Viral Pathogenesis

Viral Pathogenesis
Viral pathogenesis is the process by which a viral infection
leads to disease.
Viral pathogenesis is an abnormal situation of no value to
the virus.
The majority of viral infections are subclinical. It is not in
the interest of the virus to severely harm or kill the host.
The consequences of viral infections depend on the
interplay between a number of viral and host factors.

PATOGENESIS PENYAKIT VIRUS

PRINSIP : Terjadi siklus replikasi virus dalam sel hospes Respon imun
seluler Sitopatologi Kematian, hiperplasia, kanker, tidak
terjadi apa-apa
Infeksi Virus penyakit virus abnormalitas ( struktur/fungsi)
Subklinik : infeksi dengan gejala tidak nyata
Klinik : infeksi dengan gejala & tanda
Virus patogen mampu menginfeksi & menyebabkan penyakit
Strain virulen strain yang lebih sering menyebabkan penyakit dibandingkan
strain lain
VIRUS

SEL HOSPES PEKA

EFEK SITOPATIK (ESP)

Outcome of Viral Infection

Acute Infection
Recovery with no residue effects
Recovery with residue effects e.g. acute viral encephalitis leading to
neurological sequelae.
Death
Proceed to chronic infection

Chronic Infection
Silent subclinical infection for life e.g. CMV, EBV
A long silent period before disease e.g. HIV, SSPE, PML
Reactivation to cause acute disease e.g. herpes and shingles.
Chronic disease with relapses and excerbations e.g. HBV, HCV.
Cancers e.g. EBV, HTLV-1, HPV, HBV, HCV, HHV-8

Factors in Viral Pathogenesis

Effects of viral infection on cells (Cellular
Pathogenesis)
Entry into the Host
Course of Infection (Primary Replication, Systemic
Spread, Secondary Replication)
Cell/Tissue Tropism
Cell/Tissue Damage
Host Immune Response
Virus Clearance or Persistence

Cellular Pathogenesis

Cells can respond to viral infections in 3 ways: (1) No apparent change,

(2) Death, and (3) Transformation

Direct cell damage and death from viral infection may result from
diversion of the cell's energy
shutoff of cell macromolecular synthesis
competition of viral mRNA for cellular ribosomes
competition of viral promoters and transcriptional enhancers for cellular
transcriptional factors such as RNA polymerases, and inhibition of the
interferon defense mechanisms.

Indirect cell damage can result from

integration of the viral genome

induction of mutations in the host genome
inflammation
host immune response.

ESP (CYTOPATHIC EFFECT) :

Penggembungan spt balon

Plasmolisis
Piknosis
Karyoreksis
Pembentukan sinsitium
Pembentukan sel raksasa berinti
banyak (Multinucleated Giant Cell
Formation)
Vakuolisasi/Pembentukan sel busa
(Foamy Cell Formation)
Nekrosis/pengerutan
Pembentukan badan inklusi
(Inclusion Body Formation)

REPRODUKSI VIRUS DALAM

BIAKAN SEL :

Adanya ESP Poliomyelitis,

Varicella, Herpes Simplex, Herpes
Zooster, Morbili, Mumps,
Influenza, Dengue, Echovirus,
Coxsackievirus, Cytomegalovirus
Adanya hambatan metabolisme
sel Poliomyelitis, Echovirus,
Adenovirus Coxsackievirus
Adanya pembentukan
hemaglutinin Virus Influenza,
Parotitis epidemica, Echovirus,
Coxsackievirus
Adanya proses hemadsorpsi
Virus Parainfluenza
Adanya perubahan morfologik sel
Virus Sarcoma Rous, Simian
Virus 40 (SV 40)

TIPE ESP PADA SEL HOSPES

Biakan Sel Normal

Virus

Nekrosis/mengerut

Penggembungan

Karyoreksis
Piknosis

Plasmolisis

Badan Inklusi

Sinsitium/Sel raksasa

Vakuolisasi/Sel busa

Viral Entry

Skin - Most viruses which infect via the skin require a breach in the
physical integrity of this effective barrier, e.g. cuts or abrasions. Many
viruses employ vectors, e.g. ticks, mosquitos or vampire bats to breach
the barrier.

Conjunctiva and other mucous membranes - rather exposed site and

relatively unprotected

Respiratory tract - In contrast to skin, the respiratory tract and all other
mucosal surfaces possess sophisticated immune defence mechanisms, as
well as non-specific inhibitory mechanisms (cilliated epithelium, mucus
secretion, lower temperature) which viruses must overcome.

Gastrointestinal tract - a hostile environment; gastric acid, bile salts,

etc. Viruses that spread by the GI tract must be adapted to this hostile
environment.

Genitourinary tract - relatively less hostile than the above, but less
frequently exposed to extraneous viruses (?)

JALUR MASUK VIRUS PADA PERMUKAAN TUBUH

JALUR UMUM INFEKSI VIRUS

Infeksi menyeluruh dan
penyakit organ khusus

Jalur Masuk

Kelompok Virus

Gejala lokal pada tempat masuk

Saluran Pernapasan

Adenovirus
Herpesvirus
Poxvirus
Pikornavirus
Togavirus
Ortimyxovirus
Paramyxovirus

Kebanyakan Spesies
Epstein Barr,Herpes simplex

Rinovirus

Influenza
Parainfluenza, virus Sinsitial
pernapasan
Kebanyak Spesies

Varicella
Cacar (punah)
Beberapa Enterovirus
Rubela

Gondong, Campak

Herpesvirus
Pikornavirus

Beberapa spesies
Epstein Barr,Herpesimplex

Reovirus

Rotavirus

Cytomegalovirus
Bbrp Enterovirus, Polio dan
Hepatitis A

Papovavirus
Herpesvirus
Poxvirus
Herpes virus
Hepadnavirus
Retrovirus
Rabdovirus
Togavirus
Flavivirus

Papilomavirus
Herpes Simplex
Moluscum contagiosum,Orf

Epstein Barr, Cytomegalovirus

Hepatitis B
AIDS
Rabies
Banyak spesies EEE
Banyak spesies demam kuning

Coronavirus

Mulut dan Saluran Usus

Kulit
Luka ringan

Tusukan
Gigitan

Adenovirus

UNTUK MENYEBABKAN PENYAKIT VIRUS HARUS :

Masuk Replikasi primer Penyebaran Virus Cedera sel Respon imun Inang
Pembersihan Virus/infeksi menetap secara persisten Pelepasan Virus

INFEKSI VIRUS :
Kontak langsung
Kontak tak langsung

BAGAN POLA PATOGENESIS POTENSIAL INFEKSI VIRUS

Infeksi virus primer
Virus

Penyakit pd tempat
lokalisasi/asimptomatik

Tempat lokalisasi
Penyebaran langsung
pd target organs

Nervus perifer
Darah
Penyakit

Sistim limfatik

Target organ

Darah

Limpa
Hati
Lekosit

Penyakit

PATOGENESIS
Pemasukan & Replikasi Primer

Penyebaran virus & tropisme sel

virus menyebabkan penyakit pada tempat yang jauh dari tempat

masuknya

virus mempunyai tropisme terhadap jaringan atau sel

RESEPTOR khusus dipermukaan sel untuk virus (reseptor
komponen permukaan yang berinteraksi secara khusus dengan
suatu daerah dipermukaan virus (kapsid/selubung) untuk
memulai infeksi)
Melibatkan ENZIM-ENZIM PROTEOLITIK replikasi tidak
terjadi pada jaringan yan tidak mengaktifkan enzim pengaktif
yang tepat
Ditentukan oleh gen virus khusus penyebaran Reovirus pada
Saluran cerna ditentukan oleh protein kapsid sebelah luar

 Cedera sel dan Penyakit klinik

Infeksi virus kerusakan sel/jaringan, misalnya : hilangnya
produksi hormon
Epitel usus cepat regenerasi
Otak lambat regenerasi

Penyembuhan
akikat infeksi virus bisa terjadi kematian atau sembuh melibatkan
imunitas humoral berperantara sel, interferon, limfokin dan faktor
pertahanan lain
Pelepasan virus
banyak terjadi pada tempat masuk virus
Virus Rabies tidak mengalami pelepasan fatal

KEMUNGKINAN YANG DAPAT TERJADI PADA INTERAKSI VIRUS - HOSPES

Resisten

tak terlihat terjadi adanya hubungan

Infeksi Subklinik Penyembuhan

Infeksi Persisten
Penyakit Akut/Klinik Kematian
Sembuh dengan/Tanpa sequele
Sembuh dengan Infeksi Latent/Persisten
Infeksi Menahun (Khronik) Asimptomatik, Latent
Latent dengan Rekurensi
Persisten dengan Penyakit Khronik
nfeksi Virus Lambat (Slow Virus Infection)
Transformasi Malignan
Virus bertindak sebagai Triger Reaksi Hospes tak normal (Sindrom
Reye, Sindrom Uremik Hemolitik

Course of Viral Infection

Primary Replication
The place of primary replication is where the virus replicates after
gaining initial entry into the host.
This frequently determines whether the infection will be localized at
the site of entry or spread to become a systemic infection.

Systemic Spread
Apart from direct cell-to-cell contact, the virus may spread
via the blood stream and the CNS.

Secondary Replication
Secondary replication takes place at susceptible organs/tissues
following systemic spread.

Cell Tropism
Viral affinity for specific body tissues (tropism) is
determined by
Cell receptors for virus.
Cell transcription factors that recognize viral
promoters and enhancer sequences.
Ability of the cell to support virus replication.
Physical barriers.
Local temperature, pH, and oxygen tension
enzymes and non-specific factors in body
secretions.
Digestive enzymes and bile in the gastrointestinal
tract that may inactivate some viruses.

Cell Damage
Viruses may replicate widely throughout the body without
any disease symptoms if they do not cause significant cell
damage or death.
Retroviruses do not generally cause cell death, being
released from the cell by budding rather than by cell lysis,
and cause persistent infections.
Conversely, Picornaviruses cause lysis and death of the
cells in which they replicate, leading to fever and increased
mucus secretion in the case of Rhinoviruses, paralysis or
death (usually due to respiratory failure) for Poliovirus.

Immune Response
The immune response to the virus probably has the greatest impact
on the outcome of infection.
In the most cases, the virus is cleared completely from the body
and results in complete recovery.
In other infections, the immune response is unable to clear the
virus completely and the virus persists.
In a number of infections, the immune response plays a major
pathological role in the disease.
In general, cellular immunity plays the major role in clearing virus
infection whereas humoral immunity protects against reinfection.

Immune Pathological Response

Enhanced viral injury could be due to one or a mixture of
the following mechanisms; Increased secondary response to Tc cells e.g. HBV
Specific ADCC or complement mediated cell lysis
Binding of un-neutralized virus-Ab complexes to cell
surface Fc receptors, and thus increasing the number
of cells infected e.g. Dengue haemorrhagic fever, HIV.
Immune complex deposition in organs such as the
skin, brain or kidney e.g. rash of rubella and measles.

Viral Clearance or Persistence

The majority of viral infections are cleared but certain
viruses may cause persistent infections. There are 2
types of chronic persistent infections.
True Latency - the virus remains completely latent
following primary infection e.g. HSV, VZV. Its
genome may be integrated into the cellular genome or
exists as episomes.
Persistence - the virus replicates continuously in the
body at a very low level e.g. HIV, HBV, CMV, EBV.

Mechanisms of Viral Persistence

antigenic variation

immune tolerance, causing a reduced response to an antigen, may be due

to genetic factors, pre-natal infection, molecular mimicry

restricted gene expression

down-regulation of MHC class I expression, resulting in lack of

recognition of infected cells e.g. Adenoviruses

down-regulation of accessory molecules involved in immune recognition

e.g. LFA-3 and ICAM-1 by EBV.

infection of immunopriviliged sites within the body e.g. HSV in sensory

ganglia in the CNS

direct infection of the cells of the immune system itself e.g. Herpes
viruses, Retroviruses (HIV) - often resulting in immunosuppression.

Examples of Viral Pathogenesis

Herpes Simplex Virus

HSV is spread by contact, as the virus is shed in saliva, tears, genital
and other secretions.
Primary infection is usually trivial or subclinical in most individuals.
It is a disease mainly of very young children ie. those below 5 years.
About 10% of the population acquires HSV infection through the
genital route and the risk is concentrated in young adulthood.
Following primary infection, 45% of orally infected individuals and
60% of patients with genital herpes will experience recurrences.
The actual frequency of recurrences varies widely between
individuals. The mean number of episodes per year is about 1.6.

Pathogenesis

During the primary infection, HSV spreads locally and a short-lived

viraemia occurs, whereby the virus is disseminated in the body. Spread to
the to craniospinal ganglia occurs.

The virus then establishes latency in the craniospinal ganglia.

The exact mechanism of latency is not known, it may be true latency

where there is no viral replication or viral persistence where there is a low
level of viral replication.

Reactivation - It is well known that many triggers can provoke a

recurrence. These include physical or psychological stress, infection;
especially pneumococcal and meningococcal, fever, irradiation; including
sunlight, and menstruation.

AKTIVASI PERIODIK INFEKSI VIRUS HERPES SIMPLEX

C
G
B

J
I

Garis ambang

Infeksi initial
Stimulus

A
1

A J = Infeksi rekuren
1 = Infeksi subklinik (inapparent) covert
2 = Infeksi klinik (apparent) overt
3 = Infeksi latent
4 = Infeksi klinik
5 = Infeksi latent

Clinical Manifestations
HSV is involved in a variety of clinical manifestations
which includes ;1. Acute gingivostomatitis
2. Herpes Labialis (cold sore)
3. Ocular Herpes
4. Herpes Genitalis
5. Other forms of cutaneous herpes
7. Meningitis
8. Encephalitis
9. Neonatal herpes

GAMBARAN PENYAKIT VIRUS AKUT

INFEKSI LOKAL

INFEKSI SISTEMIK

Contoh penyakit
spesifik

Pernapasan (Rinovirus) Campak

Tempat patologi

Pintu masuk

Tempat yang
berdekatan

Lama inkubasi

Relatif pendek

Relatif panjang

Viremia

Tidak ada

Ada

Lama imunitas

Bervariasi, mungkin
pendek

Biasanya umur panjang

Ab sekretor (IgA) pada

resistensi

penting

Tidak penting

VIRUS ONKOGENIK
VIRUS DNA :

VIRUS RNA :

PAPOVAVIRIDAE

RETROVIRIDAE

Virus Polyoma
Simian Virus 40 (SV 40)
Virus Papiloma Kelinci
Virus Papiloma Bovin

Virus Leukemia Murin

Virus Friend
Virus Maldney
Virus Rauscher
Virus Gross
Virus Tumor Mammae
Virus AIDS (HTLV III/ LAV, HIV)

HERPESVIRIDAE
Virus Penyakit Marek
Virus Karsinoma Kodok Lucke
Herpesvirus Saimiri
Virus Epstein Barr
Virus Herpes Simplex

HEPADNAVIRIDAE
Virus Hepatitis B

POXVIRIDAE
Virus YABA
Virus Fibroma Kelinci

( Human T-Lymphotropic Virus Type III /

Lymphadenopathy Associated (AIDS) Virus,
Human Immunodeficiency Virus )

VIRUS DENGAN REAKSI HOSPES YANG LUAR BIASA

Sindrom Reye :
Virus Influenza
Virus Varicella Zooster
Virus Parainfluenza
Penyakit Virus Prodomal yang tak teridentifikasi Reovirus, Echovirus
Coxsackievirus, Adenovirus, Herpesvirus

SINDROM HEMOLITIK :
Coxsackievirus
Virus Janin
Virus Epstein Barr
Penyakit Virus Prodomal yang tak teridentifikasi

Sindrom Guillain Barre :

Virus Epstein Barr
Virus vaksin Influenza Babi
Virus Parotitis Epidemica

Encefalopati Pasca Infeksi :

Virus Morbili
Virus Vaccinia
Virus Varicella Zooster
Virus parotitis Epidemica

Morbili Atipik :
Virus Morbili pada orang yang diimunisasi dengan
Virus vaksin Morbili yang dimatikan

BAGAN INFEKSI AKUT DAN MACAM-MACAM INFEKSI

PERSISTEN

I
II

INFEKSI AKUT (Variola)

Morbilli Infeksi Akut (Komplikasi Lambat Jarang)

Varicella Infeksi Latent (Varicella Zooster)

III

SSPE
Zooster

Infeksi Menahun ( Choriomeningitis Lymphocytic pada mencit)

IV

Pelepasan Virus
Infeksi Menahun ; Penyakit Lambat (Leukemia Neoplastik)

V
Infeksi Lambat (Progresif)
VI
WAKTU (TAHUN)
Virus Infektif dapat didemonstrasikan
Virus tak dapat didemonstrasikan
Episode penyakit

SSPE Subacute Spongiform

Panencephalitis

INFEKSI VIRUS PADA SALURAN PERNAPASAN

Virus Penyebab yang Paling Sering
Sindroma

Gejala Utama

Bayi

Anak-anak

Dewasa

Flu

Hidung tersumbat,
pilek

Rino
Adeno

Rino
Adeno

Rino
Corona

Faringitis

Sakit tenggorokan

Adeno
Herpes Simplex

Adeno
Coxackievirus

Adeno
Coxackievirus

Laringitis, batuk dengan

sesak napas

Serak, batuk

Parainfluenza
Influenza

Parainfluenza
Influenza

Parainfluenza
Influenza

Trakeobronkitis

Batuk

Parainfluenza
Influenza

Parainfluenza
Influenza

Influenza
Adeno

Bronkiolitis

Batuk, sesak napas

Sinsitial
pernapasa
Parainfluenza

Jarang

Jarang

Pneumonia

Batuk, nyeri dada

Sinsitial
pernapasan
Influenza

Influenza
Parainfluenza

Influenza
Adeno

INFEKSI VIRUS PADA JANIN

Virus
Wanita Hamil yang Peka
Janin
Normal
In
tra

va
g

Infeksi Maternal

Infeksi
Amnion

Telur

ia
em
Vir

in
a

Abortus
Spontan

Infeksi
Plasenta

Infeksi Janin

Janin
Normal

Janin Terinfeksi
( penyakit)

Kematian Janin
(Abortus, lahir mati)

Malformasi
( mati)

INFEKSI VIRUS PERINATAL

Keseringan Waktu Infeksi
Postnatal
(Setelah
Persalinan)

Insiden
Neonatal (per
1000 lahir
hidup)

Virus

Prenatal
(dalam uterus)

Natal
(Selama
Persalinan)

Rubela

Jarang

0,1 0,7

Cytomegalovirus

++

5 - 25

Herpes Simplex

++

0,03 0,5

Varicella-Zooster

Jarang

Jarang

Jarang

Hepatitis B

++

0-7

Enterovirus

++

Tidak biasa

RESPON IMUN TERHADAP BERBAGAI INFEKSI VIRUS

Interferon dan IgA Pertahanan utama pada epitel
permukaan
Viremia Virus rentan terhadap Antibodi
Virus di dalam sel Sistim imun humoral
Sistim imun seluler
Antibodi melalui ADCC
Penghancuran virus di dalam sel Menguntungkan
Imunopatologik

Summary
Viral Pathogenesis depends on the complex interplay of a
large number of viral and host factors.
Viral factors
pathogenesis.

include

cell

tropism

and

cellular

The immune response is the most important host factor, as

it determines whether the virus is cleared or not.
Sometimes, the immune response itself is responsible for
the damage.