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Summary of all the lectures of immunopharmacology
- Instelling
- Rijksuniversiteit Groningen (RuG)
Summary of all the lectures of immunopharmacology
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Immunopharmacology lecturesLecture
SARS-CoV-2 origin; immune responses; COVID19 clinical disease.
Coronaviruses are zoonotic viruses meaning that they circulate in animals, mostly in bats, and can
sometimes mutate and infect humans too. They consist of a single RNA molecule covered by a lipid
bilayer which is coated by spike glycoproteins, giving the virus a very distinctive shape.
Researchers have estimated that around November 17 2019 in Wuhan a novel corona virus infected
a human being. This is not the first time this happened → SARS and MERS.
In 2003 a bat infected a cat and this made a jump to humans. In some of the humans this virus
caused a severe acute respiratory syndrome → SARS. The epidemic was not a great problem as of
now. In 2013 another corona virus was transmitted to humans. It circulated in camels for already
quite some time, but in 2013 it made a jump to humans. This was called the middle east respiratory
syndrome → MERS. This one was more problematic than SARS because is was more lethal. But is was
very well contained and did not spread out very much.
The one we are facing now is the severe acute respiratory syndrome corona virus 2 → SARS-CoV-2. It
causes the disease Covid-19. This jumped to humans probably through a pangolin (animal), but we
are not sure yet. How do we know that this event occurred on November 17? Because the viruses
that are isolated from humans are sequenced and their genetic information contains clues for where
they come from. Because every time a virus replicates, there are tiny mutations in the RNA and
following these mutations we can determine where they come from.
Here it can be seen that at first the virus was
mostly in China. Then it probably went to the US.
In the meantime, the virus changes by RNA
mutations and infects further and further.
If you look at the mortality related to age in SARS, MERS
and SARS-CoV-2, you can see that MERS is the most lethal
one (30%) especially in older people. SARS also mostly had
problems in older people. SARS-CoV-2 looks like the first
one, except that it appears to be even more lethal to older
people.
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,Comparison with influenza:
The corona virus is very infectious and spreads very quickly. The seasonal flu does not kill many
people, and has a slight increase in elderly. The Spanish flu (1918 influenza) was special because it
killed many young children, elderly but there also was a peak between the age of 20-40. The novel
corona virus seems to have an equal effect as the seasonal flu in younger people, but in elderly the
mortality rate increases a lot.
The severity of an epidemic also depends on the infectiousness of the virus. How the virus spreads is
defined by its reproduction number (Rnaught = R0). If the R0 = 2 it means that every infected person
can infect 2 new people. When the R0 is smaller than 1 it means that the infection will die out
eventually.
We do not know the R0 of the corona virus yet, because a lot of countries are not testing everybody
and we are also running out of components needed for the test.
For now it is estimated to be between 2 and 4. This is more infectious than seasonal flu, but much
lower than measles which is very infectious. SARS has around the same R0 as the novel corona virus.
MERS is far more deadly but had an R0 of smaller than 1.
The R0 depends on:
1. The virulence of the virus/bacteria → how much does the pathogen affect the host. So the
more virulent a virus is, the less chance there is for transmission. When you become very ill,
you will self-isolate or die so you will not have the chance to transmit the disease. Whereas if
a virus is less virulent, there is more change for transmission because you will not stay home
and thereby be able to infect many other people. For example Ebola is very virulent, so it kills
the host so rapidly that it is difficult to spread to other hosts. So the more deadly (the more
virulent) a virus will be, the smaller the R0 because the virus does not have a chance to
spread.
2. The population → a virus needs to infect people and genetics might play a role. Some people
might not be as susceptible as others. For corona, a lot of European countries show a same
rate of infections. But there are also countries (Singapore, Japan, South Korea) that have a
much slower infection rate. This could indicate that they are less susceptible, but it could also
mean that they have installed measures to prevent spread of the disease. Social distancing is
a measure that is taken to prevent spread. This was very effective in the Spanish flu.
Lodi was early with their lockdown which can be
seen in the progression of the number of positive
cases. Bergamo was much later which led to a
steep increase in cases here.
2
, 3. Vaccination/immunity → herd immunity is having many people in the population immune
against the disease to prevent spread to non-immunized people.
When people have had the disease before or are
vaccined, the spread of disease is contained. For this
you need at lead 60-70% of the population being
immune. Since we do not have a vaccine, this means
that 60-70% of the population should have had the
disease before we will reach this state. If we allow 60-
70% of the people to become ill, then we will have a
problem because many of the people will need
hospital care and there are not enough beds to take
care of all these people. So if we do nothing, we will
overwhelm our healthcare system capacity. This is
why we are in lockdown to prevent the spread. The
number of cases will be more spread out so that
everyone can be taken care of when needed →
flattening of the curve.
The corona virus mainly affects the lungs. The lungs consist of airways and alveoli. The airways
transport the air → trachea divide into smaller airways which will get to the alveoli. In the alveoli the
actual gas exchange takes place. We can protect ourselves against these viruses because the airways
and alveoli are coated with epithelial cells that will not allow entry of viruses. Depending on where
you are in the lung these epithelial cells look a bit different. In the larger airways the epithelial cells
are ciliated, which can help with removing things that we breath in by waving them up again towards
the throat. We can then swallow and digest it. There also are Goblet cells which produce mucous →
trap viruses and prevent them from infection. In the alveoli the epithelial cells are really different,
very thin wall with type I epithelial cells (really flat) and sometimes a type II epithelial cell (stem cell
which generates new type I cells when the others get damaged; they also produce mucous).
The epithelial cells are the first line of defence: they form a physical barrier to the infection, they are
very tightly connected so that the viruses cannot pass easily. They also make peptide antibiotics
which can kill the virus. Within the epithelial cells are also other immune cells that can help fighting
an infection.
How does a corona virus enter the lungs? The spike proteins recognise ACE2 which is expressed on
certain types of epithelial cells. This enzyme is normally involved in regulating blood pressure and it
also transports amino acids into the cells. So with this, the virus is transported into the cell. Once the
virus is in the cell, it will release its viral RNA and take over the machinery of the cell. New viral RNA
and proteins are formed using the enzymes of the host cell. These are then assembled into new
copies of the virus. So the cell will create many new viral copies → cell will explode and release new
particles → spread of the infection.
3
, Why does the corona virus especially infect lung epithelial cells? Because the ACE2 is expressed on
cells in the lungs. Especially the alveolar type II, club, goblet 1, goblet 2 and ciliated 2 cells contain a
lot of ACE2.
Immune response to a virus:
When a virus manages to enter the epithelial cells → incubation period/stealth phase in which the
viruses in the cells start to replicate. In this phase the immune response still is inactive.
Sensing of a virus:
There are alarm systems that tell that the cell is being invaded. An important class for this are the
Toll-Like receptors. These are either expressed on the cell membrane or within the cell. The ones
inside the cells will sense the presence of the virus (TLR8 and TLR7 sense single stranded RNA →
important for recognition of the corona virus). The Toll-Like receptors will activate certain
transcription factors and interfere with regulatory factors → IFN alpha and beta are produced. These
should lead to an antiviral state (figure 1). The cell tells its neighbours that it is infected and that they
should prepare themselves. IFN alpha and beta can be sensed by all cells in our body. The cells then
know that they need to start getting prepared for a virus. If IFN binds to a receptor (figure 2) →
translation initiation factor is phosphorylated and thereby inhibited. This results in the virus not
being able to produce viral proteins. It will also increase the RNAase expression to degrade viral RNA.
And it will also inhibit viral gene expression and virion assembly. The cell then has little chance of
surviving in this cell.
For example: People who were infected with SARS and has a very early IFN-I response that they could
contain the viral infection and only had a very mild disease. But people with a delayed IFN-I response
had a much higher viral titer and thereby a much more severe disease.
Figure 1: Production of IFN-I by Figure 2: Functions of IFN-I in
recognition of the virus via Toll-Like neighbour cells.
receptors.
Symptoms are caused because the innate immune system starts to respond to the virus. The
adaptive immune system is also involved → inflammatory phase. Dendritic cells in the lung will
sense the virus and will go to the lymph nodes to get help from lymphocytes. The innate cell will start
responding to the virus as a first line of defence (neutrophils and monocytes). Then when the
lymphocytes come in they will also help by clearing the virus → cytotoxic T lymphocytes will kill any
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