Mechanism of Viral Infection and Pathogenesis

Question 1

What is the distinction between disease and infection?

Answer 1

Disease is when you have something and it is making you ill; that does not mean you have been infected by something.

A disease is a particular abnormal condition that negatively affects the structure or function of part or all of an organism, and that is not due to any external injury. A disease may be caused by external factors such as pathogens or by internal dysfunctions (i.e. an infection).

Infection is the effect of a foreign organism in the body.

Question 2

List some sites of microbe entry.

Answer 2

• conjunctiva (the mucous membrane that covers the front of the eye and lines the inside of the eyelids)
• respiratory tract
• alimentary tract
• arthropod (e.g. mosquito) into capillary
• scratch, injury
• skin
• urinogenital tract
• anus

If you get infected through an inappropriate route, you often don’t get disease.

Question 3

What are some common virus diseases of man?

Answer 3

• Influenza
• Common cold
• Measles
• Mumps
• Chicken pox/Shingles
• Glandular fever
• Hepatitis
• Papillomas (Warts)
• AIDS
• Kaposi’s sarcoma

The main goal is get as many of these eradicated as possible using vaccinations.

Question 4

List some general patterns of infections.

Answer 4

• acute infection
• latent/reactivating infection
• persistent infection

Question 5

Describe the pattern of infection of acute infections.

Answer 5

The disease symptoms occupy the time when the virus is at its highest. That will make you feel sick, and if your immune system gets rid of this, you recover.

Question 6

List some examples of acute infections.

Answer 6

Common cold: The virus stays hopefully in your upper respiratory tract, just in your nose and throat. If our immune system can resolve this, we’re cured.

Measles: You get typical spots and ulcerations of the tongue. We can also get serious CNS problems as well.

Ebola lesion: This is caused by complete destruction of the endothelia. You get massive haemorrhaging, and most people bleed to death through internal organs.

Smallpox: it causes a high fever and a characteristic rash.

Question 7

Describe the pattern of infection for latent/reactivating infections.

Answer 7

At the first incidence of infection, your immune system is able to get it under control and you are disease-free.

But, throughout your life, there are episodic reactivations of the virus, so it has not gone away.

Somewhere, there is a reservoir in the host that is controlled by immunity, but if the immune system breaks down, even by a small degree, the virus reactivates.

Question 8

List some examples of latent/reactivating infections.

Answer 8

• Herpes simplex virus type 1 (HHV-1)
• Herpes simplex virus type 2 (HHV-2)
• Varicella zoster virus (HHV-3)
• Epstein-Barr virus (HHV-4)
• Cytomegalovirus (HHV-5)
• Human herpesvirus 6 (HHV-6)
• Human herpesvirus 7 (HHV-7)
• Human herpesvirus 8 (HHV-8)

Most of us will be infected with at least 1-4 of these viruses, but we do not portray any symptoms due to our healthy immune systems.

Question 9

Describe Herpes simplex virus type 1 (HHV-1).

Answer 9

At a primary stage, patients will get primary gingivostomatitis; they will give you a rash around your mouth.

When the virus reactivates, it will only give you a cold sore.

Question 10

Describe Varicella zoster virus (HHV-3).

Answer 10

HHV-3 is chickenpox.

If you get this early on in life, it is effectively harmless.
However, if the infection reactivates at adulthood, you get painful blistering rashes that are highly septic.

Question 11

Describe the patterns of infection for persistent infections.

Answer 11

There are two patterns:

The virus peaks, then you don’t see that many symptoms for a very long time, and then we get a big eruption. This is typical of viruses like HIV.

If an infection sets in during the first trimester (such as rubella), the body doesn’t see it as foreign; rather, it recognises it as self. The child becomes immuno-tolerant of this virus. This virus will tear through the tissues, causing congenital rubella. This one is not controlled by immunity, as the immune system thinks that it is self.

Question 12

List some examples of persistent infections.

Answer 12

• HIV: Virus infects CD4+ cells and weakens immune system.
• HCV: Virus infects hepatocytes and damages liver.

Congenital Rubella: if infected in utero, virus is seen as self, baby is born immuno-tolerant and virus continues to replicate (and cause damage) in neonatal tissues.

Question 13

Describe inapparent infections.

Answer 13

It requires that viruses be non-cytopathic and host-adapted.

90% of all poliovirus infections are asymptomatic (inapparent). Many of us get infected with parainfluenzavirus 5 without clear symptoms.

Despite the bad PR, the flu often gives rise to very mild respiratory disease.

Question 14

How does virus infection of a host lead to disease?

Answer 14

Pathogenesis results from cell and tissue damage caused by the viral infection. On most occasions the damage is limited by the host’s immune system.

On some occasions the relative limited damage caused by the virus is made worse or even caused by the host’s immune system (a phenomenon known as immunopathology).

Question 15

List examples of infections that causes disease.

Answer 15

EBOLA: It targets vascular endothelial cells, causing cytopathic damage.

All your endothelia get pureed when the virus gets into your blood vessels, causing haemorrhagic lesions.

INFLUENZA A: It targets lung epithelia, causing cytopathic damage.

Normally, lung epithelia are lined with cilia cells that beat, and move the mucus along the respiratory tract. When the virus attacks, damaged the cilia, limiting its function.

RSV: it induces syncytia in lung epithelia.

Respiratory Syncytial Virus is the single biggest cause of hospitalization of children in the west. It is associated with development of atopic life-long asthma.

The lung epithelia fuse together to create a giant heterokaryon (a multinucleate cell that contains genetically different nuclei).

Question 16

Describe the course of illness of Hepatitis C.

Answer 16

You cannot be vaccinated against it, so it is a big problem.

It starts off by causing a classical acute infection in the liver, with lots replication. If your immune system is able to cure you of it pretty early on, you will be alright.

However, in about 80% of the cases, that doesn’t happen. The infection then progresses to chronic liver inflammation, then to fibrosis. Eventually you get severe liver damage, cirrhosis or even hepatic cancer.

Question 17

Describe the immunopathology of HCV (Hepatitis C Virus).

Answer 17

Chronic hepatitis is a disease of severe liver damage and loss of hepatocytes – caused by persistent HCV infection.

HCV is non-cytopathic.

Hepatitis is associated with extensive liver infiltration of leukocytes.
The pro-inflammatory cytokine levels are very high.

Viral clearance and disease is associated with generation and infiltration of CD8+ cells which attack infected cells and destroy them.

HCV persistence is associated with the generation of HCV variants that are not recognised by CD8+ cells.

In other words:
The virus is broken down by the function of our immune system, and the peptides from it get presented on the surface of hepatocytes through MHC class 1. That signifies to your immune system that there is something there that shouldn’t be, so it attacks it. Your liver then gets full up with inflammatory response cytokines, and there is a massive infiltration of leukocytes. They will attempt to clear the infected cell.

Hence, your immune system is killing you by inflaming your liver due to it attacking a cell that would otherwise not do much damage at all. This is a classic example of immunopathology.

Question 18

Describe dengue fever.

Answer 18

Dengue virus infection is the most common mosquito-borne infection worldwide – even surpassing malaria.
There are 2.5 billion people at risk of dengue due to living in an endemic area.

There are an estimated 50–100 million infections per year, and 500,000 hospitalizations due to severe disease.
The case fatality rate from severe dengue is 1 - 5%.
There are 4 serotypes (1–4), all of which have the same clinical manifestations.

When they first get this infection, their symptoms are mild, so most people don’t get hospitalised.
If they get infected a second time, and this time by a different strain than the first one they got infected with, then they will develop a much more serious disease that requires hospitalisation.

Question 19

Describe the immunopathology of the dengue virus.

Answer 19

Severe dengue may include dengue shock syndrome (DSS), and hemorrhage.

The greatest risk is a previous infection with a different serotype.

The antibodies formed in response to one dengue infection are not cross-protective against other subtypes of the virus. In fact they may result in more severe disease due to a phenomenon known as antibody-dependent enhancement or ADE.

ADE is when non-neutralizing antibodies coat the virus, forming immune complexes which get internalised into mononuclear phagocytes through their Fc receptors.
Fixation of complement by circulating immune complexes results in release of products of the complement cascade leading to sudden increased vascular permeability, shock and death.

In other words:
When infected with the different strain, the antibodies are able to bind to the viral particle. However, rather than neutralising it, which they aren’t sufficiently good at , they create a target that can then be taken up by gamma receptors into macrophages. Thus, they provide a quick and easy way to get into a macrophage.

Question 20

Describe the pathology of influenza.

Answer 20

People of all ages are infected, but it is usually only a serious problem in the old or children with asthma.

PATHOLOGY:

• Mild URTI to severe LRTI
• Lower respiratory tract infection causing damage to lung epithelia and viral pneumonia, often secondary pneumonia
• Fever, often prolonged
• Neurological (headache, malaise)
• Myalgia (pain in a group of muscles)

The infection generates powerful, life-long immunity.
It is easy to vaccinate against if you know what’s coming.

Question 21

How can we tell what influenza is coming each year?

Answer 21

Influenza undergoes antigenic drift, and when it presents to your immune system, that little change it enough to leave you susceptible.

There are a group of scientists that study the antigenetic drift of any influenza that surfaces, and predict which strain (or their likes) will hit certain places at certain times.

Sometimes though, the virus can switch what it on its surface by the process called antigenic shift, and when that happens, we don’t know what’s coming, so people are extremely susceptible.