introduction to immunology system, and the wide range of reaction to viruses.

2. Arm Race – Viruses and Immunity

3. Immune
Response to
Viruses
Intrinsic, Innate and Adaptive
resopnse

4. Contents
Immune defenses to viruses
2ed section
Adaptive
defenses
Immunopathology
1st section
Intrinsic
defenses
Innate
defenses
Inflammation

5. Table of 1st section
contents
 Host defenses
 Intrinsic defenses
 RNA silencing
 Antiviral proteins
 Autophagy
 Apoptosis
 Innate Immunity
 Pattern recognition receptors
 Cytokines
 Sentinel cells
 complement
 Inflammation

6. Host defenses
 Physical and chemical
defenses
 1. Intrinsic defenses:
 2. Innate defenses
 3. Adaptive defenses Adapted form principles of virology 3rd ed.
Get
passed
Viral
illness

7. 1. Intrinsic defenses
Always present in the UNINFECTED cell.
Doesn’t have to be induced

8. 1.1 Intrinsic Defenses:
RNA silencing.
Antiviral proteins.
Autophagy.
Apoptosis.

9. 1.1 Intrinsic Defenses:
RNA Interference
 So old system
 RNA bases (not protein based)
 Present in (plants, invertebrate cells)
Present in
Mammals?

10. Adapted form principles of virology 3rd ed.
Virus Infection.
Digestion to 21
N.A pieces.
Small interfering
RNAs.
Targeting viral
genome.
RNA induced silencing
complex (nucleasases).

11. 1.2. Intrinsic Defenses:
Antiviral proteins
RNA silencing.
Antiviral proteins.
Autophagy.
Apoptosis.

12. 1.2. Intrinsic Defenses:
Antiviral proteins
 Example:
APOBEC3 protein. ( )
C → U and denaturate ds to ss.
Specific for HIV1 infection.
Genome crash
 Apolipoprotein B mRNA Editing catalytic polypeptide.
Althoug HIV has
olny infected
human since 1980s

13. Antiviral proteins: APOBEC3
mechanism and antagonism
 So why HIV is still infecting Human?
APOBEC is budded
with virion
converting
crashing
crashing
http://harris.cbs.umn.edu/projects.html

14. 1.2. Intrinsic Defenses:
Antiviral proteins
 It’s due to the viral counter measures:
VIF
ubiquitination
http://jvi.asm.org.sci-
hub.org/content/80/3/1067/F1.expansion.html

15.  Stress (↗T, viral infection) → Autophagy.
1.3. Intrinsic Defenses:
Autophagy
Autophagosome
lysosome
http://www.wormbook.org/chapters/www_autophagy/autophagy.html

16. 1.3. Intrinsic Defenses:
Autophagy
Always
remember: for
every measure
→ viral
countermeasure
Some viruses uses autophagy:
polio uses autophagosomes to
replicate on its surface.
Viruses interfere with
required proteins for
autophagy.

17. 1.4. Intrinsic Defenses:
Apoptosis
RNA silencing.
Antiviral proteins.
Autophagy.
Apoptosis.

18. 1.4. Intrinsic Defenses:
Apoptosis
 Used to get rid of cells.
 Tightly regulated.
 Inducers ex.:
 Stress.
 Viruses.
 Viruses
countermeasures.
A virus: Oh no,
stop it !!
I need these
cells

19. 1.4. Intrinsic Defenses:
Apoptosis
Nucleus
fragmentation
Cytoplasm
fragmentation
DNA fragments
Phagoctyes
sensing viruses >
turning innate
immunity.

21. Let’s revise:
 Question1: intrinsic defenses are always
there, which of the following are
included?
a) Ab
b) T cells
c) Autophagy
d) All
e) none

22. 2. Innate Immunity

23. 2. Innate Immunity
features:
 Quick response (min to hrs).
 Includes:
Cytokines
sentinel cells (DC, Macrophages, NK)
Has the potential to stop the infection.
complement
 Not succeeded > seeking for help
(Adaptive immunity)
 DC: dendritical cells
NK: natural killers

24. Adapted form principles of virology 3rd ed.

25. 2.1 How does innate immune
system recognize microbes and
not self?
 2.1.1 Toll-like receptors.
 2.1.2 Cytoplasmic helicases.
 2.1.3 Inflamasomes.
Pattern recognition
receptors

26. 2.1.1 Toll-like
receptors
 First discovered through working on fruit
fly.
 Key molecules for sensing foreign
products:
 Proteins
 Carbohydrates
 N. Acids
 The most important in v. inf. is
enodsomal TLRs

27. TLRs
Cascade of
activating
signals
Cytokines, INF
are expressed
Adapted form Field virology 6th ed.
Foreign genetic
matter
All viruses are
recognized?

28. 2.1.1 Toll-like
receptors`

29. 2.1.2 Cytoplasmic
Helicases
 A virus entering the cell but not
through endosomes, how is it
recognized?
 Cytoplasmic Helicases.
 Detects RNA

30. 2.1.2 Cytoplasmic
Helicases
Adapted form Field virology 6th ed.
Helicase
Cascade of
activating
signals
Cytokines, INF
are expressed
Distinguishable
5’ ppp end Distinguishable
ds RNA

31. But what about DNA?
DNA sensors
http://www.sciencemag.org/content/339/6121/763.full.html
DNA found in
the plasma
Detecting
Molecule
Close in
mechanism to
the physiology of
hormones
Cascade of
activating
signals
Cytokines, INF
are expressed

32. 2.1.3 Inflammasomes
 Strutures that detect:
ds DNA (AIM2)
Stresses
Holes in cytoplasmic membrane.
Reactive O2 species.
Potassium Efflus
Viral
infection
features

33. Cascade of
activating
signals
Inflamasome
Viral infection
features
Cytokines r released >
inflammation
Adapted form Field virology 6th ed.

34. Always Remember
that:
 Viruses and
Immunity r on an
Arm Race.
 Measures and
counter measures.
 If Viruses win >
illness.

35. Let’s revise:
 Question2: which of the following allow
the innate immune system to distinguish
between microbe and self:
a) Ab.
b) Apoptosis.
c) APOBEC3.
d) Cytoplasmic Helicases.
e) All.

36. 2.2 Cytokines
Innate Immunity

37. 2.2.1 INF
 Discovered 1970s.
 Protecting properties against viral
infection.
 Secreted from:
Infected cells.
Unifected cells. (Dendritic cells)
 INF: interferon

38. Adaptedformprinciplesofvirology3rded.
DC releasing
INF
Infected cell
releasing INF
Sentinel cells have the ability to detect both viral
proteins and nucleic acids > releasing INF

39. 2.2.1.1 INF types
INF type Secretory cells
INF - α Most virus-infected cells
INF - β Most virus-infected cells
INF - γ Lymphocytes
INF – λ (recently discovered) Epithelial cells
Adapted form principles of virology 3rd ed.

40. 2.2.1.2. INF mechanism
of Action
Cascade of
activating
signals
AdaptedformFieldvirology6thed.
ISGs expression
ISGs: Interferon stimulated genes, ISPs: INF stimulated proteins.
ISGs > 1000
molecules
Note that: interferon itself
has no antiviral activity
ISP

41. 2.2.1.3. ISP mechanism
Viperin prevents
budding.
Tetherin prvent
leaving

42. 2.2.1.5 Viral
countermeasures to INF
INF antagonists
Blocking signals
Or even making
soluble INF receptors
Adapted form Field virology 6th ed.

43. Let’s revise:
 Question3: How do INF limits viral
replication:
a) Inhibiting translation
b) Inducing TRLs
c) Inducing ISGs
d) Damaging the cell
e) none

44. 2.3 Sentinel Cells
Innate Immunity

45. 2.3.1 Dendritic Cells
(DC)
 Many kindes depending on the tissue
(skin, blood, etc.)
 Patrol our body looking for foreign
invaders (depending on proteins or
nucleic acids)
 APC > linking innate and adaptive
immunity.
 APC: antigen presenting cells

46. DC
Adapted form principles of virology 3rd ed.

47. DC actions:

48. 2.3.2 NK cells
 Independent from Ag- presenting
complex.
 Patrol our body looking for foreign
invaders (depending on the manner of
expression of MHC I)
 No memory>
 APC: antigen presenting cells

49. Adapted form Fields virology 6th ed.

50. “The most aggressive”

51. Mechanism of action

52. 2.5 Complement
Action
Innate Immunity

53. Complement
 Proteins Always present in serum.
 When activated it contributes in clearing
pathogens.
 In viral infection:
 Theses proteins coat virus particle and thus are
taken up by phagocytic cells

54. Complement Functions
In addition, it has
a function that
solubilize immune
complex, and
hence protecting
organs.

55. Let’s revise:
 Question4: What role do DC paly in viral
defenses:
a) Engulf and destroy viruses.
b) Sensing cells infected with
viruses and produce INF.
c) Only instructing adaptive immunity.
d) Lysis virus-infected cells.
e) All.

56. 2.4 Inflammation
 Infected cells > cytokines.
 ↗Blood Flow + ↗ capillaries permeability >
↗T locally .
 ↗ Phagocytes influx
 ↗ Tissue damage.
 To CNS: > fever
 To blood: sleepness, lethargy, muscle pain…
 Enhances adaptive immunity.
No good data to support thAt fever
is good in viral infection

57. 2.4 Inflammation
Cytokines
Proinflammatory TNF, IL-6, IL-12 Promote lymphocyte
activation
Antiinflammatory IL-10, IL-4 Supress activity of
proinflammatory
cytokines
Chemokines IL-8 Recruit immune cells in
early stages of immune
response

58. Adaptedformprinciplesofvirology3rded.

61. The second section
Adaptive
immunity

62. Table of 2ed section
contents
 Adaptive Immunity
Ab response
Cell mediated
 Immunopathology
Immunopathology of CD8+ cells
Immunopathology of CD4+ cells
examples

63. Why is it “Double edge
sword” immunity?

64. Innate instruction of
adaptive immunity
Adapted form principles of virology 3rd ed.
1 * 8 = 8
2 * 4 = 8
Viral
material
10 a.a viral
peptide
A killer of
infected cells

65. Viral counter
measures?
 countermeasures to
MHC II > No much
data
 However: viruses ╫
transcription of
genes that encodes
MHC II expression.
 Many viral c.m.
against MHC I, at
many levels i.e.:
Transporting MHC I.
(CMV, EBV, HSV)
Insertion of MHC I in
the ER. (CMV)

66. Let’s revise:
 Question 5 Antigen presenting by DC has
which features?
a) Viral peptide presentation on MHC I
to CD8+
b) Viral peptide presentation on MHC II
to CD4+
c) Viruses counter MHC I at many levels.
d) All.

67. From DC to
adaptive response

68. Th cells are good at secreting
cytokines
If imm.
response
requires CTL
response >
Th1
proliferate
and
differentiate
If imm.
response
requires Ab
response >
Th2
proliferate
and
differentiat
e
Most viruses
require a mix of
Th1 and Th2
response
Adapted form principles of virology 3rd ed.

69. Ab response
Ab:
 Essetial defense against
many viruses.
 Some neutralize virions in the
blood (× . ҉ spread)
 i.e. IgA at mucosal surfaces
(blocks entry)
 Some neutralizing Ab r
important 4 recovery from
infection
Adapted form principles of virology 3rd ed.

70. Ab response
IgG persist on long time terms
The nature of Ab is used to tell when a person has had
infection:
Rapid peak of IgM
Adapted prof V. Racaniello video

71. Ab secretory outcomes
1. Some non-neutralizing
Ab > inhibition of:
1. virus release
2. virus replication
2. Blocking Attachment.
3. Blocking encoding.
Viruses c.m.: HIV is
brilliant at evading Ab
response.
No treatment yet.
Adapted form Immunology Nature 2002

72. Ab secretory outcomes
1. Some neutralize viruses >
× infectivity.
2. However, st binds 2 the
wrong paratope.
(Ab epitope – paratope Ag)
3. Coating viruses >
complement > lysing.
or > phagocytized.
Adapted form Immunology Nature.

73. Never forget C.M.
Viruses c.m.: Ploygenetic
types: Rhinovirus has 150
genotype
You have cold couple times a year
Adapted prof V. Racaniello video

74. Let’s revise:
 Question 6 which statement about
antiviral Antibodies is incorrect?
a) Important for protection against many viral
infections.
b) Always neutralize virus infectivity.
c) Block attachment.
d) Can be found at any mucosal surfaces.
e) IgM is the first to appear then IgG.

75. Cell mediated
immunity
 Important for clearing
most viruses infection.
 CTL lysises target cell:
Perforin action
apoptosis
Adapted form principles of virology 3rd ed.

76. CTL or AB
 For some infections, CTL response
↗↗ important than Ab response. (although
Ab respone is usually ↗ important for protection)
 The process begins in lymph tissues (DC
tells naïve cells the nature of invader)
Adaptedformprinciplesofvirology3rded.

77. Th1 or Th2?
 The decision is made in
part by special T helper
and affected by:
 Nature of presented
peptide
 Nature of cytokines
released fom DC
 Nature of virus
 Virus location
Adapted form principles of virology 3rd ed.

78. CTL-antibody balance
 Information exchanged
causes differentiation
of Th1 or Th2.
 There r c.m.
Most infections r mix of the two Th
response
Differentiates into CTL
Stimulates B cell and Th1
differentiation
Ab response
Adapted form principles of virology 3rd ed.

79. Let’s revise:
 Question 7 for some infection, CTL are more
important for protection than antibody. How is the
CTL-antibody balance determined?
a) By TLRs.
b) Intrinsic defenses.
c) Autophagy of infected cells.
d) By the mix of peptides and cytokines presented
by Dcs (virus nature)
e) It depends on whether the capsid is icosahedral or
helical.

80. Adaptive response
memory
 Long life cells.
 Rapid and specific
(when again entered)
 Memory is the basis
of vaccination.
Adapted form principles of virology 3rd ed.

81. Memory cells
 Memory B cells. (already differentiated)
 In spleen, Lymph nodes.
 Do not produce Ab unless stimulated by Ag
 Long lived plasma cells
 Bone marrow
 Produce low level of Ab > low level of
protection
 Memory T cells

82. Memory B cells life-
time table.
AdaptedformFieldsVirology6thed.
Interesting
short
persistance
They are hard to be immunized.

83. Let’s revise:
 Question 8 What’s Characteristic of
immune memory?
a) Memory B cells.
b) Long-lived plasma cells.
c) Lasting a long time without more exposure
to virus.
d) Humoral Ab that last a long time
e) All above

84. Too much of a good
thing is a bad thing
Immunopathology

85. Immunopathology
 CPE and host
response > Clinical
symptoms of viral
infection
(fever, tissue damage,
etc.)
 immune response to
viruses
usually > disease is
entirely
immunopathologic.
Lytic viruses

86. Immunopathology
example
LCMV
LCMV
8 days
Persistent
infection
Adoptive
immuniztion
Lethal choriomeningitis
8 days
Lethal
choriomeningitis
AdaptedprofV.Racaniellovideo
Viral disease mediated by CD8+ CTLs

87. Immunopathology of
CD4+ cells
1. Elaborate ↑
cytokines than
CD8.
2. These soldiers are
protective but
cause tissue
damage.
3. Immunopathology
is the result of the
war.
CD4+
Neutrophils and
Mononucleated cells
Non-specific
effectors cells
Recruiting to war
(infection)
Destructive war weapons: proteases,
reactive radicals, cytokines TNF a

88. Immunopathology of
CD4+ cells
 Example:
 Herpes stromal keratitis >
Blindness.
 Immunopathological
mechanism.
 Infection affects corneal
epithelium. (no effect on
vision)
 Th2 comes and secretes
cytokines > reaches stromal
cells > damage > opacity.

89. Let’s revise:
 Question 9 Which of the following is a
mechanism for cell mediated
immunopathology:
a) Memory B cells lysing infected cells.
b) Cytokines damaging stromal tissue.
c) CD8+ CTL that damage infected cells.
d) Non-neutralizing antibodies that enhance
infection.
e) All above.

91. Answer Key
 1 -

92. References
 FlINT J., ENQIUST L., RACANIELLO V., SKALA A., Viruses Offenese Meets Host Defense:
Early Action in “Principles of Virology Third Edition”
 http://4f20lz3r4bii3yfqutfxz0o17ou.wpengine.netdna-cdn.com/wp-
content/uploads/2013/10/virus-defense-595x240.jpg
 https://r8---sn-
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WOh3NEsag#spark_video_download
 https://www.youtube.com/watch?v=XLOcG8pZNZE
 https://www.youtube.com/watch?v=HNP1EAYLhOs