Summary of the lectures given + the guest lectures. Some additional information added from the working groups. Lectures: viruses, emerging viruses, parasites, viral innate immune response, general infectious agents & immunity, controlled human infection models, one health, introduction to bacteria,...
Summary lectures infectious agents & immunity
Biomedical sciences year 2, Leiden University, Year 2021/2022
Lecture 1: viruses
Virus classification
Viruses are classified according to four main characteristics
1. Nature of the nucleic acid (DNA, RNA)
2. Symmetry of the protein shell
3. Presence of absence of lipid membrane (enveloped
or naked virus)
4. Dimensions of virion & capsid
Baltimore classification
o Classification described the relationship between
the viral genome and mRNA (So mRNA is the central
focuses of this scheme
o Baltimore scheme lacks information on viral
genome synthesis, the second universal function of
viral genomes
Figure 1 Baltimore classification
Structure and components of a virus particle
Virus particles are meta-stable structures. They have not yet attained the minimum free energy
conformation. This only achieved when an unfavourable energy barrier is surmounted, followed by
irreversible conformational changes during attachment and entry.
All aspects of viral propagation depend on host cell machinery
o Viral genomes encode three types of proteins
1. Proteins for replicating the genome
2. Proteins for packaging the genome and delivering it to the cells
3. Proteins for modifying the structure or function of the host cell to enhance
replication of the virus
Viral genome packaged in protein coat that is called a nucleocapsid
Nucleocapsid proteins interactions are either:]
Is built by using the same type of
o Equivalence
protein over and over again, this way
• All subunits interact with
the virus limits the amount of genes
neighbours in an identical
needed for the capsid in the genome.
matter
o Quasi-equivalence (nucleocapsid of most icosahedral structure of capsid of most viruses is
viruses shows quasi-equivalence) either helical symmetry (results in
• Bonding properties cylindrical structure; e.g. Influenza &
of subunits in different measles) or icosahedral symmetry
structural environments (e.g. polio & herpes)
are similar but not
, identical
Some viruses only have a nucleocapsid (naked virus) and some viruses have an envelope. An envelope
is a lipid bilayer that the virus acquires in the process of budding from the host cell plasma membrane.
(The virus does this without disrupting the membrane or killing the cell). A naked virus can only leave
the cell by lysing it.
Figure 2 Comparison naked vs enveloped virus
Viral matrix proteins: Structural proteins that link the viral envelope with the virus core. These proteins
play a crucial role in virus assembly.
Viral enveloped glycoproteins: Integral membrane glycoproteins. Consist of the ectodomain
(attachment, antigenic sites, fusion) and the internal domain (assembly). The corona spike proteins
and the influenza H and N proteins are examples. Viral spike proteins form oligomers that are
homomeric or heteromeric structure.
Viral attachment and entry
When a virus enters a cell it is the start of the infection. There are three general steps:
1. Binding to the receptor
a. The initial binding of the virus to the cell receptor is weak but because most of the
time the virus binds with a dimer or trimer the avidity is strong enough for the virus to
enter the cell
2. Penetration of the membrane
3. Uncoating to allow replication, transcription and translation
That are different penetration strategies
o pH independent fusion (plasma membrane)
• Virus fuses directly with host cell plasma
membrane to release their genome and
capsid proteins in the cytosol
o Acid activated fusion (endosomal membrane)
• Virus initiates receptor mediated
endocytosis and when it is the
endosome it gets activated by the
Lab test to determine which route unknown virus uses:
Add NH4CI to the medium. If virus is pH independent is can still infect the host
the cell. If virus is acid activated it is not able to infect the host cell
, lowered pH. It is than able to leave the endosome and release its genome into the
cytosol.
Figure 3 Different virus entry routes
Replication and translation of the virus
Virus can either have a DNA genome or a RNA genome. The nature of the genome and/or the site of
replication and transcription will determine which of the enzymes needed for replication and
transcription have to be encoded by the virus.
DNA genome: replication in the nucleus
RNA genome: replication in the cytoplasm
o General characteristics of DNA virus replication
o Always requires expression of virus genes for initiation. It starts at an origin of
replication, it requires a primer, and it has an 5’
to 3’ extension
o The host cell provides most enzymes for DNA
replication
o Induction of host replication enzymes is required
▪ Some virus for example force the cell into
the S cycle so the cell starts the DNA
replication and the virus can use the
machinery
To make mRNA the virus uses RNA polymerase II of the host. The
transcription is regulated by viral proteins that act as transcription
activators (in combination with host transcription factors. Often
there is temporal regulation of gene expression. Also the virus
uses alternative splicing to make more than one mRNA from one Figure 4 Transcription and replication of DNA virus
particular gene. The advantage of this is that virus can have more
proteins encoded on a smaller genome.
o General characteristics of RNA virus replication
o A RNA virus always has to provide for an RNA-dependent RNA polymerase (RdRP)
because human cells do not have this
o The virus being a + stranded or – stranded RNA virus makes a big difference
▪ A + stranded RNA virus is more infectious because the genome directly serves
as mRNA which makes the replication much faster
o It is often impossible to discriminate between replication and transcription in +
stranded RNA viruses
, • + stranded RNA viruses
o Genomes serves as a mRNA (so no RdRP
necessary)
o Complimentary strand serves as a template
for new genome RNA
o Expression of the viral genes as a
polyprotein or by the synthesis of one or
more sub genomic mRNAs
• - stranded RNA viruses
o Genome RNA cannot serve as a mRNA so
virus has to bring RdRP itself. (This is
nucleocapsid)
o Genomic RNA is used as a template for viral Figure 5 Difference in transcription and replication of [-]
sub genomic mRNAs and anti-genomic + and [+] stranded RNA viruses
strand RNA
o Expression of the viral genes from the individual mRNAs
• Retroviruses
o Contain a + stranded RNA as genome
o RNA is transcribed in dsDNA copy by the viral reversed
transcriptase
o This viral cDNA is then integrated in the host genome
DNA
o Viral mRNA and genome RNA are then produced by
transcription of the inserted DNA copy of the virus by the
host RNA polymerase II
o RNA splicing and proteolytic processing of poly protein
are used for the expression of the viral genes
The production of new virus particles
Assembly and maturation of new virus particles
o Nucleocapsid formation
• This usually occurs at the site where the newly synthesized
viral genomes resides
Figure 6 Transcription and
o Acquiring lipid enveloped (If this virus has one) replication of retrovirus
• Takes place at the lipid structures where the glycoproteins
accumulate
▪ This can be at the RER, Golgi or at the plasma membrane
Non enveloped viruses rupture the plasma membrane to get out of the cell. Enveloped virus bud from
the cell at either the plasma membrane or at the intracellular membranes.
Drivers of virus evolution
o Mutations
• Errors made by the replicase during DNA/RNA synthesis. (nucleotide substation,
small insertions/deletions
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