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