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Rabies

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Davis Han

on 25 May 2015

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Transcript of Rabies

Rabies
HISTORY
HISTORY
1883

Louis Pasteur and Emile Roux creates a rabies vaccine from the spine of an infected animal and tests it on dogs
PATHOGENESIS
Infection Process
HISTORY
PRESENT

Once symptoms develop, no known treatment for Rabies

TRANSCRIPTION AND REPLICATION
DIAGNOSIS
Two forms of Rabies Virus
Furious
Paralytic
- CNS Infecting Virus
Rabies Virus Transcription and Replication
Rabies virus (RABV) and rabies-related viruses belong to the
Lyssavirus
genus of the
Rhabdoviridae
family
Rabies virus particle
N is bound to the genomic RNA and together with P and L forms the ribonucleoprotein(RNP) that constitutes the active viral replication unit.
L–P binding to the N–RNA probably triggers conformational changes that allow access of the polymerase to the RNA.
G protein is an integral transmembrane protein that is involved in viral entry.
M protein is located beneath the viral membrane and bridges the nucleocapsid and the lipid bilayer.
Rabies virus genome organization
2300 B.C

Dog owners in the Babylonian city of Eshnunna are fined heavily for deaths caused by their dogs biting people..
-The genes are usually separated by conserved nontranscribed intergenic
Regions(IGR). The length of the IGRs
plays an important role in regulating gene expression.

-The first and last nine
nucleotides (nt) of the viral RNA are inversely complementary and conserved.

PEP (Post Exposure Prophylaxis)
Rabies

Immunoglobulin injection over a
30-day period
100% Success Rate

The viral cycle is cytoplasmic. After receptor binding, the virusenters the cell via the endocytic pathway
The neo-synthesized genomic RNP either serves as a template for secondary transcription or is transported to the cell membrane and assembles with the M and G proteins for the budding of neo-synthesized virions
Reinitiation of the transcription at each TIS does not always occur, generating a gradient of amounts of transcript (leader RNA > mRNA G > mRNA N > mRNA P > mRNA M >mRNA G > mRNA L)
Transcription and replication
During transcription (B), the mRNA is capped and methylated on its nascent 5' extremity at the end of the gene.
During replication (C), the newly synthesized RNA is instantly encapsidated by incoming N–P complexes.
Viral cycle
Negri body-like structures(NBLs)
(A)Analyzed at different times postinfection by confocal microscopy and by using an antibody directed against the viral N protein

(B)NBLs display a granular dense structure that is surrounded by a double membrane derived from RER

(C) All viral RNAs are detected in the NBLs (16-h p.i.) as shown by FISH experiments. The N protein (green) forms a cage around the viral RNAs (red).

(D) Viral RNAs are synthesized inside the NBLs. Short-term RNA labeling in the presence of Bromo UTP (BrUTP) indicates that the RABV polymerase incorporates BrUTP into RNA that is actively synthesized within the NBLs.

perception
behavior
How to make it possible?
architecture & physiological property
mechanistic understanding of the operation of the brain’s neural circuits.
The structure, the physiological, and the integrative properties of the neurons
relationship between the structure of its
neuronal circuits and their physiological function
1. Modifying the viral genome by
deletion of a gene required for the production of infectious viral particles
.

-> viral spread to be mono-synaptically restricted using the trans-complementation

2.The second modification was to
alter the tropism of the virus(Pseudotyping)
so that it could only infect a genetically specified neuronal population



APPLICATION
Revealing the secrets of neuronal circuits
with recombinant rabies virus technology

Pseudotyping
- the process of producing viruses or viral vectors in combination with
foreign viral envelope proteins

To test infection selectivity, isolated neurons in cultured brain slices were transfected using the gene gun with two genes, one encoding
TVA
, and the other,
DsRed2
.
ASLV-A-pseudotyped rabies virus [SADΔG-
EGFP
(EnvA)] was applied the next day and images were taken 6 days following

(A and C)
DsRed2
expression marking transfection with TVA
(B and D)
EGFP
expression indicating subsequent selective infection of the same TVA-expressing cells with pseudotyped virus
Isolated neurons were transfected with three genes encoding
TVA
to permit viral infection,
DsRed2
to mark transfected cells, and the rabies
virus glycoprotein gene
to complement the deletion in the viral genome.
(E)
DsRed2
fluorescence indicating a transfected
cell, marked with a dotted line, at the center of the cluster shown in (F).
(G and H) Two more examples of clusters surrounding a single transfected cell. The initially infected cells expressing both
EGFP
and
DsRed2
appear yellow
Gaining insight into brain function by the dissection of neuronal circuits. Recent advances in RABV G technology provide invaluable tools for gaining a better understanding of the function and structure of neuronal circuits.
(
A
) there-
organization of neuronal
circuits
resulting from plasticity or disease can be revealed by comparing the
wiring diagram of experimental and control brains. (
B
) We can learn more about
plasticity in the adult brain
by studying the integration of adult-born neurons into existing neuronal networks. Similar approaches might be used to study circuit integration following stem cell therapy.
(
C
) The analysis of the
physiological properties of synaptic connections
between defined neuron types(inaddition to the anatomical wiring diagram) is greatly aided by this technique. Furthermore, the spatial and temporal integration of signals from a
larger number of presynaptic neurons can be examined in postsynaptic neurons.
(
D
) The population activity of a
defined neuronal circuit can also be measured during active sensory stimulation or behavior
and subsequently correlated with the anatomical input network of a defined starter population.
(
E
) The receptive field properties of individual neurons can be combined with the analysis of the anatomical wiring diagram of their presynaptic network.
Thank you for listening
&
Feel free to ask Q
1.History, Pathogenesis and Diagnostics
2.Transcription & Replication
3.Application
THE BITE
Transmission
Site of Injury
Incubation Period
Incubation Period
Rabies virus inhibits its own transcription and translation of proteins
Low replication rate
- Mechanisms leading to disease symptoms
CONTENTS
Nervous System
CNS
Length of time
before onset of symptoms depends on the
number of nerve endings at wound site
- Eclipse phase (Weeks to Years)
During incubation
Remains in
muscle/inoculated portion
Downregulation of Dendritic cells
Insufficient innate and adaptive immune response
Incubation Period
Key Aspect of the Rabies Virus
(Prevent host cells from apotosis)
What we can achieve from these new technology
What we need to understand our brain
Recombinant Rabies virus
`
Furious (2/3)
Typical symptoms
Fluctuating consciousness
Changed mental status
Inspiratory spasms
Relatively easy diagnosis
Paralytic (1/3)
Clinically indistinguishable from GBS (Guillain-Barre Syndrome
Limited tests available
Ag-detection
Ab-assays
Virus isolation
Diagnosis
Once symptoms develop, very
rare
where patient makes
full recovery
Animal
DFA
Test
(Direct Fluorescent Antibody)

Looks for presence of Rabies virus antigen in brain tissue
Humans
Multiple tests
- As we cannot obtain brain tissue from living human being
Ante-mortem
Post-mortem
(Easy)
(Difficult)
saliva, serum, spinal fluid, hair follicles of neck
Baltimore Class V
(-) ssRNA
Presenters
HAN JI HO
MIN HYUNG GEUN
LEE JAE SUNG

References

-Costimulation of AMPA and Metabotropic Glutamate Receptors Underlies Phospholipase C Activation by Glutamate in Hippocampus

-Revealing the secrets of neuronal circuits with recombinant rabies virus technology

-Monosynaptic Restriction of Transsynaptic Tracing from Single,
Genetically Targeted Neurons

-Design and generation of recombinant rabies virus vectors

-Structural aspects of rabies virus replication

-Human rabies-neuropathogenesis, diagnosis, and management
SAMPLES
-
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