF CAPSID, RELEASED ON ENTRY TO HOST CELL

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28
Q

dsRNA virus genome replication

A

dsRNA > pos mRNA > dsRNA
uses RDRP
dsRNA packaged into virion

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29
Q

Retrovirus genome replication

A

pos RNA > ssDNA (in capsid) > dsDNA (in capsid) > integration > EITHER mRNA or pos RNA
mRNA makes proteins
posRNA gets packaged
RETROVIRUSES ARE POS STRAND RNA
RT enters with pos RNA genome, RT activated, makes ssDNA WITHIN CAPSID
ssDNA in capsid, RT also makes antisense DNA IN CAPSID
INTEGRATION into host genome, then follows normal dsDNA genome after

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30
Q

genome strucutre of retroviruses

A

pos sense RNA

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31
Q

naked vs enveloped virus exit

A

naked = rupture and kill host cell
enveloped = budding, usually do not directly kill host cell

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32
Q

methods for quantifying virus

A

biological assays: 1. plaque assay, 2. endpoint calculations, 3. focus formation assay (transformation)
physical assays: 1. hemagglutination assay, 2. direct particle count, 3. nucleic acid (genome) testing

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33
Q

virus growth in embryonated egges

A

eggs 11-12 days post fertilization
Inject into chorioallantoic membrane (amniotic fluid), seal, incubate, harvest fluid
still used to make flu vaccines

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34
Q

list the CPEs (cytopathic effects)

A

cell lysis
rounding (or other morphology changes)
syncytia
inclusion bodies

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35
Q

ways to measure virus growth

A

CPE
hemadsorption
transformation

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36
Q

what is a syncytia

A

a single cell or cytoplasmic mass containing several nuclei, formed by fusion of cells or by division of nuclei

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37
Q

what is an inclusion body

A

dense areas in cell where virus components accumulated; aggregate of virus particles or virus-induced proteins characteristic of virus infection; Crystalline array of viral components
are often sites of assembly

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38
Q

hemadsorption

A

Virus makes proteins that bind carbs on surface of RBCs, when cell is infected virus makes it express that protein
Virus added to cells > cell expresses protein > add RBCs > wash > if RBCs stuck, those cells are infected
used for viruses with no obvious CPE
Usually enveloped viruses

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39
Q

transformation

A

property of some oncogenic viruses
exhibit one or more of the following: 1. Immortalization, 2. Colony formation, 3. Tumor formation in immunocompromised mice, 4. Loss of anchorage dependence, 5. Loss of contact inhibition, 6. loss of polarization

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40
Q

what is a transformation focus

A

area where cells have been transformed and display oncogenic properties; colony formation, loss of contact inhibition, etc.

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41
Q

plaque assay

A

“gold standard”
Virus added to monolayer > overlay with agar on top (only infect nearby cells) > after replication it spreads to neighboring cells, count the number of plaques

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42
Q

plaque assay method

A

Serial 10x dillutions, Allow to infect for hr or so, Add agar, At termination point count plaques.
Concentrated virus kills all cells, dilute virus kills few cells
Number of plaques * dilution = PFU

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43
Q

plaque assay titer

A

number of plaques * dilution factor = PFU

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44
Q

endpoint titration TCID50 assay

A

Can be used to quantify virus by measuring CPE, transformation, or viral fluorescence (eg, GPF) per well. ea well gets yes/no with many replicates per dilution

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45
Q

focus forming assay (transformation)

A

foci formed from loss of contact inhibition
count number of foci relative to titer

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46
Q

hemagglutination assay

A

Viruses that bind to sialic acid on surface of RBCs
Bc virus has multiple binding sites, can bind more than one RBC ea, get ‘bridges’
Round bottom well –> RBCs form dot in middle
In presence of virus NO DOT bc RBCs are stuck to virus and not all in one spot, form pink halo

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47
Q

hemagglutination assay method

A

2 fold dilutions of virus with equivalent number of RBCs per well
Highest dilution that hemagglutinates = 1 HA unit
ie if the 8, 16, and 32x dilution has NO DOT, but the 64 has a dot, the titration is 32 HA units

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48
Q

direct particle count

A

Count particles using EM
Add exact conc of beads, count beads and virus particles, calc number particles per ml

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49
Q

nucleic acid testing

A

qPCR for virus genes
can quantify using standard dilutions

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50
Q

what is MOI

A

MOI (multiplicity of infection) = the number of INFECTIOUS PARTICLES per CELL
they must be infectious!!
determined by plaque assay

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51
Q

notes on different quantitative assays

A

remember what the assay is measuring;
there are more genomes than particles, and there are more particles than virions

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52
Q

direct vs indirect virus diagnosis

A

direct:
1. virus particles, 2. virus proteins (Ags), 3. virus nucleic acids (genomes)
indirect:
serology (Abs)

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53
Q

high confidence vs easy access diagnostic methods

A

high confidence: virus isolation, genome detection, Ag detection
easy access: serology

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54
Q

methods for direct detection of virus

A

EM, IF, ELISA, PCR

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55
Q

EM

A

visualizations of virus particles
used to detect viral particles in lesions or type is unknown
don’t need spec Abs

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56
Q

IF

A

immunofluorescence visualization of virus proteins (particles or Ags)
Uses virus-specific antibodies to detect a specific viral protein, usually in TISSUE SECTION OR CELLS
1’ Ab binds Ag, 2’ Ab (conjugated to fluorophore) binds 1’ Ab,

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57
Q

ELISA

A

Ab detection of virus proteins (particles or Ags)
virus-specific antibodies to detect virus particles or secreted viral proteins in FLUID
capture ELISA = sandwich, indirect Ag to 1’ Ab to 2’ Ab

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58
Q

rapid ELISA: lateral flow assay

A

covid tests, pregnancy tests
analyte added to one end, moves through and binds labeled Ab, moves to 1’ Ab (test line) and then 2’ Ab (control line)
sandwich on test line if Ag present
control line recognizes the labeled Ab and will always show color

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59
Q

PCR

A

molecular detection of virus na (genomes or transcripts)
realtime qPCR (DNA) or RT-qPCR (RNA) can be used to quantify virus genomes

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60
Q

Serology

A

indirect detection
Ab to virus proteins are generated by BCs in response to infection, Serology is detection of Ab in serum
if Ab exists for virus, the imm sys has in contact w that virus
most commonly use ELISA

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61
Q

RNA vs protein vs serology

A

Early during infection cannot detect Abs (takes about 7 days for full Ab response)
Pos serology test does NOT mean ongoing infection
Serology shows they have been exposed, not necessarily actively sick (tho they can be depending on how long the virus causes disease for)

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62
Q

Serology ELISA

A

Instead of capturing virus, you are capturing the Ab THE HOST PRODUCED
sandwich with viral protein on well, then serum, then 2’ Ab
1’ Ab is in the serum if the patient has come into contact w virus

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63
Q

Serology neutralization assay and hemagglutination inhibition assay

A

add test serum to virus, see if it can prevent CPE (virus infecting monolayer) or hemagglutination

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64
Q

syndromic testing

A

multiple pathogens within a single panel, based symptoms

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65
Q

pathogenesis

A

the process by which one organism causes disease in another

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66
Q

2 components of viral disease

A
  1. Effects of virus replication on the host
  2. Effects of host response on virus and the host
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67
Q

outcome of most viral infections

A

subclinical, resolve on their own w/o symptoms
no disease DOES NOT mean unsuccessful replication
there is no inherent value to the virus to make a person sick

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68
Q

tamiflu

A

neuraminidase inhibitor
After virus buds, virus is stuck to host cell, needs to cleave interaction between sialic acid and the viral receptor to be released
Does so through neurominidase
Block neurominidase > block viral budding > virus cannot propagate

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69
Q

why study pathogenesis

A

identify targets for
1. antiviral drugs
2. immunomodulation
3. vaccines

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70
Q

most common point of viral entry

A

mucosal surfaces: GI, respiratory tract, urogenital

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71
Q

key features of the skin

A

outer layer is dead keratinized cells > no virus replication
entry via breaks or punctures
Epidermis has no blood/lymphatics – local infection
Dermis and sub-dermal tissues are highly vascularized – infections may disseminate

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72
Q

common skin viral infections

A

Herpes, pox, papilloma, arbo
(arbo requires an insect vector)

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73
Q

key features of respiratory tract

A

most common route of viral entry
high absorptive area and high turnover
barriers: mech - mucous, cilia, sneezing/coughing
cellular: MO
humoral: IgA
Entry via aerosolized droplets or contact w saliva

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74
Q

common respiratory viral infections

A

upper: rhino, corona, influenza, parainfluenza, RSV, herpes, adeno, boca, coxsacki
lower: influenza, parainfluenza, RSV, adeno, boca, metapneumo

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75
Q

key features of GI tract

A

entry via eating/drinking
contents always in motion - allow for more virus-host interactions
barriers: environmental - acidic stomach, alkaline intestine, digestive enzymes, mucus
homoral - IgA

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76
Q

common GI tract viral infections (and how they survive the GI)

A

Reoviruses – require proteases for entry; use microbiota to enhance infection
Noroviruses – stable at large pH range; may use IgA to facilitate uptake by intestinal epithelial cells; use microbiota to enhance infection
Coronaviruses – enveloped; resistance mechanism(s) not clear

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77
Q

M cells in the GI

A

Host needs to sample material in gut lumen
M cells - Able to transfer gut lumen materials into the imm cells in peyers patch, important for imm resp, virus can use it tho :(
M cells do NOT have microvilli

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78
Q

key features of urogenital tract

A

Barriers: mech - mucus, environment - low pH
Entry via minute abrasions from sex
Some viruses produce local lesions (HPV)
Some viruses spread from urogenital tract (HIV, HSV)

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79
Q

common urogential tract viral infections

A

HPV, HIV, HSV

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80
Q

key features of eyes

A

barrier: blinking
entry: minute abrasions, environment (swimming pools)
localized infection - conjunctivitis
disseminated infection - spread to CNS (HSV-1)

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81
Q

common eye viral infections

A

conjunctivitis (just means eye inflamm, caused by many viruses)
HSV-1 (can spread to CNS)

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82
Q

possible outcomes of infection

A

cell death
abortive infection
persistant infection
transformation

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83
Q

abortive infections

A

virus can enter but cannot produce infectious particles
lack of right conditions or host antiviral activity
cells may still be damaged, killed, or transformed, but no new virions

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84
Q

cell death after viral infection

A

most common outcome
apoptosis and necrosis collectively called CPE
diversion of cell E
shutoff host synthesis
competition of mRNAs for ribosomes
competition for cellular transcription factors
cell lysis

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85
Q

pyrogens

A

trigger fever
IL1 IL6 TNF

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86
Q

what causes pyrogen release

A

cell lysis
pyrogens induce fever, trigger stronger imm resp, impairs normal cell funct
disease is coming from imm resp to virus, not directly from virus

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87
Q

persistent infection

A

no cell death and cells are not altered significantly in their growth
virus enters but no cell death or new virion formation
3 types: chronic, latent, and recurrent

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88
Q

chronic persistent infections

A

constant production of virus
long incubation period before disease
HBV (hep B), HCV (hep C)

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89
Q

latent persistent infections

A

no progeny virus but virus genome is maintained
small number of virus proteins produced (genome maintenance)
may have constant low-level reactivation that is pathogenically silent
herpesviruses

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90
Q

recurrent persistent infections

A

reactivation of latent virus infection
e.g., stress can reactivate latent HSV to produce virus (cold sore)

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91
Q

mechanisms for transformation

A

encode viral oncogene derived from cellular gene (papilloma blocks tumor suppressor)
integration into host chromosome causes disruption in normal genes (retroviruses)
chronic infections causing constant injury/repair cycle (HCV (hep C) liver damage) - virus is not directly causing cancer

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92
Q

tropism

A

tissues infected by a particular virus
limited vs pantropic (many tissues susceptible)

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93
Q

determinants of tropism

A
  1. Accessibility of the permissive cell, 2. Presence of appropriate cell surface receptors, 3. Presence of intracellular host factors required for virus rep, 4. Absence of suppressive antiviral mediators (most important is interferon)
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94
Q

disseminated infection

A

virus spreads beyond 1’ site of infection, usually to a 2’ target tissue
polio enters through GI, disseminates through lymph to blood to CNS

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95
Q

systemic infection

A

many organs infected
flavi enter bloodstream via insect bite, spread to many tissues

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96
Q

localized infection

A

1’ infection site only
rhino contained to upper resp tract

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97
Q

how can virus disseminate

A

breaching of physical and imm barriers
facilitated by virus (direct destruction of cells) or imm resp (inflammation causing leaky barriers)

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98
Q

directionality of virus release

A

apical vs basolateral
apical - facilitates dispersal to neighboring cells
basolateral - deeper tissues, blood stream, rest of body

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99
Q

hematogenous spread

A

Most effective, rapid, and common dissemination
Viruses can enter blood directly through capillaries, by replicating in endothelial cells, or through vector bite
Virus in extracellular fluid can be taken up by lymphatic capillaries (more permeable than circulatory capillaries), then spread to blood
Once in blood, virus has access to almost all tissues
Can occur cell-associated or as free virus particles
still dependent on tissue tropism
can atach to migratory cells (DCs, MOs, lymphocytes) or RBCs/platelets (w/o replicating)

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100
Q

1’ vs 2’ viremia

A

viremia - virus in bloodstream
1’ – virus rep at 1’ infection, then enters blood
2’ – reaches 2’ tissue via blood stream (from 1’), enters bloodstream AGAIN, much higher amount of virus than 1’

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101
Q

passive vs active viremia

A

Passive: virus introduced to blood w/o replication; rep AFTER it reaches target organ
(ie direct inoculation of arbovirus to blood from bite)
Active: virus replication occurs BEFORE viremic phase, then enters bloodstream (ie virus replicates in mucosal epithelium, then virus enters bloodstream)

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102
Q

neural spread

A

TRAVEL RETROGRADE
Axon > cell body > synpase with PREVIOUS neuron > axon etc
definitive characteristic of rabies and HSV
infrequent diversion in polio and reovirus
can also happen hematogenously

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103
Q

hematogenous neural spread

A

rare bc of BBB
can be thorugh transcytosis (virus travels through cell one side to other) or cell-associated (infected imm cell that enter CNS) - normally prevented by tight juncts (can be leaky from inflamm)

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104
Q

immunopathology (imm resp to viral infection)

A

greatest impact on outcome of infection
can be the major contributor of pathogology
typical there is clearance w/o symptoms
no clearance= infection and possible persistence

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105
Q

type 1 IFN

A

induces antiviral state
Cell infected > recog foreign molecules > upreg gene expression of IFN1 beta > IFN1b release binds to recptr on same or neighboring cells > upreg ISGs (IFN stimulated genes) > cell blocks virus
ISGs are antiviral, block viral rep, 100s of genes

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106
Q

virus evasion strategies

A
  1. suppress IFN resp (via blocking IFN induction, signaling, or IFN-induced proteins), 2. block other cytokines, 3.suppress innate imm cell resp, 4. replicate in imm privileged sites, 5. interfere w Ag processing/presentation, 6. alter MHC trafficking, 7. direct cell-to-cell spread, 8. Ag variants (diff strains)
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107
Q

types of immunopathology

A

flu-like symptoms, over stimulation of innate imm resp, ADE, generation of immune complexes

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108
Q

vasoconstriction during fever

A

reduces heat loss through skin – person feels cold

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109
Q

why get fever when sick

A

certain imm cells work better at higher temps

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110
Q

what causes over stimulation of innate imm resp

A

high levels of pro inflamm cytokines
can cause immune suppression and cytokine storm
ex: ebola and dengue hemorrhagic fever

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111
Q

ADE

A

Ab dependent enchancement
happens in 2nd dengue infection with a different strain
1st infection, dengue infects MO, gets cleared
2nd infection, Ab from memory can bind the dengue but does not neutralize, MO takes up Ab through Fc receptor, transfers dengue directly into MO

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112
Q

generation of imm complexes

A

chronic infections result in constant Ab production and formation of imm complexes, deposited in kidney activation of complement and inflamm in kidney, damage renal filtration,
chronic ineffect BC stimulation can lead to BC cancers

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113
Q

types of virus transmission

A

horizontal (person to person via touch, saliva, sex etc)
vertical (partent to offspring via bodily fluid during birth or breast milk)
zoonotic (animal to human via bite, meat, contact etc)

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114
Q

congenital infection

A

infection caused during pregnancy that continues after child is born

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115
Q

wt lab vs natural strains

A

natural - mix of genomes
lab - consensus seq of natural, dubbed wt, “quasi-species”

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116
Q

selection vs screen in a mixed population

A

selection - conditions exist in which only the desired virus grows (ideal)
screen - both desired and unwanted virus grows (more common)

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117
Q

essential vs nonessential genes

A

describes phenotypes and depends on ASSAY CONDITIONS
mutations give advantage or disadvantages

118
Q

attenuation via passaging

A

passaging a virus many times in specific conditions allows for evolution and selection for viruses more adapted for those conditions
if cultured away from normal target tissues, virus bc attenuated and cannot infect normal target
(basis for Sabin polio vaccine)

119
Q

recombination

A

nucleic acid seq from two genotypically diff parental viruses are exchanged, progeny contains seq from both parents
in DNA viruses - homologous recombination
in nonsegmented RNA viruses - copy-choice recombination

120
Q

copy choice recombination

A

nonsegmented RNA viruses
uses Rdrp
generates intermediate neg sense, jumps to neighboring genome, continues until it gets to end
pos RNA can be made from this strand to propagate the mutation

121
Q

reassortment

A

segmented RNA genome
2 strains infect same cell, reassort genome segments
RARE, most segments will stay together
ex: influenza virus

122
Q

types of mutations

A

spontaneous (classical)
induced (classical)
engineered (modern virology)

123
Q

spontaneous mutations

A

spontaneous mutations from replication
much higher in RNA than DNA viruses bc of poor fidelity, faster replication, and no proofreading
DNA is more stable, RNA is more adaptible

124
Q

laboratory consequence of spontaneous mutations

A

RNA viruses have higher rates of spontaneous mutations, more likely to have reversion mutations

125
Q

induced mutations

A

inductions inc mutation frequency
goal of single nt change
chemical mutagens
physical means (UV crosslinking)

126
Q

engineered mutations

A

consider genome size, what nucleic acids are infections (DNA, pos or neg RNA)
used most often in lab now
clone into plasmid, reintroduce in virus

127
Q

forward vs reverse genetics

A

forward - phenotype to genotype (see an diff phenotype, analyze genes to see where change is)
reverse - genotype to phenotype (engineer specific mutation, see how it affects phenotype)

128
Q

picornavirus general overview

A

small nonenveloped virus
pos sense RNA
4 capsid proteins
lacks 5’ cap (uses IRES instead)
5’ structural / 3’ non structural

129
Q

important picorna viruses

A

polio, hep A (HAV), foot-and-mouth disease virus (FMDV), rhino

130
Q

picorna genome organization

A

pos ssRNA
single ORF –> makes polyprotein
polyprotein gets cleaved into diff segments (mostly by viral protease (3C) but also some host)
structural at 5’, nonstructural at 3’

131
Q

picorna 3C protein

A

protease, cleaves polyprotein

132
Q

picorna 3CD protein

A

protease, cleaves polyprotein

133
Q

picorna 2A protein

A

protease, cleaves elF4G

134
Q

picorna P1 protein

A

structural, part of virion, cleaved into VP0, 1, and 3

135
Q

picorna P2 and P3 proteins

A

nonstructural, enzymatic, genome regulation

136
Q

picorna 3D

A

polymerase (RdRp),
efficient,
asymmetrically makes both neg and pos RNA (much more pos made than neg)
error prone (target for anti-viral drugs)
handle structure, palm = active site, RNA runs through tunnel
VPg uridylyation

137
Q

picorna IRES

A

internal ribosomal entry site
long 5’ untranslated region, initiates translation

138
Q

picorna VPg

A

aka 3B
present instead of 5’ cap, before IRES, protects RNA
primer for RNA replication

139
Q

picorna capsid structure

A

60 subunits, 20 protomers
1 promoter = VP1 + VP2 + VP3
VP1-3 have no seq homology but same topology (wedge)
VP4 is internal (packaging), protect N terminus of VP3, seals and prevents pore
pH stability dependent on replication tropism (enteric resistant to low pH, respiratory are acid-labile)

140
Q

picorna receptors

A

many receptors depending on virus, (Ig-like domains, adhesion, integrins, etc)
some share (CD55 aka DAF)
some use single receptor and some use co-receptors

141
Q

picorna receptor binding site on virion

A

in canyon, not peak for polio and rhino (binds ICAM-1)
some picorna don’t have canyons, bind on surface loops

142
Q

picorna genome release from capsid

A

2 mechanisms:
1. pH dependent - receptor-mediated endocytosis followed by uncoating triggered by acidification in endosomes.
evidence: blocked by blocking acidification, Ab coated virus can bind Fc receptors and infect cells
2. receptor-induced cellular mem pore formation
evidence: capsids stable even at v low pH, blocking acidification does not inhibit, Ab coated virus cannot infect

143
Q

picorna pore formation in HOST CELL

A

receptor binds in canyon > pocket factor dissociates > tighter binding of virus > VP1 inserts N terminus and VP4 inserts myristal group > unknown factor removes VP3 plug > release genome into cell

144
Q

picorna hydrophobic pocket and WIN

A

Tunnel under canyon has pocket factor
need to release pocket factor
Block pocket factor from dissociating > virus cannot enter
WIN compounds blocks pocket factor, does not dissociate, virus cannot enter

145
Q

picorna translation initiation

A

pos sense (translation read)
works via IRES
2’ structure hairpin structure in 5’ region
recruits host translation initiation factors > bring ribosomes
do not need all host translation factors (does not need elF4E, only needs C terminus of elF4G)

146
Q

picorna translation: elF4E and 4G

A

elF4G is a scaffold for other elF’s, one of which is elF4E
4E binds 5’ cap of host RNA
picorna has no 5’ cap so 4E is unnecessary (and therefore 5’ end of 4G which is what recruits 4E)
virus has mech to cleave 4G to remove N terminus (5’), leaving C terminus (3’) > host can only make virus proteins

147
Q

picorna polyprotein cleavage

A

cleaved as it is translated, never detect full molecule
cleaved by 3C, 3CD, and 2A
3 main regions: P1, 2, 3
P1 contains VP0 (later 2 and 4), VP1, and VP3

148
Q

advantages of polyproteins

A

smaller genome, many functions from a single RNA
timing control
quantity control

149
Q

picorna RNA replication via VPg

A

VPg (aka 3B) is attached to 3A, 3AB inserts into membranes, at 5’ end of RNA > 2C binds RNA genome (circular) > hydroxy group attaches to nt > uridylylated by 3D at CRE hairpin > Us templates to polyA tail > polymerizaton by 3D > 3C cleaves 3B and 3A, release primer and nascent RNA
additional 3B (VPg) gets uridylylated, pool of more primers
polymerase (3D) unwinds dsRNA and 2’ structures
happens on membranes to sequester away (dsRNA = danger signal)
primes both pos and neg RNA synthesis

150
Q

picorna assembly

A

P1 cleaved into VP0 (VP2+VP4), VP3, and VP1 > One copy ea of VP0, VP3, and VP1 > 5 protomers (protomer = VP1+3+0) assemble (5 fold vertex)
2 models: capsid first or simultaneously?
capsid first = capsid is formed, RNA is threaded into capsid via pore
simultaneous = pentamers form around genome (more likely)
unknown how VP0 gets cleaved, likely autocatalytic

151
Q

where does picorna enter

A

respiratory (rhino, localized) or GI (enteric, systemic)
enteroviruses - enteric, intestinal track, drain to lymph node, travel to blood, viremia, can enter CNS

152
Q

what type of virus is polio

A

picorna

153
Q

polio pathogenesis

A

fecal-oral transmission
Viral rep in intestine epithelium, then lymph node, then viriemia
Then extraneural tissue (muscle and fat) - reaches high titer
Then CNS (retrograde axonal transport) > kill neurons

154
Q

poliomyelitis

A

most infections asymptomatic
some abortive poliomyelitis (fever, headache, sore throat)
rare nonparalytic poliomyelitis (severe headache, neck stiffness)
very rare spinal paralytic poliomyelitis (weak lower limbs and respiratory muscles, incomplete recovery, fatality from asphyxiation)
very very rare bulbar paralytic poliomyelitis (cranial nerve paralysis, vasomotor and resp centers, fatality from asphyxiation)

155
Q

polio vaccines: Salk vs Sabin

A

Salk = formalin-inactivated polio vaccine (IPV)
injected, weak mucosal immunity
used from 1955-1961 in U.S., reintroduced into U.S. in 2000 - present
Sabin = oral polio vaccine (OPV)
oral, can rep in intestine but not in neurons, shed for 30-60 days better mucosal immunity
introduced in 1962, was more effective bc of community protection - transmitted to unvaccinated children via fecal-oral route
used in U.S. from 1961-2000, eliminated poliovirus in U.S., discontinued due to viral reversion

156
Q

polio eradication effort

A

Global Polio Eradication Initiative (GPEI)
why polio?
Species specific - no animal reservoir
Lifelong immunity after vacc
close to eradicated, only 2 polio-endemic countries left
Wild virus can spread to polio free countries
High risk countries need to continue oral vaccine
However risk of reverted vaccine polio
2022 - cause of paralytic polio in NY (cVDPV = reverted vaccine polio)

157
Q

enterovirus D68

A

rare infections until recently
resp disease in children
rarely causes poplio-like symptoms (acute flaccid myelitis - AFM)

158
Q

calici general overview

A

pos sense RNA
nonenveloped
1 capsid protein
translation via VPg cap substitute
5’ nonstructural / 3’ structural
broad host range w variety of symptoms

159
Q

astro general overview

A

pos sense RNA
non enveloped
1 capsid protein (processed into at least 3)
translation via VPg cap substitute (maybe??)
5’ nonstructural / 3’ structural

160
Q

calici capsid structure

A

icosahedral w 32 cup shaped depressions
nonenveloped

161
Q

what type of virus is noro

A

calici
most significant calici for humans

162
Q

why are noroviruses hard to treat

A

many many genotypes
hard to detect, treat, and immunize against

163
Q

norovirus genome organization

A

ss pos RNA
5’ nonstructural / 3’ structural
uncapped but poly-A tail present
5’ end covalently attached to VPg (but no IRES)
produces subgenomic RNA that encode structural proteins (also VPg linked)
polyprotein makes NS1-7 (nonstructural), sgRNA makes VP1 and 2 (2 ORFs)

164
Q

noro NS5 protein

A

VPg

165
Q

noro NS6 protein

A

only protease, 3CLpro, cleaves polyprotein cotranslationally (never see full polyprotein)

166
Q

noro NS7

A

polymerase, RdRp, picorna 3D
in vitro replicaiton assays do not require polyA tail or U primer, maybe primer independent replication

167
Q

what genes are on the sgRNA of norovirus

A

structural: VP1 and VP2
read by ORF4
stop codon exists between VP1 and 2
also has VPg at 5’ end

168
Q

noro p48

A

potential picorna 2AB activity
disrupts intracellular protein trafficking, localizes to golgi and disrupts golgi
possible scaffolding role for replication

169
Q

noro NTPase

A

NS3
potential picorna 2C activity

170
Q

noro p22 protein

A

potential picorna 3A activity
hydrophobic mem domain
inhibits host protein secretion and leads to golgi assembly

171
Q

noro VPg

A

picorna 3B
linked to 5’ ends of genomic and sg RNAs
translation initation
maybe protein primer for RNA synthesis

172
Q

astrovirus genome organization

A

5’ nonstructural, 3’ structural
VPg at 5’ end, has poly-A tail
2 polyproteins
makes structural proteins from subgenomic message

173
Q

norovirus capsid structure

A

single capsid protein (VP1) that forms dimers, each dimer makes archlike protrusion
large hollows at 5 fold vertex
very stable at low pH, low Cl conc, high and low temp
does not need RNA to fold properly

174
Q

noro VP1 structure

A

has S - P1 - P2 - P1 organization
S - conserved, core of VP1
P2 - variable, protrudes, binds receptor, targetted by imm resp

175
Q

noro VP2 structure

A

inside the virus capsid
minor protein (1-8 copies)
basic, associates with capsid shell of VP1
required for replication
highly variable between strains

176
Q

astro capsid structure

A

nonenvleoped
icosahedral
very stable (low pH, resistant to chloroform, detergents, etc)
star shape is rare
capsid protein cleaved into 3 smaller peptides
processing - caspase removes acidic domain, trypsin cleavage produces VP27 and VP25 extracellularly

177
Q

calici receptor binding site

A

binds carbohydrates on cell surface, possible dual carbohydrate strategy
(most viruses that bind carbs needs a protein receptor, none known for calici)

178
Q

calici viral entry

A

entry by proteases (no norovirus), acidicficaiton, or sialic acid (murine norovirus)

179
Q

calici translation initiation

A

VPg at 5’ end acts as cap and initiates - binds elF4E, forms initiation complex
start codon close to 5’ end
VPg is not cleaved from incoming genomes

180
Q

calici genome replication

A

NS7 = RdRp, makes neg compliment to pos strand
RNA flows through tunnel
how is sgRNA made? 2 theories:
1. premature termination - start 3’ end, move towards 5’ end, come into contact w stop codon, makes short transcript, Rdrp then makes pos strand
2. full length pos strand makes full length neg strand, internal initiation sites on neg strand, makes other initaition that forms sg sized RNA

181
Q

noro VP2 translation

A

translation termination-reinitiation (TTR) on sgRNA
VPg recruits ribosome to ORF2 making VP1
ORF3 overlaps ORF2, short region of complementarity between to the 40S subunit of the ribosome and reinitiation motif
At low level, ribosome complements with subgenomic message, release of 60S, re-initiation
Don’t need true start codon
controls amount of protein made (much more VP1 than 2)

182
Q

noro pathology

A

gastroenteritis, esp infants, young children, elderly, immunocompromised (dehydration)
leading cause of severe childhood gastroenteritis
all ages susceptible
short time course

183
Q

noro transmission

A

fecal-oral
sick food handler, contaminated water on food, oysters (seafood) grown in contaminated water
stable - can exsist on surface for long time
person to person
associated w winter, long term care facilities, food, and cruise ships

184
Q

noro virus intestinal entry

A

enters through M cells (used to sample environment), viruses use it to pass themselves
Virus can also infect macrophage that also samples the environment

185
Q

noro virus strain / tissue tropism

A

MNV-1 (murine norovirus 1) prefers to infect Peyer’s patch (imm cells) over epithelial cells - cause more severe disease
MNV-CR6 infects tuft cells (rare and more specialized) - less severe disease
Genetically v similar

186
Q

how does norovirus cause diarrhea

A

proinflamm cytokines
disruption of tight junctions

187
Q

noro receptors

A

murine - CD300If, on muliple imm cells and tuft cells, there must be another determinant
human - attach to HBGAs (not receptor), present on RBCs, most pople also have on mucosal cells, polymorphism of HBGA means everyone is resistant to some norovirus

188
Q

role of microbiota in noro infection

A

microbiota important for metabolism, immunity, and homeostasis
VIRUS BENEFITS FROM COMMENSAL BACTERIA
microbiota inc noro infectivity

189
Q

flavi basic overview

A

pos RNA
enveloped
icosahedral
transmitted mostly by arthropods (arbovirus) (can also rep in them)

190
Q

Toga basic overview

A

pos RNA
enveloped
icosahedral
transmitted mostly by arthropods (arbovirus) (can also rep in them)

191
Q

what type of virus is dengue

A

flavi

192
Q

what type of virus is west nile

A

flavi

193
Q

what type of virus is yellow fever

A

flavi

194
Q

what type of virus is hep C (HCV)

A

flavi
not arbo

195
Q

what type of virus is Ross river

A

toga

196
Q

what type of virus is chikungunya

A

toga

197
Q

flavi genome organization

A

pos RNA
5’ cap, no poly-A tail
single polyprotein w one ORF
5’ structural / 3’ nonstructural
some have IRES instead of 5’ cap (HCV)

198
Q

flavi C protein

A

capsid, associates w genome
acts as scaffold for envelope proteins and lipid bilayer

199
Q

flavi prM protein

A

glycoproteins embedded in mem
interacts w E during assembly

200
Q
A
201
Q

flavi E protein

A

glycoprotein embedded in mem
binds cell surface and directs fusion
lays parallel to envelope (smooth structure)

202
Q

flavi NS5 protein

A

methyltransferase-polymerase, used to give cap (normal RNA gets cap in nucleus, flavi never enters nucleus)

203
Q

flavi NS3 protein

A

protease helicase

204
Q

toga genome organization

A

pos RNA
5’ cap and poly-A tail
5’ nonstructural / 3’ structural
uses sgRNA for structural proteins
nonstructural made first, then structural

205
Q

toga nsP1 protein

A

RNA capping enzyme

206
Q

toga nsP2

A

cysteine proteinase

207
Q

toga nsP4

A

RNA pol (RdRp)

208
Q

flavi virus structure

A

enveloped
icosahedral
180 glycoproteins (prM-E heterodimers) embedded in envelope
immature have spikes, mature is smoother (release of pr peptide)

209
Q

toga virus structure

A

enveloped
icosahedral
80 flower-like structures ea w 3 subunits (petals)
ea petal is E1/E2 heterodimer
240 capsid protein molecules in contact w 240 envelope petals
identical symmetry (unusual for enveloped virus)

210
Q

flavi receptor binding

A

bind attachment factors that concentrate virus on surface (glycans such as heparan sulfate)
then bind primary receptor (TIM family)
taken up by endocytosis

211
Q

flavi entry

A

E dimer on virion surface > low pH induced E dimer dissociation, lifts stem, FP (fusion peptide) interacts w target mem > E protein trimerization > initiation of stem zippering - E come together and push towards target > hemifusion intermediate w fused other leaflets > postfusion hairpin-like E trimer w FPs and TM domains on same side of molecule

212
Q

flavi translation

A

translated as one polyprotein
co and post translationally processed by NS2B/NS3 (viral) and host factors
10 mature proteins

213
Q

flavi processing of polyprotein

A

co and post translationally processed by NS2B/NS3 (viral) and host factors
polyprotein as multiple TM domains, nonstructural on cytoplasmic side, structural (E and M) on ER luminal side
E and M have to be glycosylated via ER and golgi
exception: NS1 (imm evasion) in ER lumin
cleavage takes place on ER mem cytoplasmic cleavage by viral protease, ER luminal cleavage by host protease

214
Q

flavi AncC protein

A

capsid, associates w RNA genome after rep, inefficient cleavage, doesn’t happen until later in life cycle

215
Q

flavi RNA replication

A

viral replicase assmbled using NS proteins and genomic RNA and host factors > replicase associates w cellular mem > genome length neg template made > switch to synthesis of progeny genomes (pos sense)

216
Q

how does flavi get an envelope

A

budding into ER and trafficking though golgi exocytosis
polyprotein insert in ER mem (M and E luminal side), AncC stuck on mem > AncC associates w genome to make nucleocapsid and M and E (have all components) > budding of immature virion into ER > glycosylation in golgi > fuse w plasma mem to release virion > right at budding, cleavage of prM by furin (keeps FP away so it doesn’t fuse bud back into same cell)

217
Q

how does toga get an envelope

A

bud at plasma mem
capsid protein and RNA remain cytoplasmic and move to plasma mem
C terminus folds to form protease that self cleaves capsid, N terminus binds RNA at packaging signal in NS region of genome (no sgRNA or neg strand RNAs) release from ER mem, travel to plasma mem
envelope inserts to ER mem and trafficked through golgi, glycosylation, inserted into plasma mem
capsid meets up with glycoproteins on plasma mem

218
Q

flavi pathogenesis

A

humans are dead end (incidental) hosts
infect and cause disease but cannot spread to new host (human or insect)

219
Q

west nile virus zoonosis

A

infection via mosquitoes (arbo)
birds harbor virus indefinitely
can infect human or horses, both dead end

220
Q

what determines flavi virus disease

A

disease dictated by 2’ tissue tropism
1’ infection is blood
febrile illness (fever) with arthralgia (joint pain)
hemorrhagic fever
encephalitis (inflammation of parenchyma)

221
Q

west nile virus encephalitis pathogenesis

A

deposit into tissue (skin) > replicate > spread to lymph nodes > replicate > enter blood > disseminate to spleen > CNS > damage neurons

222
Q

how does WNV breach BBB

A

TNF induced cell permeability
breakdown of endothelial junctions (MMPs)
trojan horse via infected imm cells
direct axonal retrograde transport

223
Q

hep C pathogenesis

A

sex, blood, iv drug transmission (not arbo)
persistant infection
silent virus - symptoms appear 10+ yrs later
cause chronic hepatitis
lead to cirrhosis and cancer

224
Q

hep C treatment

A

treatment used to be long with significant side effects
sovaldi is new best drug, nt analog, inhibits RdRp
expensive
sovaldi + ledipasvir = harvoni
can cure HCV, but not accessible bc of cost

225
Q

what type of virus is zika

A

flavi

226
Q

zika pathogenesis

A

tansmission from mosquitoes (also sex, blood, and perinatal)
usually mild
cause microcephaly in fetus of pregnant woman
zika infects placental cells, disrupts barrier, inflamm resp to infection, cytokines cause microcephaly
ADE might happen in zika bc of close relation to dengue

227
Q

alphavirses (toga) pathogenesis

A

natural host is usually wild mammals and birds
humans and horses are dead end hosts

228
Q

chikungunya pathogenesis

A

mosquito vector
acute febrile illness, persistent arthralgic disease in some
rarely lethal
people are NOT dead end hosts, can spread back to mosquitos
infects osteoblasts (make bone), release inflamm cytokines, pro-osteoclastic (break down bone) molecules, both loss of bone formation and inc bone loss –> joint pain

229
Q

what type of virus is rubella

A

toga

230
Q

rubella pathogenesis

A

only non arbo togavirus, spread though air or contact
causes rash
congenital rubella causes fetal abnormalities and brith defects
in MMR vaccine

231
Q

corona general overview

A

pos sense RNA
enveloped
large genome
unique replication w high recombination rate
mature virions bud at intracellular membranes
infect many species, cause wide range of disease

232
Q

corona S protein

A

spike (all corona) glycoprotein
promotes binding and fusion
glycosylated
4 domains: S1 - globular head (variable, receptor binding), S2 - fusion promoting stalk (more conserved), trans mem domain, cytoplasmic domain
some coronas require proteolytic cleavage at one or two sites to have fusion activity (S1/S2 border or S2’)
forms as a trimer on virion
some corona have additional HE spike protein (not SARS)

233
Q

corona N protein

A

nucleocapsid, densely coats genome
forms helical ribonucleoprotein complexes
interacts w M to drive particle formation
only known particle to localize to nucleus
inhibits cytokines and IFN

234
Q

corona M protein

A

membrane
forms inner core shell
short n terminal domain outside of envelope, spans mem 3 times, large c terminus inside envelope
thicker than most viruses
budding of virions, targeted to golgi

235
Q

corona E protein

A

envelope
small, hydrophobic
required for budding, also localized to golgi
gained from budding intracellularlly
not entirely understood, has ion channel activity and induces apoptosis

236
Q

corona genome organization

A

5’ nonstructural / 3’ structural and accessory
frameshift allows for ORF1a or ORF1b (includes 1a proteins) to be translated
5’ cap and poly A tail
5’ has leader (L) after cap
nested mRNA

237
Q

corona nsp3 and nsp5 proteins

A

viral proteases

238
Q

corona nsp12 protein

A

polymerase, Rdrp

239
Q

corona nsp13 protein

A

helicase

240
Q

corona nsp16 protein

A

methyltransferase

241
Q

CoV-2 entry

A

S binds ACE2 > cleaved at S1/S2 boundary and S2’ site by host > activated S2 ?fusion of viral and host membranes at plasma mem and endocytic vesicles
some coronas are pre-cleaved by furin (MERS)

242
Q

corona nonstructural protein production

A

ORF1a and ORF1b translated from incoming genomic RNA
1ab is produced by a ribosomal frameshift (-1) mechanism involving pseudoknot in RNA
Both polyproteins are cis-cleaved into 16 active products
Once nonstructural proteins are made, they replicate the genome

243
Q

corona replication

A

replication complex involves many viral proteins
pos > neg > pos sense RNA
if full length, packaged into nucleocapsid
if sgRNA, translation to proteins

244
Q

corona sgRNAs

A

3’ coterminal (all have same 3’ end, variable 5’ length)
only makes the 5’ most coding region into protein even tho longer sgRNAs obviously also contain other proteins
monocistronic - one gene = one protein
all get leader and TRS

245
Q

corona discontinuous transcription during neg-strand synthesis

A

only one leader at 5’ end but all sgRNAs get it
multiple TRSs
TRS acts as pause, located at 5’ end of a nested RNA
polymerase initatiates transcription at 3’ end, when it hits TRS it pauses, can release RNA or continue
happens at ea TRS
hets leader from polymerase jumping - TRS repeats are identical, TRS on new RNA complements TRS on on template strand, repolymerizes, adds full leader to all sgRNAs

246
Q

why does corona have high recombination rate

A

polymerase jumping promotes recombination between 2 diff genomes bc it can go from one TRS to diff viral TRS on diff nearby corona genome (trans polymerase switch)

247
Q

corona cis vs trans polymerase switch

A

cis - polymerase jumping within a single genome, genome folds on itself
trans - polymerase jumping between 2 diff genomes, genome folding w another copy of the genome (from same or diff corona)

248
Q

why does corona have high fidelity replication

A

most RdRps are error prone
corona has proofreading funct from the exonuclease (ExoN, nsp14)
low mutation rates compared to most RNA viruses
important bc of big genome, size exceeds error threshold of most Rdrps

249
Q

corona assembly

A

N binds RNA = NC > M and E insert into ER membranes for glycosylation > S inserts into intracellular and plasma membranes > M interacts with N and S and initiates budding > Budding occurs into ERGIC (ER-golgi intermediate compartment) > Viral glycoproteins glycosylated in golgi after budding > Release occurs upon vesicle fusion with plasma mem (via exocytosis)

250
Q

corona accessory proteins

A

at 3’ end w structural proteins
nonessential
little to no homology
more important in vivo than in vitro (subverts imm resp)
some may be packaged

251
Q

corona pathogenesis

A

diverse, infect mammals and birds
respiratory, GI, and CNS disease
respiratory disease is usually acute and self limiting, can sometimes cause chronic infection
replicates in alveolar lining, causes multi-nucleated giant cells (synctia), caused by S protein on plasma mem between 2 neighboring cells
infiltrate MO
efficient at evading IFN type 1 but induce high inflamm cytokine levels
infection thickens lining of lungs, thinning of air sacks
common cold via 229E and OC43 prototypes
SARS was first serious corona disease (2002-2003)
able to actively rep in GI but does not damage, how does it cause gastroenteritis
note: GI infection odd bc it is an enveloped virus, how does it survive pH??
can cause systemic infection in severe cases

252
Q

SARS triphase pattern of disease

A

wk 1: prodromal (nonspecific) phase - fever, non-productive cough, sore throat, diarrhea
wk 2: shortness of breath, fever, diarrhea; respiratory decline in severe cases
wk 3: acute respiratory distress, likely due to cytokine storm
most disease is immunopathogenic
sheds in both resp and GI tract, high correlation between age and severity

253
Q

SARS (2002-3 epidemic) cross species transfer

A

workers in markets w raccoon dogs and calm civet cat were infected, animals had related virus
probably not true reservoir: no wild animals w it (they did not bring it in from wild the picked it up at market), causes disease in these animals (reservoirs are usually asymmtomatic)
horseshoe bat are true reservoir; bat > civet > human
civet was intermediate host

254
Q

SARS-CoV 2 receptor

A

ACE2
species specific -14 residues in receptor binding domain contact 18 residues on ACE2, only 2 differ between human and civet
changes: 1. pos charge on S repels ACE2 2. methyl group on S allows for tighter binding into groove
few changes lead to zoonotic jump

255
Q

MERS corona pathogenesis

A

2012 epidemic
severe pneumonia
high mortality rate but also comorbidities
not efficient human to human transmission
widespread in dromedary camels in several Arbian countries, most MERS is linked to camels (others are hospital-acquired)
Bat > camel > human

256
Q

measuring death toll of SARS-CoV 2

A

reported vs excess deaths do not line up, inaccurate records either purposefully or just poor reporting methods
diff qualifications: die in hospital/community? comorbidities? was there testing?
how to count?
satellite images of grave sites, reported numbers compared to computer models

257
Q

SARS-CoV 2 pathogenesis

A

upper then lower resp tract
diff symptoms for ea strain
children and young adults asymptomatic, elderly more severe disease
5 day incubation, 8 day disease
highest shedding BEFORE symptoms, makes hard to control

258
Q

Possible SARS-CoV 2 origins

A
  1. direct jump bats to human
  2. reservoir intermediate host to people
    no intermediate identified yet
    simliar viruses in pangolins and bats
  3. lab escape (accidental or engineered)
259
Q

why do people think SARS-CoV 2 was lab escaped

A

unique furin cleavage site: extra seq compared to closest relatives, only in human strain, inc in infectivity
does occur independently in other members of CoV family, maintained bc of inc in infectivity
codon usage in furin cleavage site: multiple codons for ea aa, specicies preferences, 6 possible codons for R, humans prefer 3, CGG is least common for corona but two of the R in furin cleavage site use it
Rare but it exists in all coronaviruses, roughly proportional to others in family, If artificially produced and corona didn’t like it, it could mutate to preferred seq, however despite all diff strains 99.8% use CGG
RRAR is rare furin cleavage and is suboptimal (researchers would not have picked it)

260
Q

evidence for zoonotic transmission of SARS-CoV 2

A

75% early cases associated with market (none w Wuhan institute), evidence of animals at market (illegal), testing of surfaces in market, pos for SARS-CoV 2

261
Q

SARS-CoV 2 vaccine

A

modified from 1st SARS vaccine development (already tested in animals and early human trials)
only had to change S protein for new vaccine
Spike cloned into RNA, introduced into host cells, translated by host, presented to imm sys, elicit imm resp
disparity over who is getting vaccine (low income countries)

262
Q

influenza general overview

A

neg sense RNA
segmented genome
helical structure (all neg sense RNA viruses)
enveloped
replication in nucleus (odd for RNA viruses)

263
Q

influenza genome organization

A

segmented (7-8 segments)
mostly monocistronic, exceptions: segments 7 and 8, ea have 2 proteins via alternative splicing
replication in nucleus
unusual twin helical conformation w central loop
coated w NP
both 5’ and 3’ ends complexed to PB1 (polymerase subunit)
PB1 binds PB2 and PA

264
Q

influenza HA protein

A

hemagglutinin, glycoprotein, binds receptor and fuses w host mem
(HA and NA determine classification)
forms trimer in envelope
binds sialic acid-containing receptors at head
initiates receptor mediated endocytosis and fusion in endosomes
generated as fusion incompetent until cleavage by cellular proteases (fusion buried until it gets cleaved in endosome)

265
Q

influenza NA protein

A

nuerominidase, glycoprotein, release of progeny from surface during budding
(HA and NA determine classification)
cleaves sialic acid
needed to release bound virions by mucoproteins in resp tract

266
Q

influenza classification

A

influenza A causes most human disease, w occasional influenza B and rarely influenza C
HA and NA determine classification
A has many serotypes (differential Ab reactivity)
144 possible serotypes of A, only 19 observed

267
Q

influenza virus structure

A

helical
enveloped
pleiomorphic - adopt diff conformations; can be spherical or filamentous
filamentous - better cell to cell (larger)
spherical - better person to person (smaller)

268
Q

influenza NP protein

A

nucleocapsid protein, binds w segments of genome, 1 of ea segment per virion

269
Q

influenza M2 protein

A

ion channel
forms tetramers to create pores in envelope, upon acidification in endosome - ion channels open > H+ cross > drives release of viral nucleocapsid into cytoplasm
anti-influenza drug amantadine blocks M2 ion channel

270
Q

amantadine mode of action and efficacy

A

pits into M2 pore, prevents H+ exchange
not used anymore, most strains are imm to amantadine now, only a few aa changes for resistance

271
Q

influenza M1 protein

A

matrix

272
Q

influenza what coats the genome segments

A

nucleocapsid protein + polymerase complex proteins (PA, PB1, and PB2)
needs to have polymerase in virion bc of neg sense RNA, cannot directly translate upon entry into host
1 of ea segment per virion

273
Q

influenza cytoplasm/nucleus shuttling

A

HA binding > endocytosis
gets shuttled between nucleus and cytoplasm
genome enters nucleus for transcription, mRNA goes to cytoplasm for translation
glycoproteins move through ER and golgi, all other proteins go back to nucelus to associate w genomes during replication, these then get exported to cytoplasm and directed to plasma mem > budding

274
Q

influenza genome replication

A

neg > pos > neg RNA
intermediate pos is used as mRNA for translation
replication in nucleus:
segment enters nucleus > transcription > 5’ cap and poly-A tail > cytoplasm > make viral proteins > proteins go back to nucleus to help w RNA rep > progeny exit nucleus to get packaged

275
Q

what type of virus is influenza

A

orthomyxo

276
Q

influenza cap stealing

A

most RNA viruses encode their own capping enzyme, influenza cap-steals
cellular pre-mRNA has cap, PB2 binds to it > PB1 cleaves mRNA downsream of A or G (allows UC repeat at 3’ end to bp w opposite end) > PB2 bound cap acts as primer for transcription > PB1 is polymerase (Rdrp), initiates transcription 5’ to 3’
all viral influenza mRNAs have some host at 5’ end

277
Q

influenza poly-A tail

A

All influenza genome segments contain a short poly-U stretch at their 5’ end, PB1 pauses and stutters here, reading through poly-U several times and repeatedly adding complementary A residues
PB1 eventually terminates at this position; thought to be due to presence of another PB1 molecule at the 5’ end of template RNA

278
Q

influenza alternative splicing

A

M1 and NS1 mRNAs
M1 splicing = M2
NS1 splicing = NS2
low fraction (10%) is spliced (quantity regulation)
unspliced and spliced both transported to cytoplasm

279
Q

influenza translation

A

in cytoplasm, some proteins shuttle to nucleus for rep
pos RNA template for translation and rep but process is distinct
genome replication requires free NP, made by translation, when there is a lot of NP it drives rep over translation
after neg RNA is made, complexes w M1 and NS2 (has NES) > exported

280
Q

influenza NS1 protein

A

most abundant protein in infected cell
shuts down host cell
interferes w host poly-A tail formation (does not affect viral bc of stuttering mechanism), combined w cap stealing, most cellular pre-mRNA is degraded
suppresses IFN
NS1 mutations result in poor replication (unless IFN deficient cell)

281
Q

influenza assembly

A

7/8 genome segments interact w M1 protein which interacts w cytoplasmic tails of HA and NA and ion channel (M2)
Cleavage at neck
NA needed to cleave from sialic acid

282
Q

influenza A pathogenesis

A

severe acute disease
sore throat, cough, fever, headache, muscle ache
partially due to tissue damage from virus, mostly due to immunopathological levels of cytokines and chemokines (in severe cases can have cytokine storm)
annual epidemics, pandemics every 10-50 yrs
fatality usually only in juvenile, elderly, and immunocomp
influenza targets goblet cells, kills them, causes symptoms
lack of mucus allows for 2’ infections
imm resp also causes disease (proinflamm cytokines and robust BC resp)

283
Q

how can influenza kill its host

A

influenza usually does not - 2’ bacterial infection can cause fatal pneumonia
influenza targets goblet cells, kills them, causes symptoms
lack of mucus allows for 2’ infections
immunopathology as well

284
Q

influenza Ag shift vs drift

A

drift - point mutations during error prone replication, Mutations in HA or NA can allow for imm evasion, subtype of strain DOES NOT CHANGE however diff can mean less protection for people already infected w original strain
Shift – reassortment of 2 diff flu strains together (ex: swine + human in same host)
Segments mix
NEW SUBTYPE GENERATED ex: H2 to H3

285
Q

influenza pandemics: shift vs drift

A

shift (reassortment) more likely to cause pandemic bc of big diff in Ag/Abs
allows for zoonosis
often human w bird flu
sometimes swine (2009)
1918 was fully avian, might be exception - drift not shift, mutations in HA and RdRp

286
Q

why was 1918 spanish flu so bad

A

high infectivity
global bc of war travel (and close contact)
severe symptoms (cytokine storm)
majority of deaths from 2’ infection
targeted young adults (unusual for flu)

287
Q

why did 1918 spanish flu target young adults

A

Originally thought imm resp was stronger, so worse immunopathology
Now - less protected from previous immunity:
Born before 1889 had some immunity to H1
Born during 1889 only exposed to H3
Born after 1900 had circulating H1 strain
People born between 1889 and 1900 had no prior immunity to H1

288
Q

HPAI

A

Highly pathogenic avian influenza (HPAI) viruses
H5N1 and H7N9
2 strains that are avian, highly pathogenic in birds
Also highly pathogenic in human but rare human to human spread
Usually people in close contact w birds
Very concerned about H5N1 bc few mutations will allow may allow spread human to human, many many will die
H5 has been detected en masse in birds (domestic poultry and wild birds)
pos human infection and some wild mammals

289
Q

influenza treatment

A

M2 inhibitors - amantadine, most/all strains are resistant now
NA inhibitors - temiflu

290
Q

influenza prevention

A

vaccines
killed wt, live attenuated, recombinant HA protein made in insect cells
multivalent nature - WHO monitors and predicts which strains ea year (usually quadrivalent: influenza A H1N1, influenza A H3N2, and two influenza B viruses) - varied effectiveness

GMS6121 - Infectious Diseases (4 decks)

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