Module 11: Viral Pathogenesis (Viral Interactions with Host)

Question 1

What are the two main pathways in which viruses cause cytopathology?

Answer 1

1) Inhibition of translation/transcription

2) Evasion/avoidance of host immune system

Question 2

Viral induced cytopathology =

Answer 2

CPE (cytopathic effects)

–> Changes in morphology of host cells due to viral infection

Question 3

Viral-induced cell damage usually leads to…

Answer 3

CELL DEATH

Question 4

What are the 4 main ways host cells die from viruses?

Answer 4

1) Necrosis
2) Apoptosis
3) Syncytia formation
4) Inclusion Body formation

Question 5

How is host cell translation/transcription inhibition beneficial to viruses?

Answer 5

It frees up resources (enzymes, building blocks, etc.) needed for viral replication

Question 6

How does Poliovirus cause virally-induced damage?

Answer 6

Through inhibition of host mRNA translation by blocking translation initiation

Question 7

What viral protein does Poliovirus produce to inhibit translation of host cell mRNA?

Answer 7

Protease 2A

Question 8

Protease 2A

Answer 8

A viral protein of Poliovirus that degrades eIF-4G

Question 9

eIF =

Answer 9

Elongation Initiation Factor

Question 10

What are Elongation Initiation Factors?

Answer 10

(eIFs) Are a family of proteins that bind to the 5’ end (CAP) of mRNA to direct the correct positing of ribosomal binding and initiator tRNA

eIFs are essential for translation initiation

Question 11

eIF-4G

Answer 11

A scaffold protein that allows for the binding of other eIFs to form the CAP-BINDING COMPLEX

(The eIF that Polivirus Protease 2A degrades)

Question 12

Cap-Binding Complex

Answer 12

A complex of eIFs that forms at the 5’ end of an mRNA to allow for proper ribosomal binding and initiator tRNA positioning to initiate translation

Question 13

Process of poliovirus-mediate translation inhibition:

Answer 13

1) Viral Protease 2A cleaves host eIF-4G

2) Cleaved eIF-4G cannot bind to host mRNA == no other eIFs can bind == no cap-binding complex forms == no ribosomal binding

3) Fragment of cleaved eIF-4G binds to the IRES region of poliovurs mRNA

4) Cap-independent ribosomal recognition occurs on the poliovirus mRNA with bound eIF-4G fragment

5) Ribosome and initiator tRNA bind to poliovirus mRNA and translation begins

Question 14

IRES =

Answer 14

Internal Ribosomal Entry Site

Question 15

What is an internal ribosomal entry site (IRES)?

Answer 15

RNA element that allows for ribosomal binding without the typical cap-dependent initiation (ribosomal scanning)

Question 16

Poliovirus does not ONLY cleave eIF-4G, what else does it do with this eIF?

Answer 16

It “steals” a fragment of it to use for its own mRNA to get the host ribosome to recognize it!

Question 17

Why must poliovirus use cap-independent ribosomal recognition?

Answer 17

Because it lacks the appropriate sequences in its 5’ end that allows for typical ribosomal binding and scanning

Question 18

What is the overall result of poliovirus-mediated translation inhibition?

Answer 18

Virus subverts translation machinery to increase viral production while decreasing host cell protein production

== Ultimately leads to cell death!

Question 19

How do Bunyaviruses cause virally-induced damage?

Answer 19

Through inhibition of translation by degrading host cell mRNA in a “cap snatching” method

Question 20

What is an example of a Bunyavirus?

Answer 20

Tomato Spotted Wilt Virus (TSWV)

Question 21

Cap snatching process:

Answer 21

1) VIRAL RNA polymerase binds to 5’ end of host mRNA

2) Viral RNApol CLEAVES the host mRNA around 10-20 nucleotides from the 5’ end

3) Cleaved host mRNA is DEGRADED

4) 5’ cap end fragment (“snatched cap”) is used by virus as a PRIMER for viral mRNA synthesis!

–> Viral RNA polymerase uses viral genome as a template for mRNA production + builds off of the snatched host cap to make the mRNA

5) STABLE viral mRNA is produced with the host cell 5’ cap

6) Capped viral mRNA is recognized by ribosomes and is translated

Question 22

In bunyaviruses, why is the cap snatching process beneficial?

Answer 22

Because it allows the viral mRNA to become STABLE (not degraded by host cell) and allows for host cell translation machinery to recognize the viral mRNA!

Question 23

What is the overall result of cap snatching?

Answer 23

Viral protein production increases but destruction of host mRNA leads to a lack of host cell proteins resulting in host cell death

Question 24

How do orthomyxoviruses cause viral-induced cell damage?

Answer 24

ALSO through cap snatching! (like bunyaviruses)

(but occurs in the nucleus!)

Question 25

How does cap snatching differ between bunyaviruses and orthomyxoviruses?

Answer 25

Bunyaviruses = cap snatching happens in cytoplasm Orthomyxoviruses = cap snatching happens in nucleus

Question 26

What are the 2 ways poxviruses lead to viral-induced cell damage?

Answer 26

1) Blocking host translation by viral protein binding to 40S ribosomal subunity (blocking ribosomal-mRNA binding) 2) By degrading ssDNA = preventing host genome replication

Question 27

Necrosis

Answer 27

Uncontrolled, "accidental" cell death in which chemical or physical cell injury results in **cell rupture** (cell bursts open)

Question 28

Necrosis is referred to as a... (analogy)

Answer 28

Cellular train-wreck

Question 29

Is necrosis safe?

Answer 29

NO --> Necrosis is not safe for neighboring cells as it releases cytotoxic elements (such as inflammatory cytokines)

Question 30

Apoptosis

Answer 30

Controlled, programmed cell death

Question 31

What are 3 characteristic changes cells undergo during apoptosis?

Answer 31

1) Fragmentation of chromosomal DNA 2) Global mRNA decay 3) Blebbing

Question 32

Apoptosis vs Necrosis

Answer 32

**Apoptosis** = controlled, does NOT usually cause inflammation (no release of cytokines) **Necrosis** = uncontrolled, usually causes inflammation due to release of cytokines

Question 33

How is apoptosis beneficial to host cells?

Answer 33

Apoptosis may cause localized tissue damage but the kiling an infected cell can limit viral spread within the host == mitigates the infection

Question 34

How is inhibition of apoptosis beneficial to viruses?

Answer 34

Inhibition of apoptosis prevents host from destroying infected cells allowing for viral production to continue = greater viral spread

Question 35

What are 2 example viruses that inhibit apoptosis?

Answer 35

Adenoviruses + Herpesviruses

Question 36

How do Adenoviruses and Herpesviruses inhibit host apoptosis?

Answer 36

By producing viral proteins that MIMIC natural anti-apoptotic proteins found in their host cells

Question 37

Syncytia

Answer 37

(singular = syncitium) = A multinucleated giant cell formed via fusion of adjoining cells (may be infected or not)

Question 38

Why are syncytia bad?

Answer 38

Typically all cells involved in the syncytium die

Question 39

How is syncytium formation beneficial to viruses?

Answer 39

Allows them to evade the extracellular host immune response! (Cell-cell transmission can occur without having to enter the extracellular environment where immune cells are active)

Question 40

What are 3 example viruses that cause syncytia formation?

Answer 40

1) RSV 2) Measles 3) HIV

Question 41

Inclusion Bodies

Answer 41

Microscopically visible structures (granules) within host cells that are composed of aggregated cellular or viral materials

Question 42

Why are inclusion bodies bad?

Answer 42

Because they typically disrupt cell morphology and normal functionality leading to cell death

Question 43

Where are inclusion bodies found?

Answer 43

Nucleus or cytoplasm

Question 44

What are 3 example viruses that cause inclusion bodies to form?

Answer 44

1) Rabies 2) Adenoviruses 3) Reoviruses

Question 45

In many cases, clinical signs of infectious disease are NOT directly due to the virus but rather due to __________

Answer 45

The host immune response

Question 46

What are the "arms" of the immune system?

Answer 46

2 arms = Innate and adaptive

Question 47

In response to viral infection, the immune system must balance what?

Answer 47

The amount of infected cells it kills and the amount of damage that cell death causes

Question 48

How does immune response to Ebola cause disease symptoms?

Answer 48

--> Ebola infection produces viral proteins that stimulate macrophages to secrete a large amount of inflammatory cytokines --> The strong release of cytokines cause extensive vasodilation which leads to the hemorrhage seen in Ebola patients which leads to shock and death

Question 49

What effect do cytokines have?

Answer 49

They cause blood vessels to become leaky so that immune cells can leave the blood vessels to get to the areas of infection

Question 50

How does immune response to rhinoviruses cause the common cold symptoms?

Answer 50

1) Rhinoviruses cause immune cells to release pro-inflammatory cytokines Interleukin (IL) 6 + 8 (IL-6 and IL-8) 2) IL6 and IL8 cause increased vasodilation 3) Vasodilation causes fluid buildup in upper respiratory system which causes cold symptoms

Question 51

What are the different ways in which immune responses can cause different outcomes of Heptatitis B viral infection?

Answer 51

**Acute infection** = immune response is strong enough and virus is cleared (no obvious disease occurs) **Chronic infection** = immune response not strong enough to clear: two immune responses trigger different disease --> 1) Liver Cancer = A result of t-cell response 2) Kidney Damage = A result of antigen response

Question 52

Hepatitis B Infection: T-cell response

Answer 52

Causes hepatitis! --> Cytotoxic t-cell-mediated destruction of hepatocytes causes hepatitis which can then lead to liver cancer

Question 53

Hepatitis B Infection: Antigen response

Answer 53

Causes kidney damage! --> Hepatitis B Virus antigen : immune antibody complexes form and deposit in the kidneys

Question 54

The clinical outcomes of Hepatitis B infection are ________ and depend on ___________

Answer 54

The clinical outcomes of Hepatitis B infection are **VARIED** and depend on **the type + strength of immune response**

Question 55

Autoimmunity

Answer 55

Immune reactions directly incorrectly against body's own cells

Question 56

Autoimmunity causes ______

Answer 56

Autoimmune diseases (Like MS, Rheumatoid Arthritis, Lupus)

Question 57

Autoimmunity is usually ___________ but in some cases ________ are involved via ________________

Answer 57

Autoimmunity is usually **genetic** but in some cases **viruses** are involved via **molecular mimicry**

Question 58

Molecular mimicry

Answer 58

Process in which immune cells react against HOST cell antigens that resemble PATHOGEN antigens (viral antigens activate immune cells that then cross-react with similar host antigens)

Question 59

What is the process of molecular mimicry in MS (Multiple Sclerosis)?

Answer 59

1) Macrophage presents viral antigen to T-cell (via MHC I which "holds" the viral antigen) 2) CD8 and TCR of T-cell interact with the antigen presented by the macrophage and ACTIVATE 3) Activated T-cell undergoes clonal expansion 4) Activated T-cells circulate through body 5) T-cell finds antigen like the viral one (could be of the virus OR a self-peptide) and tries to destroy it --> In MS the self-peptide is MYELIN!