Infection And Immunity

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

Viruses may be transmitted in the following ways 

Direct transmission from person to person by contact The major means of transmission may be by droplet or aerosol infection (e.g., influenza, measles, smallpox); by the fecal-oral route (e.g., enteroviruses, rotaviruses, infectious hepatitis A); by sexual contact (e.g., hepatitis B, herpes simplex virus type 2, human immunodeficiency virus); by hand-mouth, hand-eye, or mouthmouth contact (e.g., herpes simplex, rhinovirus, Epstein-Barr virus); or by exchange of contaminated blood (e.g., hepatitis B, human immunodeficiency virus).

Transmission from animal to animal, with humans an accidental host. Spread may be by bite (rabies) or by droplet or aerosol infection from rodentcontaminated quarters (e.g., arenaviruses, hantaviruses).

Transmission by means of an arthropod vector e.g., arboviruses, now classified primarily as togaviruses, flaviviruses, and bunyaviruses.

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 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

Sites of virus entry

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  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  Viruses

 Rhinoviruses  Rotaviruses  Papillomaviruses

Primary Replication U.R.T. Intestinal epithelium 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.

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  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  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 

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  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.

: Localized Infections: Primary Replication: U.R.T. Intestinal epithelium

Virus: Rhinoviruses Rotaviruses Papillomavirus Epidermis es Systemic Infections: Virus: Enteroviruses Herpesviruses

Secondary Primary Replication: Replication: Lymphoid tissues, Intestinal epithelium C.N.S. Oropharynx or Lymphoid cells, C.N.S. G.U.tract

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

Measles

9-12d

HIV

1-10y

Types of Infection  Inapparent

infection( Subclinical

infection) .  Apparent infection: 



Acute infection Persistent Infection

Chronic infections Latent Infection Slow virus infections

Inapparent or subclinical infections occur when too few cells are infected to cause clinical symptoms. But, infections are major source of contagion and can result in sufficient antibody stimulation to cause immunity from further infections.

Acute infections occur when clinical manifestations of disease are observed for a short time (days to weeks) after a short incubation period. Infections have recoveries associated with elimination of the virus from the body. The infection is classified as localized or disseminated, depending on whether the virus has traveled from its site of implantation to its target organ. 。 Acute infections may lead to persistent or latent infections.

Viral Persistence Viral infections are usually self-limiting. Sometimes, however, the virus persists for long periods of time in the host. Longterm virus-host interaction may take several forms.

Chronic Infection  Virus

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

Chronic infections occur with a number of animal viruses, and the persistence in certain instances depends upon the age of the host when infected. Infants infected with hepatitis B virus frequently become persistently infected (chronic carriers); most carriers are asymptomatic. Animal studies have shown that in chronic infections the viral population often undergoes many genetic and antigenic changes

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

Herpesviruses typically produce latent infections. Herpes simplex viruses enter the sensory ganglia and persist in a noninfectious state that is not understood at the molecular level. There may be periodic reactivations during which lesions containing infectious virus appear at peripheral sites (e.g., fever blisters). Chickenpox virus (varicella-zoster) also becomes latent in sensory ganglia. Recurrences are rare and occur years later, usually following the distribution of a peripheral nerve. Other members of the herpesvirus family also establish latent infections, including cytomegalovirus and Epstein-Bart virus. All may be reactivated by immunosuppression. Consequently, reactivated herpesvirus infections may be a serious complication for persons receiving immunosuppressant therapy.

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 .

Spongiform encephalopathies are a group of chronic, progressive, fatal infections of the central nervous system caused by unconventional, transmissible agents called prion. The best example of this type of "slow virus" infection is Kuru and Bovine spongiform encephalopathy occurs in humans.

Overall fate of the cell 



The cell dies in cytocidal infections this may be acute (when infection is brief and selflimiting) 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 alternate between the two by way of latency and reactivation - Steady state infection

Special cases  Transformation-Integrated

(Viruses and Tumor)  Apoptosis

infection

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

Mechanisms of viral cytopathogenesis 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