M31: Immune Evasion Strategies III: Antigenic Variation

Question 1

Immune system:

Innate immunity

a. _ line of defense
b. (5)
c. (Specific / Not specific) to a single pathogen or antigen
d. Memory?

Adaptive immunity

a. _ / _
b. _ cells
c. (Specific / Not specific) for a pathogen or antigen
d. Memory?

Answer 1

a. First
b. Barriers (e.g. skin), neutrophils, macrophages, NK cells, complement
c. Not specific
d. No memory response

a. Antibody/B cells
b. T
c. Specific
d. Immunologic memory (responds more vigorously second time)

Question 2

Antigenic variation:

Definition: systematic changes or variations in _ or other structures on the
surface of _ to _.

a. Avoidance of _, usually
b. Mechanism for (intracellular / extracellular) pathogens, or those that have (intracellular / extracellular) phase (because antibodies are in the this space)

Why antigenic variation?

a. evolution of the _ in response to the _
b. selective pressure by _ to change (intracellular / extracellular) protein to avoid being killed
c. need successive changes to avoid _

Answer 2

proteins
pathogens
avoid elimination by the adaptive immune system of the host

a. antibodies

b. extracellular
extracellular

a. population
immune response of the host

b. antibodies
extracellular

c. pre-existing antibodies

Question 3

Antigenic variation:
Phase variation:

switching on or off _ that produce a phenotype

i. Salmonella _
ii. E. coli _
iii. _ in E coli
iv. molecular “switch” (_), _, _
v. _ during DNA replication (mutations that can turn off a gene)

Antigenic drift: accumulation of _ that alter _

i. error prone replication results in _
ex. (3)

Antigenic shift: abrupt change in _

i. gene _, _, _
ex. (3)

Answer 3

genes

i. flagella
ii. fimbriae
iii. pap pilus operon
iv. (inversion), mutations, methylation
v. slipped strand mispairing

mutations
antigenic composition
i. mutations

ii. influenza virus
iii. rhinovirus
iv. HIV

surface antigen
i. conversion, rearrangement, reassortment

ii. influenza virus
iii. Neisseria gonorrhoeae
iv. Trypanasoma brucei

Question 4

Influenza virus:
Virus basics:

a. Family _
b. (Positive / Negative) sense, (ss / ds) (DNA / RNA) virus with segmented genome

c. Three genera: influenza type _, _, _
i. _ is the only one of major importance to human disease
ii. Type _ causes annual outbreaks and epidemics and pandemics

Answer 4

a. Orthomyxoviridae

b. Negative
ssRNA

c. A, B, C
i. A
ii. A

Question 5

Influenza virus:
Influenza outbreaks

a. Seasonal _
b. _ (outbreaks within a _ location: community, town, country)
c. _ (severe outbreaks that rapidly progress to involve all parts of the world, associated with a _ to which the overall population has no immunity)
d. Principal determinant in whether Influenza outbreaks occur is degree of match in specificities between _ and _ against them that exist in the population

Answer 5

a. flu

b. Epidemics
confined

c. Pandemics
new virus

d. surface antigens
antibodies

Question 6

Influenza virus:
Pathogenesis

a. Virus infects _ and causes death of cells
b. _ protein: main target for antibodies and vaccine
i. Binds to _ on host cells
ii. Cleaved to form _, which allows release of viral _ inside cell
c. _: release of new viral particles (necessary for infection of new cells)
d. Host cell derived _
e. 8 (DNA / RNA) segments make up genome (important for _ and _)

Answer 6

a. respiratory epithelium
b. Hemagglutinin (HA)
i. carbohydrates

ii. HA2
RNA

c. Neurominidase (NA)
d. envelope

e. RNA
reassortment and antigenic shift

Question 7

Influenza virus:
Pathogenesis

a. Hemagglutinin is essential for _ and causing _ (which allows _)
b. HA is cleaved by host protease (present in _ and _ mucosa) to _ and _. Virus is endocytosed and the vacuole is _. HA2 is the fusion peptide that allows the viral gene segments to enter the cell for _.
c. _ is important for preventing viral aggregation and release of new viral particles

Answer 7

a. binding to cell
fusion
entry of virus into cell

b. respiratory and GI
HA1 and HA2
acidified
viral replication

c. Neuraminidase

Question 8

Influenza virus:
Clinical aspects

a. _ infection, spread by _ — can transmit before onset of obvious symptoms
b. _ and _ most susceptible to severe disease

c. Yearly seasonal outbreaks of influenza
• _ months (northern and southern hemisphere)
• Usually ~21,000 deaths per year US

d. Symptoms in uncomplicated influenza
i. Incubation period 1-2 days, then sudden onset of symptoms: (6) —lasting ~3 days (duration of fever)
ii. _ most important physical finding: peak of 100-104°F, can be higher, lasts 3 days
iii. As disease progresses: _ symptoms, especially _
iv. Recovery can be 2 weeks, with accompanying (3)

Answer 8

a. Respiratory
respiratory droplet inhalation

b. Children and elderly
c. Winter
i. fever, chills, headache, myalgia, malaise, anorexia
ii. Fever

iii. respiratory
cough

iv. malaise, myalgia and cough

Question 9

Influenza virus:
Complications

i. Primary influenza viral _: rare outside of pandemics, but caused many deaths in 1918-19 pandemic
ii. Secondary bacterial _: Elderly people most susceptible
iii. Classic influenza course (4-14 days) followed by return of _ and symptoms consistent with bacterial pneumonia: _, _, areas of _ in lung.
iv. Bacteria: most often _ or _
v. Usually responsive to _ therapy
vi. Other complications: _, exacerbation of _ diseases (eg bronchitis, asthma)

Answer 9

i. pneumonia
ii. pneumonia

iii. fever
cough, sputumconsolidation

iv. Streptococcus pneumoniae or Haemophilus influenzae
v. antibiotic

vi. croup
chronic

Question 10

Influenza virus:
Diagnosis and treatment

a. diagnosis can be made on _ grounds or by testing _ or _ swabs for virus
b. treatment: _ and : active against influenza A—interacts with _ protein. Reduces clinical symptoms and virus shedding.
c. _ () is a neuramindase inhibitor (prevent infection/disease)
d. _ can develop to these drugs

Answer 10

a. epidemiologic
nasal or throat

b. amantadine and rimantadine
M2

c. Tamiflu (oseltamivir)
d. Resistance

Question 11

Influenza virus:
Vaccines

a. _ virus and _ virus vaccines—mostly work by stimulating antibodies against HA and NA
b. _ vaccine: two strains of influenza A and one influenza B
c. Live attenuated is given _ (Flumist)
d. Vaccine is very effective if there is good antigenic match between _ virus and _ virus (70-90% effective)
e. Vaccine strains are grown in _, can’t be given to people with severe _ allergies
f. The 2013-2014 inactivated flu vaccine is composed of two Influenza _ strains (H1N1, H3N2)(same as 2012) and a new influenza _ strain

Answer 11

a. inactivated
live attenuated

b. Trivalent
c. intranasally

d. vaccine
epidemic

e. chicken eggs
egg

f. A
B

Question 12

Antigenic variation and influenza:
Antigenic drift:

a. primarily involves _ and _ proteins
b. relatively minor changes in antigens due to accumulations of _ during _ in the human host
c. poor fidelity of _ transcription
d. antibody mediated selection: antibody generated by “” virus doesn’t _ “” virus as effectively, _ virus predominates.
e. That is: Changes in _ selected for by host antibody response to ongoing infecting virus

Answer 12

a. HA and NA

b. point mutations
replication

c. RNA

d. “parent”
neutralize
“drifted”
new

e. surface antigen

Question 13

Antigenic variation and influenza:
Antigenic shift

a. major changes in viral _ as a result of “_” — may result in a strain that _ (in terms of HA or NA), and then can cause a pandemic
b. Pandemic:
i. rapid _ with concurrent outbreaks worldwide, disease outside of normal _
ii. high _ rates in all age groups
iii. high _ rates
iv. 10 pandemic events during past 300 years, avg 3/century
v. this century 1918-1919 (20-40 million deaths) 1957-58, 1968-69
vi. new pandemic was _, 2009-2010

Answer 13

a. genome
reassortment
hasn’t been “seen” by humans

i. transmission
seasonality

ii. attack
iii. mortality
vi. H1N1

Question 14

Antigenic variation and influenza:
Antigenic shift

c. Antigenic shift: when two influenza viruses are _, _ can occur
example: 1957 pandemic caused by _ virus. Apparently caused by human _ and avian _ viruses coinfected a host, and new virus was HA, NA, PB1 genes from avian virus and the remainder from human virus.
d. 1918-19 virus _ : shift and drift

example of drift: two _ in HA make it much more transmissible.

Answer 14

c. present within the same host
exchange of segments

H2N2
H1N1
H2N2

d. H1N1
point mutations

Question 15

Antigenic variation and influenza:
“Bird flu”

a. _ virus circulating in many avian species now, including domestic and migratory birds. Very _ in some species.
b. Birds carry many viruses so possibility of _ high
c. Avian viruses usually don’t infect _ (HA binds to a different form of sialic acid). Viruses in pigs bind to the same _ form as humans, and therefore adaptation of avian virus thought to occur in _ (although not necessary).
d. H5N1 has infected and killed humans but has not caused an _ yet
e. Vaccine against bird flu can’t be made until the virus “_”—vaccine is based on sequence of _ and _, and that is constantly changing (antigen drift).
f. outbreak of avian flu: antigenic shift and drift: shift for _ that hasn’t been seen by humans and drift to make it _ / _ for humans. Could occur in humans or in other animals or even birds.

Answer 15

a. H5N1
virulent

b. reassortment

c. humans
sialic acid
pigs

d. epidemic

e. shows itself
HA and NA

f. HA
virulent / pathogenic

Question 16

Neisseria gonorrhoeae:

a. _ infection
b. gram (positive / negative) _, oxidase (positive / negative)

modified media is used (_ agar with _with antimicrobial agents often used: _)

c. highest case rate is males and females 15-24 yrs of age
d. Transmission is through _, primarily

Answer 16

a. sexually transmitted

b. negative
diplococci (cocci in pairs)
positive

chocolate
glucose
Thayer-Martin

d. sexual intercourse

Question 17

Neisseria gonorrhoeae:

e. Symptoms: Male
i. Acute _, usually 2-5 days after exposure
ii. _ (purulent) and _
iii. Most would resolve if not treated within several _
iv. _ cause men to seek treatment

f. Symptoms: Female
i. _ is primary locus of infection
ii. Can be _ or only minor symptoms
iii. If symptoms occur: _, _

iv. Complication: _ 
• 10-20% of women with _
• low, bilateral _ pain 
• tenderness in _ and surrounding area 
• _ sometimes 
• _ secondary to fallopian tube obstruction most common serious outcome

Answer 17

i. urethritis
ii. Urethral discharge
dysuria
iii. weeks
iv. Symptoms

i. Endocervix
ii. asymptomatic
iii. cervicitis, urethritis

iv. pelvic inflammatory disease (PID)
• gonorrhea 
• abdominal 
• uterine
• fever 
• infertility

Question 18

Neisseria gonorrhoeae:

g. Can be transmitted to baby _ or during _
• _ most common (but silver nitrate in eyes of newborns prevents this manifestation)

h. Diagnosis: _ of organism from affected site (specialized media). Also some _ tests available.

i. Treatment: _
• _

j. Co-infection with _ (_) common and should be tested for 15-25% men, 35-50% women with gonorrhea

Answer 18

g. in utero
delivery
• Conjuctivitis

h. culture
molecular

i. cephalosporins
• Ceftriaxone

j. Chlamydia (C. trachomatis)

Question 19

Neisseria gonorrhoeae:
Pathogenesis and virulence factors

a. A strictly _ pathogen
b. Organism needs to attach to _ cells (non-ciliated)—allows penetration to _ tissues

c. _: major virulence factor needed for attachment
• Undergoes _ and _

d. _ proteins: strains can express 0-11 opa proteins, some simultaneously (not usually more than 3 at a time)
• _ and _
• Increase _ between bacteria and to host cell

e. _: _
• Lipid _ and core oligosaccharide without _ antigenic side chains
• Core sugars undergo _ and _

Answer 19

a. human

b. columnar epithelial
submucosal

c. Pili
phase and antigenic variation

d. Opa
Phase and antigenic variation
adherence

e. LOS: lipoligosaccharide
A
O
phase and antigenic variation

Question 20

Neisseria gonorrhoeae:
Pilus phase and antigenic variation

a. conserved and variable regions in _ protein (subunit for pilus)
b. _ locus is expression site; _ contains variable regions, 1-6 copies of pilS in chromosome. PilS is transferred to _ site for expression. “_”
c. Neisseria naturally _ (take up DNA)

pilS sequences can come from other Neisseria in _ and by _, be expressed from pilS

d. Also can occur between two copies on the _
e. Leads to _ (each pilS is different)
f. can lead to _ (turning pilus off) if non-functional pilE/S combination occurs
g. no immunity to _ due to antigenic variation
h. antibodies against pilus cannot be protective against challenge with a strain with an _
i. vaccine?

Answer 20

a. pilin

b. PilE
pilS
pilE
“gene conversion”

c. transformable

population
homologous recombination

d. same chromosome
e. antigenic variation
f. phase variation
g. reinfection
h. antigenically distinct pilus
i. no vaccine because of antigenic and phase variation

Question 21

Trypanosoma brucei sp gambiense or rhodesiense:

a. Causative agent of _
b. parasitic organism: _ _ _
c. transmitted by _ which are found only in _
d. trypomastigote form lives within the _ of mammalian host ((intracellular / extracellular) parasite)
e. disease course:
i. Stage I: _ at site of infection (tsetse fly bite), then systemic spread with _, onset of _ (intermittent high _ and _ states), _, transient _, _
ii. Stage II: _ involvement. Parasites reach _ and _. Different _ manifestations—including sleeping during the day.

Answer 21

a. African trypanosomiasis (Sleeping sickness)
b. flagellated protozoan parasite

c. tsetse fly
Africa

d. blood
extracellular

i. chancre 
lymphadenopathy
fever 
fevers and afebrile
anemia
transient edema
rash 

ii. CNS
brain and meninges
neurologic

Question 22

Trypanosoma brucei sp gambiense or rhodesiense:
Pathogenesis

a. Must survive in _ (intracellular / extracellular), with antibodies developing against parasite.
b. Survival requires antigenic variation of _ which surrounds parasite (major protein on surface)
c. As antibodies are raised against one type of _, new parasite with antigenically distinct _ emerges
d. Waves of _ occur

Answer 22

a. bloodstream
extracellular

b. variable surface glycoprotein (VSG)

c. VSG
VSG

d. parasitemia

Question 23

Trypanosoma brucei sp gambiense or rhodesiense:
Antigenic variation

a. VSG variation occurs by several mechanisms, but mainly _
b. _ of silent VSG sequences into an active VSG expression site (_): most important
c. _ exchange downstream of expression site
d. Turning on a new _ while turning off the old one
e. Mechanisms for many of these still not clear
f. Allows escape of parasite from _ and survival in _

Answer 23

a. gene conversion

b. Homologous recombination
gene conversion

c. Telomeric
d. expression site

f. antibodies
bloodstream

Question 24

Trypanosoma brucei sp gambiense or rhodesiense:
Diagnosis and treatment

a. epidemiology and clinical findings help establish diagnosis, but definitive diagnosis requires demonstration of _
b. _ if stage I may yield parasites
c. _ examination essential in stage II: increased cell count, parasites
d. Some _ available for treatment, depends on clinical stage, parasite, side effects, etc.

Answer 24

a. parasite
b. blood smear
c. CSF
d. drugs

Question 25

Other Trypanosoma species of medical importance: Trypanosoma cruzi

a. causative agent of _
b. location: _
c. _ stage and _ stage
d. Does NOT undergo classical _ of surface proteins (mostly (intracellular / extracellular) in human host)
e. Evades _ to avoid killing in the blood

Answer 25

a. Chagas disease
b. South America (Brazil)

c. Blood
intracellular

d. antigenic variation
intracellular

e. complement

Question 26

Other examples of antigenic or phase variation:

_ (malaria)
_ (Lyme disease)
_ (meningitis)
_ (flagellar phase variation)

(6)

Answer 26

Plasmodium falciparum
Borrelia burgdorferi
Neisseria meninigitidis
Salmonella

Haemophilus influenzae 
E. coli 
Campylobacter 
Bordetella pertussis 
Stretococcus pneumoniae 
Streptococcus pyogenes