Infection and Immunity

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Infection and Immunity
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What does a pathogen have to do?

• Infect (infest) a host
• Reproduce (replicate) itself
• Ensure that its progeny are transmitted to
  another host

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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.
• Close personal contact - especially exchange of
  bodily fluids Sex Blood, e.g. Herpesviruses

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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 mechanisms
  (cilliated epithelium, mucus secretion, lower
  temperature) which viruses must overcome.

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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 (?)
• Conjunctiva - an exposed site and relatively
  unprotected

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Sites of virus entry
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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.
• 3. Germ line infection - via ovum or sperm.

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Primary Replication

• Having gained entry to a potential host, the
  virus must initiate an infection by entering a
  susceptible cell. This frequently determines
  whether the infection will remain localized at
  the site of entry or spread to become a systemic
  infection

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Localized Infections

• Viruses Primary
  Replication
• Rhinoviruses
  U.R.T.
• Rotaviruses Intestinal
  epithelium
• Papillomaviruses Epidermis

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Systemic Infections

• Virus Primary Replication Secondary
  Replication
• Enteroviruses
• Intestinal epithelium
  Lymphoid
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  tissues, C.N.S.
• Herpesviruses
• Oropharynx or
  Lymphoid cells,
• G.U.tract
  C.N.S.

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Spread Throughout the Host

• Apart from direct cell-cell contact, there are 2
  main mechanisms for spread throughout the host
• via the bloodstream
• via the nervous system

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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 secondary viraemia as
  the virus reaches other target tissues or
  replicates directly in blood cells

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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, allowing the virus to jump from one
  cell to another

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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.) with a specific receptor molecule on the
  surface of a cell, and has considerable effect on
  pathogenesis. Many V.A.P.'s and virus receptors
  are now known.

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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 occur, generally
  no disease results.

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Incubation periods of viral infections
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Types of Infection

• Inapparent infection( Subclinical infection) .
• Apparent infection
• Acute infection
• Persistent Infection
• Chronic
  infections
• Latent Infection
• Slow virus infections

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Chronic Infection

• Virus can be continuously detected mild or no
  clinical symptoms may be evident.

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Latent infection

• The Virus persists in an occult, or
  cryptic, from most of the time. There will be
  intermittent flare-ups of clinical disease ,
  Infectious virus can be recovered during
  flare-ups . Latent virus infections typically
  persist for the entire life of the host

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Slow virus infection

• A prolonged incubation period, lasting months or
  years, daring which virus continues to multiply.
  Clinical symptoms are usually not evident during
  the long incubation period .

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Overall fate of the cell

• The cell dies in cytocidal infectionsthis 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 infectionsthis may
  be productive or nonproductive (refers to whether
  or not virions are produced) or it may alternate
  between the two by way of latency and
  reactivation - Steady state infection

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Special cases

• Transformation-Integrated infection (Viruses and
  Tumor)
• Apoptosis

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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
• DNA viruses -
  Immortalization
• RNA viruses
  Immortalization

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Mechanisms of viral cytopathogenesis
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3. Viral Immunopathology
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Viral Immunopathogenesis

• Influenza-like symptoms( IFN, lymphokins)
• DTH and inflammation(Tcell, PMNs)
• Immune-complex disease(AB, complement)
• Hemorrhagic disease( T cell,AB, Complement)
• Postinfection cytolysis( T cells) enveloped
  viruses
• Immunosuppression HIV CMV measlesvirus and
  influenza

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Persistence

• Long term persistence of virus results from two
  main mechanisms
• a) Regulation of lytic potential
• b) Evasion of immune surveillance

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Persistence vs. Clearance
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Antiviral Immunity
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Overview of the Immune System
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Components of the Immune System
macrophages, neutrophils NK cell
complement, interferon, TNF etc.
T cells other effectors cells
antibodies
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Innate or Nonspecific Immunity
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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
• Inflammatory Barriers and fever
• Mucociliary clearance

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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
• Anti-tumor and regulation of immunity

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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 variety of tumor
  promoters induce IFNs. , in particular
  PTA-phorbol tetradecanoate acetate, butyrate,
  dexamethasone

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Properties of human interferons
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Activities of interferon
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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, 25 oligoadenylate synthetase,
  and ribonuclease L
• Viral infection of the cell activates these
  enzymes
• Inhibition of viral and cellular protein
  synthesis occurs

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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
• Breast cancer combined with tamoxifan.

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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
• NK cells target and kill virus infected cells

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NK cell
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Macrophages

• Macrophages filter ciral particles from blood
• Macrophages inactivate opsonized virus particles
• Macrophages present viral antigen to CD4 T cells

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Complement

• Enhancing neutralization of Antibody
• Enhancing phagocytosis of virus particles
• Lysis

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Specific immunity

• Active/passive

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Overview of Specific immunity

• specific recognition and selective elimination of
  foreign molecules.
• Involves specificity, diversity, memory, and
  self/nonself recognition.

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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 (APC).

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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 surface MHC molecules.

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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
  responses, and pointed to the important role that
  products of the major histocompatibility complex
  play in the cell mediated immune response. The
  major histocompatibility complex consists of a
  cluster of genes, most of which encode products
  with immunologically related functions.

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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 MHC-encoded, membrane-spanning proteins,
  the alpha and beta polypeptide chains of the MHC
  class II molecule.

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The Role of MHC
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MHC class I molecules present antigen to CD8 T
cells
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MHC class II molecules present antigen to CD4 T
cells
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T cells
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Antibody
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Humoral Immunity
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Antibody dependent cellular cytotoxicity or ADCC
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Antibody
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Antibody

• Neutralization antibody
• Other antibody

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Passive Immunity

• A high titer of antibody against a specific virus
• A pooled sample from plasma donors that contains
  a heterogeneous mixture of antibodies with lower
  titer