Summary
Summary Pathogenesis and Clinical Aspects of Tropical Infectious Diseases (16/20)
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This is a summary of the course that is given in the master Infectious and Tropical Diseases.
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Summary pathogenesis1. Emerging and re-emerging viruses
1) Introduction
There are many different infectious disease outbreaks in the 21st century, with the most recent one
Sars-CoV2. Most of these outbreaks are caused by either arthropod borne viruses or pulmonary
infections. Examples for arthropod borne viruses are: chikungunya and zika. Examples for pulmonary
viruses are: SARS, MERS or influenza.
A lot of the diseases that causes an outbreak or have the potential to become one day pandemic are
listed by the WHO on their pathogen priority list. This list sums up all the viruses where research for
it has priority. On this list are infections like Ebola, MERS, SARS and Zika. But we will see that there is
also a disease X on the priority list. This disease stands for all the unknown diseases that haven’t been
discovered yet but one day can be on this list. SARS-CoV-2 was almost such a disease, the only thing
that differs between SARS2 and disease X was that SARS-CoV family isn’t unknown to us seeing there
was an outbreak of both SARS1 and MERS prior to SARS2. Furthermore we will see that some diseases
are up for promotion to get a spot on the priority list, examples of this are Chikungunya, Lassa virus,
coronaviruses but others then SARS and MERS.
All the viruses can be classified using the Baltimore classification, this system is based on how the
genome looks and how it gets to its mRNA to translate its proteins.
Extra info about the Baltimore classification
Klasse I: dsDNA genomen
Deze klasse van virussen gaan hun genoom eerst gaan overschrijven naar een mRNA door gebruik te
maken van een DNA dependet RNA polymerase, dit wordt ook wel eens RNA polymerase II genoemd.
Anders gezegd deze virussen gaan meestal, een uitzondering is het POX virus, de machinery van de
host gebruiken om aan hun mRNA te geraken. Vanuit het mRNA kunnen er eiwitten getransleerd gaan
worden en dan gaan de deze de verdere replicatie gaan reguleren.
1
,Klasse II: virussen met ssDNA genoom
De ss kan zowel de + als de – strand zijn. Deze virussen moet hun genoom eerst gaan omzetten in
dsDNA. Deze omzetting gaat gebeuren door de host zijn DNA polymerase. De bekomen viraal dsDNA
gaat dan, door gebruik te maken van de host zijn RNA polymerase II, een mRNA aanmaken. Dit mRNA
kan dan verder gebruikt worden om eiwitten aan te maken die de verdere replicatie gaan reguleren.
Klasse III: dsRNA genomen
Deze hebben een zelfdee probleem als de -ssRNA virussen namelijk er moet een omzettingsstap
gebeuren van ds naar ss +. De eiwitten voor deze omzettingsstap zijn niet aanwezig in de host en
moeten dus mee met het genoom worden geïnjecteerd in de cel. Ook hier gaat het probleem opgelost
worden door gebruik te maken van RNA depended RNA polymerase. De + strand van dit RNA
moleculen gaat gebruikt worden om zowel mRNA aan te maken als om nieuwe dsRNA aan te maken.
De RNA dependet RNA polymerase gaan het RNA herkennen en deze gaan omzetten naar een +mRNA.
Dit +mRNA gaat gebruik worden om dan eiwitten aan te maken die dan de verdere replicatie gaan
reguleren.
Klasse IV: (+) ssRNA genomen
Deze klasse van virussen gaan hun genomen in een cel brengen. In de cel kunnen de host ribosomen
het ssRNA genoom ineens gaan transleren in eiwitten. Deze eiwitten gaan dan de replicatie verder
gaan reguleren. Meeste van de virussen in deze klassen hebben kleine lineaire genomen.
Klasse V: (-) ssRNA genomen
Deze klasse van genomen gaan na infectie van de cel eerst hun complementaire + streng moeten
aanmaken. Om deze omzetting te kunnen doen moet het virus zijn eigen gespecialiseerd eiwit gaan
aanmaken, dit omdat de cel zo’n eiwit niet nodig heeft en dus niet bezit. Dit eiwit wordt het RNA
dependet RNA polymerase genoemd. Dit eiwit gaat samen met het genoom in de hostcellen
geïnjecteerd worden. Eens dat we een + ssRNA streng hebben zitten we terug in hetzelfde principe als
bij klasse I, namelijk de host ribosomen gaan het +ssRNA gaan translateren naar eiwitten welke dan op
hun beurt de replicatie verder gaan reguleren.
Klasse VI: retrovirussen met een ss (+) RNA genoom
Deze virussen hebben dan wel hetzelfde genoom als de virussen in klasse I maar gaan een totaal
andere pathway volgen om tot aan hun mRNA te komen. De retrovirussen gaan gebruik maken van
een reverse transcriptase om van hun ssRNA genoom een dsDNA moleculen te maken. Vanuit dit
dsDNA moleculen gaan we met behulp van een RNA polymerase II het mRNA aanmaken. Het mRNA
kan dan getranscripteerd worden door het RNA polymerase II naar eiwitten. Deze eiwitten kunnen dan
de verdere regulatie op zich nemen.
Klasse VII: dsDNA retro virus (dsDNA met een ss gap)
De ss gap zal door DNA polymerase ingevuld gaan worden zodat er een volledig dsDNA moleculen
ontstaat. Dit dsDNA moleculen kan dan door gebruik te maken van de transcriptie machinery van de
host mRNA gaan aanmaken. Dit mRNA kan dan verder gebruikt worden voor de aanmaak van de
verschillende eiwitten.
We gaan echter virussen in deze klasse hebben die gebruik gaan maken van een reverse transcriptase.
Dit reverse transcriptase gaat gebruikt worden voor de aanmaak van het DNA voor de gap te vullen.
Het DNA dat de gap moet vullen gaat komen van het RNA moleculen van het volledige genoom. Een
voorbeeld van een virus dat het doet via de laatste beschreven mechanisme is het hepadnavirus.
2
,We will see that the mutation rate of a
organism is tight to its genome size. If the
genome size is big then the mutation rate
will be low. How bigger the genome size how
lower the mutation rate. This can be seen in
the evolution of an organism as an individual
or species. An example of the mutation rate
of one individual can be seen if we look at the
phylogenetic tree of a single HIV patient.
Then we will see that the HIV virus mutates
through the time it is in the patient to better
adapt to its host. We will see that the
mutations will move away from the initial
sequence in a ladder shape pattern.
Furthermore we will see that every organism
and the pool of available quasispecies will go
through different bottlenecks. One of these
bottlenecks are the barriers that the
qausiespecies have to pass to give an
infection. Each barrier is a bottleneck so when a virus needs another organism it has more bottlenecks
it has to pass.
Some viruses will have a zoonotic origin making it that there need to be contact between the infected
animals and the humans for getting a disease in humans. This contact where humans get sick is called
a spill over event. Notice that not every contact will lead to an infection. These contacts can be direct
or indirect, active or passive between wild animals and domestic animals or wild animals and humans
directly. These viruses have to adapt if they want to live in each host. We see that these spill over
events are increasing in the past couple years. This is due to increase in livestock, life food markets,
bush meat consumption, deforestation and a lot of other things.
An increase in the human population makes it that there is more likely to be a spill over event and a
disease can be transmitted more to other humans and become pandemic. A disease has more chance
of becoming pandemic due to the increase of the human population but also due to urbanisation and
globalisation. Furthermore climate change will make more areas perfect for the vector to survive there
and thus increase the chance of transmission of the disease. The human population has been
drastically been increased in the last 100 years. But we see that the increase in human population is
mostly in the South. It is calculated that in 2050 most of the global population will be living in South-
Asia and the Sub-Indian continent.
The conclusion is that in the future we will have more and more emerging viruses and pathogens,
with often a zoonotic origin. This due to human invasion in different untouched ecosystems, changing
human demographics, climate change and high mobility of goods and people. This can then also be
combined with rapidly evolving RNA viruses.
3
, 2) Ebola virus
Ebola virus is part of the filoviruses. There are
different Ebola viruses with some occurring
more often than others. The most occurring
Ebola virus is Zaire Ebola virus. Followed by
Sudan Ebola. The Reston Ebola is a bit different
from the others, this because it is airborne, not
lethal for humans and above all it is the only one
that was first found outside Africa. Reston Ebola will infect pigs which then can be the intermediate
host to the way for infecting humans. CFR = case fatality rate.
In the family of filoviruses we will also see viruses like Marburg and Ravn. These two viruses are quite
lethal for humans. There are still new Ebola viruses discovered nowadays. But as far as we know now
only Sudan, Bundibugyo and Zaire are Ebola viruses that can infect humans.
The Ebola virus (EboV) have a large particle and a
ss(-)RNA genome. For the symptoms of Ebola we
have to differentiate between the first or chronic
and the second or systemic phase. In the first phase
we have symptoms like headache, fever and muscle
pain. In the second phase we will display symptoms
like internal bleeding, impaired liver and kidney
disfunction, vomiting and diarrhoea.
The Ebola proteins can be differentiated into
glycoproteins (GP), virion proteins (VP) and
nucleoproteins (NP). The GP are important for the
infection process of the cell, these proteins will bind
to the receptors and will make it that the particle
can be up taken by the host cell due to
macropinocytosis. The VP are important to shield
the particle from the immune system of the host. It
will protect the particle against the innate immune
response and later they will interfere with the
immune response.
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