Mechanisms of Pathogenesis Flashcards
General patterns of infection (4)
- Acute- rhinovirus
- Latent- HSV
- Persistent- asymptomatic- JC virus
- Persistent- pathogenic- HIV
Virokines
Artificial chemokines encoded by viruses
Viroceptors
A viral mimic of host cell chemokine/cytokine receptors
Latent infection
The virus goes through some periods of causing symptoms and some asymptomatic periods. This can occur throughout a person’s lifespan
Persistent asymptomatic infection
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
Persistent pathogenic infection
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
Course of a typical acute infection
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
Course of persistent viral infections
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
Why use mouse models to study the immune system?
Mice demonstrate 85% similarity in their protein coding regions. Therefore, the mouse immune system is very similar to the human immune system
Humanized mice
Express human immune cells in immunodeficient mice. These models are necessary because some viruses do not infect mice- includes HIV
NSG mouse model
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
Myeloablation
Immunodeficient mice are exposed to radiation to cause DNA damage and completely deplete their immune system. Prevents graft vs host disease
Applications of humanized mice (4)
- HIV replication
- Antiviral activity of compounds
- Pathogenesis: neuro, CVD,
inflammation, Aging - Eradication studies: HIV latency
Transgenic mice model for poliovirus
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
hACE2 transgenic mice for SARS CoV-2
These mice were made to express the human ACE2 receptor in the lungs, which Covid binds to
Mouse models for Zika virus infection
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
SJL (Swiss Jim Lambert) mice
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
Main methods for measuring viral virulence (2)
- Measure the survival of the host- did one serotype demonstrate a higher survival rate than the other?
- Measure the pathological lesions- did one serotype exhibit more pathological lesions?
Which factors impact viral virulence?
May vary depending on route of infection, dose, host species, sex, age, and susceptibility
Pathogenesis
A process by which an infection leads to disease
Viral virulence genes
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
Host factors that determine virulence (4)
- Genetic variations- innate gene mutations, SNPs
- Pre-existing conditions
- Age
- Sex- male or female
Determining which genes are virulent
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
Attenuation of viral virulence by a point mutation
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
Virulence genes modification of host defense mechanisms
These genes may modify MHC class 1 and MHC class 2 signaling
HSV modification of host defense mechanisms
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
How do viral proteins impact MHC class 1 signaling?
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
NSP4 (enterotoxin)
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
HSV encephalitis
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
Clinical signs of an uncontrolled immune response
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
Symptoms of viral disease are caused by
The primary host immune response
Mechanism of measles immunosuppression
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
Mechanism of immunosuppression in the Hendra virus
Infects respiratory tract epithelial cells- inhibits translocation of STAT1 to the nucleus
Mechanism of immunosuppression of the rubella virus
Infects B and T lymphocytes- decreased turnover of lymphocytes, persistent infection
Mechanism of immunosuppression in HIV
Infects CD4 T cells and macrophages- there is a decline in CD4 T cells. Causes AIDs, opportunistic infections, and cancer
Tissue tropism
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
Virus induced lethality caused by CD8 T cells
CD8 T cells kill infected cells using perforin. In perforin-knockout mice, the mice cannot kill infected cells and have a severe outcome
Antibody dependent enhancement of Dengue infection
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.
Systemic inflammatory response syndrome (SIRS) symptoms
Fever, cough, pneumonia, edema, acute lung injury, and acute respiratory distress. The worst outcomes include multiorgan failure and death
Systemic inflammatory response syndrome (SIRS)
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
