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Infection and Immunity. What does a pathogen have to do?. Infect (infest) a host Reproduce (replicate) itself Ensure that its progeny are transmitted to another host. Mechanisms of Transmission.

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what does a pathogen have to do
What does a pathogen have to do?
  • Infect (infest) a host
  • Reproduce (replicate) itself
  • Ensure that its progeny are transmitted to another host
mechanisms of transmission
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
entry into the host
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.
entry into the host1
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
transmission patterns
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.
primary replication
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
localized infections
Localized Infections
  • Viruses Primary Replication
  • Rhinoviruses U.R.T.
  • Rotaviruses Intestinal epithelium
  • Papillomaviruses Epidermis
systemic infections
Systemic Infections

Virus Primary ReplicationSecondary Replication

Enteroviruses

Intestinal epithelium Lymphoid

tissues, C.N.S.

Herpesviruses

Oropharynx or Lymphoid cells,

G.U.tract C.N.S.

spread throughout the host
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
via the bloodstream
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
via the nervous system
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
cell tissue tropism
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.
secondary replication
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.
slide17

Localized Infections:

Virus:

Primary Replication:

Rhinoviruses

U.R.T.

Rotaviruses

Intestinal epithelium

Papillomaviruses

Epidermis

Systemic Infections:

Virus:

Primary Replication:

Secondary Replication:

Enteroviruses

Intestinal epithelium

Lymphoid tissues, C.N.S.

Herpesviruses

Oropharynx or G.U.tract

Lymphoid cells, C.N.S.

:

types of infection
Types of Infection
  • Inapparent infection( Subclinical infection) .
  • Apparent infection:
  • Acute infection
  • Persistent Infection

Chronic infections

Latent Infection

Slow virus infections

chronic infection
Chronic Infection
  • Virus can be continuously detected ; mild or no clinical symptoms may be evident.
latent infection
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

slow virus infection
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 .
overall fate of the cell
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
special cases
Special cases
  • Transformation-Integrated infection (Viruses and Tumor)
  • Apoptosis
types of viral infections at the cellular level
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

viral immunopathogenesis
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
persistence
Persistence

Long term persistence of virus results from two main mechanisms:

  • a) Regulation of lytic potential
  • b) Evasion of immune surveillance
slide34

Components of the Immune System

complement, interferon, TNF etc.

macrophages, neutrophils

NK cell

antibodies

T cells; other effectors cells

innate or nonspecific immunity1
Innate or Nonspecific Immunity
  • Anatomic andPhysiologic 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
slide37
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
interferon inducing agents
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
mechanism of action
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
  • Inhibition of viral and cellular protein synthesis occurs
diseases currently treated with ifn alpha and ifn beta
Diseases currently treated withIFN-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.
nature killer nk cell

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

macrophages
Macrophages
  • Macrophages filter ciral particles from blood
  • Macrophages inactivate opsonized virus particles
  • Macrophages present viral antigen to CD4 T cells
complement
Complement
  • Enhancing neutralization of Antibody
  • Enhancing phagocytosis of virus particles
  • Lysis
specific immunity

Specific immunity

Active/passive

overview of specific immunity
Overview of Specific immunity
  • specific recognition and selective elimination of foreign molecules.
  • Involves specificity, diversity, memory, and self/nonself recognition.
the role of mhc
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 anantigen presenting cell (APC).
the role of mhc1
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.
the role of mhc2
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.
the role of mhc3
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 termedclass 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.
antibody2
Antibody
  • Neutralization antibody
  • Other antibody
passive immunity
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