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
