Mechanisms of Pathogenesis

Question 1

General patterns of infection (4)

Answer 1

1. Acute- rhinovirus
2. Latent- HSV
3. Persistent- asymptomatic- JC virus
4. Persistent- pathogenic- HIV

Question 2

Virokines

Answer 2

Artificial chemokines encoded by viruses

Question 3

Viroceptors

Answer 3

A viral mimic of host cell chemokine/cytokine receptors

Question 4

Latent infection

Answer 4

The virus goes through some periods of causing symptoms and some asymptomatic periods. This can occur throughout a person’s lifespan

Question 5

Persistent asymptomatic infection

Answer 5

The virus initially proliferates, then establishes viremia that persists through the person’s life. They remain asymptomatic throughout the course of infection. The virus might cause serious illness if the person becomes immunocompromised

Question 6

Persistent pathogenic infection

Answer 6

The virus causes viremia and symptoms upon infection, then the symptoms are resolved and the virus is put into a suppressed state. In the later stages, when the immune system is compromised, the virus reactivates and causes disease

Question 7

Course of a typical acute infection

Answer 7

Most of these infections are cleared before we exhibit symptoms. There is a short course of infection, but people can sometimes experience severe outcomes. Upon infection, the virus activates innate defenses, but there must be a threshold level of the virus in order to activate the adaptive immune response. The adaptive immune response often isn’t necessary to clear infection, but it produces immune memory

Question 8

Course of persistent viral infections

Answer 8

Occurs when the body is unable to clear the primary infection. The viral genome may remain silent, and often doesn’t cause a strong innate immune response. The virus may interfere with antigen presentation, causing a weak TH1 response

Question 9

Why use mouse models to study the immune system?

Answer 9

Mice demonstrate 85% similarity in their protein coding regions. Therefore, the mouse immune system is very similar to the human immune system

Question 10

Humanized mice

Answer 10

Express human immune cells in immunodeficient mice. These models are necessary because some viruses do not infect mice- includes HIV

Question 11

NSG mouse model

Answer 11

Non obese diabetic/SCID mice. These mice do not express Pkrdc gene (VDJ recombination, DNA repair) or X-linked Ilrg gene. The mice are basically immunodeficient, as they are deficient in mature lymphocytes, have undetectable serum Ig and NK cell cytotoxic activity is extremely low. When the immune system is in this condition, it supports the engraftment of human CD34+ hematopoietic stem cells

Question 12

Myeloablation

Answer 12

Immunodeficient mice are exposed to radiation to cause DNA damage and completely deplete their immune system. Prevents graft vs host disease

Question 13

Applications of humanized mice (4)

Answer 13

1. HIV replication
2. Antiviral activity of compounds
3. Pathogenesis: neuro, CVD,
   inflammation, Aging
4. Eradication studies: HIV latency

Question 14

Transgenic mice model for poliovirus

Answer 14

Poliovirus recognizes poliovirus receptor (PVR). In this model, Human PVR (CD155) was expressed in mice, although mice do not express this receptor naturally. The mice were infected with poliovirus and exhibited symptoms such as paralysis

Question 15

hACE2 transgenic mice for SARS CoV-2

Answer 15

These mice were made to express the human ACE2 receptor in the lungs, which Covid binds to

Question 16

Mouse models for Zika virus infection

Answer 16

In humans, Zika encodes non-structural protein 5, which can cause cleavage of mSTAT2. NS5 helps the virus to evade the immune system. However, mice can clear the infection because NS5 can’t cleave mSTAT2. When mice that lacked interferon response were used, Zika virus was able to cause microcephaly

Question 17

SJL (Swiss Jim Lambert) mice

Answer 17

Immunocompetent mice that are susceptible to autoimmune encephalomyelitis. They have high levels of circulating T cells. Can still be infected with Zika and exhibit microcephaly, but need a higher PFU

Question 18

Main methods for measuring viral virulence (2)

Answer 18

1. Measure the survival of the host- did one serotype demonstrate a higher survival rate than the other?
2. Measure the pathological lesions- did one serotype exhibit more pathological lesions?

Question 19

Which factors impact viral virulence?

Answer 19

May vary depending on route of infection, dose, host species, sex, age, and susceptibility

Question 20

Pathogenesis

Answer 20

A process by which an infection leads to disease

Question 21

Viral virulence genes

Answer 21

Viral genes that allow them to cause disease. The genes may alter viral replication, modify host defense mechanisms, and allow the virus to spread in the host. Determine viral tropism- may cause the virus to be multitropic. The genes may cause infected cell lysis and code for toxins

Question 22

Host factors that determine virulence (4)

Answer 22

1. Genetic variations- innate gene mutations, SNPs
2. Pre-existing conditions
3. Age
4. Sex- male or female

Question 23

Determining which genes are virulent

Answer 23

Mouse models can be used to determine the effects. If a mouse is infected with a wild type strain, the strain will exhibit the virulent effects. In a strain with a gene mutation in a gene that encodes reproduction, the reproduction will be poor and the virus will be attenuated. Not many plaques will be formed. If there is a mutation in a gene specifically required for virulence, there is no impact on the plaques formed, but the virus does not reproduce well in an organism. The virus is still considered attenuated because it can’t cause disease

Question 24

Attenuation of viral virulence by a point mutation

Answer 24

Virulence genes can be present in non-coding regions. For example, a point mutation in the 5’ untranslated region causes attenuation of the virus, and the virus can’t replicate efficiently. This is the basic of Sabin’s oral poliovirus vaccine. There are 3 different versions, depending on which nucleotide is changed

Question 25

Virulence genes modification of host defense mechanisms

Answer 25

These genes may modify MHC class 1 and MHC class 2 signaling

Question 26

HSV modification of host defense mechanisms

Answer 26

HSV protein ICP 34 counters PKR. PKR is a kinase that phosphorylates and interrupts protein synthesis. It is activated by viral infection to shut off protein synthesis so that the virus cannot produce viral proteins. PKR is activated by the double stranded DNA produced by HSV. However, on the HSV genome, some genes are transcribed in converging directions, they transcribe toward each other so that they have some overlapping regions, and mRNA is produced from this. PKR can sense the double stranded DNA once it’s in the cytoplasm and will phosphorylate eukaryotic initiation factor 2A. Viral protein PC 1A keeps removing the phosphate so proteins will be synthesized

Question 27

How do viral proteins impact MHC class 1 signaling?

Answer 27

When processing of antigens is taking place, cellular proteases degrade them into small polypeptides. The antigens are placed into the groove of MHC 1 molecules in the ER. EBV is one example- it disrupts the processing of viral proteins so peptides can’t be produced. Adenoviruses disrupt transcription of MHC class 1. HIV would impact transportation of RNA to the ER lumen, where it is translated. CMV and HIV proteins cause internalization of MHC class 1, so it will be degraded. Immune response is blunted, which is why most of these viruses are persistent

Question 28

NSP4 (enterotoxin)

Answer 28

A toxin produced by rotavirus to induce diarrhea by inhibiting the sodium-glucose luminal cotransporter, which inhibits water reabsorption. The cells can’t retain water. It also induces the phospholipase C dependent calcium signaling pathway. Chloride is secreted and reduces water retention

Question 29

HSV encephalitis

Answer 29

HSV is a persistent virus. Not everyone experiences symptoms, but some experience severe symptoms. Mutations in TLR3, TRIF, TRAF, and UNC93B are more common in patients with severe disease, as these mutations blunt the immune response. A blunted immune response results in encephalitis. Viremia occurs at 2 points in the lifespan- in 6 month to 3 year olds and people older than 50

Question 30

Clinical signs of an uncontrolled immune response

Answer 30

Pain, redness, nausea, fever, and tissue damage. An uncontrolled host response can cause severe or life threatening consequences. These mechanisms can be caused by CD8 T cells, CD4 T cells, or B cells

Question 31

Symptoms of viral disease are caused by

Answer 31

The primary host immune response

Question 32

Mechanism of measles immunosuppression

Answer 32

Skewing of the T cell response to TH2 T cells and reduced T cells, enhancing measles infection. Measles infects monocytes, dendritic cells, and epithelial cells

Question 33

Mechanism of immunosuppression in the Hendra virus

Answer 33

Infects respiratory tract epithelial cells- inhibits translocation of STAT1 to the nucleus

Question 34

Mechanism of immunosuppression of the rubella virus

Answer 34

Infects B and T lymphocytes- decreased turnover of lymphocytes, persistent infection

Question 35

Mechanism of immunosuppression in HIV

Answer 35

Infects CD4 T cells and macrophages- there is a decline in CD4 T cells. Causes AIDs, opportunistic infections, and cancer

Question 36

Tissue tropism

Answer 36

Viruses may infect very specific tissues depending on receptor susceptibility, permissibility, accessibility, and proteases (FP cleavage). Viruses can either have limited tropism or be pantropic, infecting multiple different tissues. Similar factors determine host range

Question 37

Virus induced lethality caused by CD8 T cells

Answer 37

CD8 T cells kill infected cells using perforin. In perforin-knockout mice, the mice cannot kill infected cells and have a severe outcome

Question 38

Antibody dependent enhancement of Dengue infection

Answer 38

Dengue virus has 4 serotypes. The primary infection is generally self-limiting, febrile, and may cause hemorrhagic fever or Dengue shock syndrome. Antibodies are generated. In serotypes 2-4, a secondary infection is much more severe and complications are more likely. The existing antibodies bind to virus particles, but the antibodies aren’t neutralizing and can’t neutralize the virus. Antibodies bind to infected monocytes and bring them close to permissive cells, making them much more likely to be infected. Viremia increases compared to the primary infection.

Question 39

Systemic inflammatory response syndrome (SIRS) symptoms

Answer 39

Fever, cough, pneumonia, edema, acute lung injury, and acute respiratory distress. The worst outcomes include multiorgan failure and death

Question 40

Systemic inflammatory response syndrome (SIRS)

Answer 40

Also referred to as cytokine storm. Common in young, malnourished, or immunocompromised people. The virus replicates at a high rate due to delayed interferon response. There is enhanced epithelial and endothelial cell apoptosis, increased vascular leakage, sub-optimal T cell and antibody responses, and impaired virus clearance