What does a pathogen have to
do?
• Infect (infest) a host
• Reproduce (replicate) itself
• Ensure that its progeny are transmitted to
Mechanisms of
Transmission
• Aerosols - inhalation of droplets, e.g.
Rhinoviruses, the 'Common Cold Virus' or
Adenoviruses.
• Faecal-Oral - e.g. Astroviruses, Caliciviruses; these viruses cause acute gastroenteritis.
• Vector-borne - e.g. in Arthropods such as
mosquitos, ticks, fleas: Arboviruses.
Entry into the Host
• Skin - dead cells, therefore cannot support virus replication. 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.
• 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
Entry into the Host
• Gastrointestinal tract - a hostile
environment; gastric acid, bile salts, etc
• Genitourinary tract - relatively less hostile than the above, but less
frequently exposed to extraneous viruses (?)
Transmission patterns
• Horizontal Transmission: Direct
person-to-person spread.
• Vertical Transmission: Relies on
PERSISTENCE of the agent to transfer infection from parents to offspring.
Several forms of vertical transmission can be distinguished:
• 1.Neonatal infection at birth, e.g. gonorrhorea, AIDS.
• 2.Infection in utero e.g. syphilis, CMV, Rubella (CRS), AIDS.
Primary Replication
•
Having gained entry to a potential host, the virus must initiate an infection by entering a susceptible cell. This frequently determineswhether the infection will remain localized at the site of entry or spread to become a systemic
Localized Infections
• Viruses Primary Replication
• Rhinoviruses U.R.T. • Rotaviruses Intestinal
epithelium
Systemic Infections
Virus
Primary ReplicationSecondary Replication
Enteroviruses
Intestinal epithelium
Lymphoid
tissues, C.N.S.
Herpesviruses
Spread Throughout the Host
• Apart from direct cell-cell contact, there are
2 main mechanisms for spread throughout
the host:
via the bloodstream
• Virus may get into the bloodstream by direct inoculation - e.g. Arthropod vectors, blood
transfusion or I.V. drug abuse. The virus may travel free in the plasma (Togaviruses, Enteroviruses), or in association with red cells (Orbiviruses), platelets (HSV), lymphocytes (EBV, CMV) or monocytes
(Lentiviruses). Primary viraemia usually proceeds and is necessary for spread to the blood stream, followed by more generalized, higher titre
via the nervous system
• spread to nervous system is preceded
by primary viraemia. In some cases,
spread occurs directly by contact with
neurons at the primary site of infection,
in other cases via the bloodstream.
Once in peripheral nerves, the virus can
spread to the CNS by axonal transport
along neurons (classic - HSV). Viruses
can cross synaptic junctions since these
frequently contain virus receptors,
Cell/Tissue Tropism
• Tropism - the ability of a virus to
replicate in particular cells or tissues - is controlled partly by the route of
infection but largely by the interaction of a virus attachment protein (V.A.P.)
Secondary Replication
•
Occurs in systemic infections when
a virus reaches other tissues in
which it is capable of replication,
e.g. Poliovirus (gut epithelium -
neurons in brain & spinal cord) or
Lentiviruses (macrophages - CNS +
many other tissues). If a virus can
be prevented from reaching tissues
where secondary replication can
:
Localized Infections: Virus: Primary Replication:
Rhinoviruses U.R.T.
Rotaviruses Intestinal epithelium Papillomavirus
es Epidermis
Systemic Infections:
Virus: Primary Replication: Secondary Replication:
Enteroviruses Intestinal epithelium Lymphoid tissues, C.N.S.
Herpesviruses Oropharynx or
Incubation periods of viral infections
Influenza 1-2d Chickenpox 13-17d
Common cold 1-3d Mumps 16-20d
Bronchiolitis,croup 3-5d Rubella 17-20d
Acute respiratory disease
5-7d Mononucleosis 30-50d
Dengue 5-8d Hepatitis A 15-40d
Herpes simplex 5-8d Hepatitis B 50-150d
Enteroviruses 6-12d Rabies 30-100d
poliomyelitis 5-20d Papilloma 50-150d
Types of Infection
• Inapparent
infection( Subclinical infection)
.
• Apparent infection
:
• Acute infection
• Persistent Infection
Chronic infections
Chronic Infection
•
Virus can be continuously detected ;
Latent infection
The Virus persists in an occult, or cryptic,
from most of the time. There will be
Slow virus infection
• A prolonged incubation period, lasting
Overall fate of the cell
• The cell dies in cytocidal infections
this may be acute (when infection is brief and self-limiting) or chronic (drawn out, only a few cells infected while the rest proliferate)-Cytocidal effect
• The cell lives in persistent infections
this may be productive or nonproductive (refers to whether or not virions are produced) or it may
Special cases
•
Transformation-
Integrated infection
(Viruses and Tumor)
Types of Viral infections at the cellular level
Type Virus production Fate of cell Abortive - No effect
Cytolytic + Death Persistent
Productive + Senescence Latent - No effect Transforming
Inhibition of cellular protein
synthesis Polioviruses, HSV, poxviruses, togaviruses Inhibition and degradation of
cellular DNA herpesviruses Alteration of cell membrane
structure
Glycoprotein insertion Syncytia formation
Disruption of cytoskeleton permeability
All enveloped viruses HSV, VZ virus, HIV HSV, naked viruses Togaviruses,
herpesviruses Inclusion bodies Rabies
Toxicity of Virion components Adenovirus fibers
3. Viral
Viral Immunopathogenesis
•
Influenza-like symptoms( IFN, lymphokins):
•
DTH and inflammation(Tcell, PMNs):
•
Immune-complex disease(AB, complement):
Persistence
Long term persistence of virus results from
two main mechanisms:
•
a) Regulation of lytic potential
H u m o r a
l
C e llu la r
N o n s p e c if ic
H u m o r a l
C e llu la r
S p e c if ic
macrophages, neutrophils NK cell complement, interferon, TNF etc.
T cells; other effectors cells antibodies
Components of the Immune
System
Innate or Nonspecific
Immunity
• Anatomic and Physiologic Barriers:
Intact skin / Mucus membrane
Temperature /Acidity of gastric juices
Protein factors
• Phagocytic Barriers : 3 major types of
phagocytic cells
IFN
•
Interferons are proteins produced by
cells infected with viruses, or exposed to
certain other agents, which protect other
cells against virus infection or decrease
drastically the virus yield from such cells.
Interferon itself is not directly the
anti-viral
agent, but it is the inducer of one or
many anti-viral mechanisms
Interferon inducing agents
•
(1) Viruses.
•
(2) dsRNA is a potent inducer, both viral
intermediates, and synthetic polyI-C.
•
(4) Certain Bacterial infections, and the
production of endotoxin.
•
(5) Metabolic activators/inhibitors.
Mitogens for gamma induction, also a
Properties of human interferons
Property IFN-alpha IFN-beta IFN-gamma Principal cellsource Epithelium leukocytes Fibroblasts Lymphocytes genes >20 1 1
Introns in genes no no yes
induction Viruses dsRNA Viruses dsRNA Immune activation Glycosylation no yes yes
Stability at pH2 stability stability labile Function Antiviral
infection
activation of NK cell
Activities of interferon
Antiviral actions
Interferons initiate an antiviral state in cells Interferons block viral protein synthesis Inferons inhibit cell growth
Immunomodulatory actions
Interferons-alpha and IFN-beta activate NK cells Interferons-alpha activates macrophages
Interferons-gamma activate macrophages Interferons increase MHC antigen expression Interferons regulate the activities of T cells
Other actions
Mechanism of action
• Release from an initial infected cell occurs
• IFN binds to a specific cell surface receptor on an other cell
• IFN induces the “antiviral state” : synthesis of protein kinase, 2’5’ oligoadenylate synthetase, and ribonuclease L
• Viral infection of the cell activates these enzymes
Diseases currently treated with
IFN-alpha and IFN-beta
• hepatitis C • hepatitis B
• papilloma warts and early trials with cervical carcinoma
• Kaposi sarcoma of AIDS, • colon tumors
• kidney tumors ( usually in combination with other drugs).
• Basal cell carcinoma
Nature killer/ NK cell
•NK cells are Activated by IFN-alpha/beta
•NK cells are Activated by IFN-alpha and IL-2
and
Activate macrophage
Macrophages
• Macrophages filter ciral particles from blood
• Macrophages inactivate opsonized virus particles
Complement
• Enhancing neutralization of Antibody
• Enhancing phagocytosis of virus
Specific immunity
Overview of Specific immunity
• specific recognition and selective
elimination of foreign molecules.
The Role of MHC
• The molecular basis of antigen recognition
by T cells is well understood. The TcR
recognizes short antigen-derived peptide
sequences presented in association with self
MHC class I or MHC class II molecules at
the surface of an
antigen presenting cell
The Role of MHC
• T cell recognition, therefore, involves direct
cell-cell contact between the
antigen-specific TcR on the T lymphocyte and an
MHC compatible cell which presents the
processed antigen in association with
The Role of MHC
• The finding that self MHC molecules are involved in the recognition of antigen by T lymphocytes led to the concept of "MHC restriction" of T cell
The Role of MHC
• In humans, the MHC is located on the short arm of
chromosome 6 and spans approximately 4 megabases of DNA. It can be divided into three regions termed class I, class II and class III:
• The class III region contains genes which encode a number of complement components and the tumour necrosis factor cytokines, amongst other molecules.
• MHC class I molecules consist of a polymorphic,
MHC-encoded, membrane-spanning heavy chain, and a monomorphic light chain, beta2-microglobulin.
• MHC class II molecules consist of a heterodimer of two
T cells
T cells are essential for controlling enveloped and noncytolytic viral infections
T cells recognizes viral peptides presented by MHC molecules on cell surfaces
Antigenic viral peptides can come from any viral protein TH1 CD4 responses are more important than TH2 responses
CD8 cytotoxic T cells respond to viral peptide-class I MHC protein complexes on the cell surface
TH2 CD4 responses are important for the maturation of antibody response
Antibody
Antibody neutralizes extracellular virue: it blocks viral attachment proteins it destablilizes viral structure
Antibody opsonizes virus for phagocytosis
Antibody promotes killing of target cell by the complement cascade and antibody-dependent cellular cytotoxicity
Antibody resolves lytic viral infections
Antibody blocks viremic spread to target tissue IgM is an indicator of recent or current infection IgG is more effective than LgM
Antibody
IgG IgM IgA
Function Memory Blood and tissue
Primary response
Clear viruses in blood
Mucus immunit
y
C: classic
pathway +++ -
-C : -C3 pathway - - +
placenta +++ -
-Antibody
Passive Immunity
• A high titer of antibody against a
specific virus
