Mechanisms of Infection and Spread in the Body

1.            Pathogenesis in the infected patient involves:

a.            Transmission of the virus and its entry into the host.

b.            Replication of the virus and damage to cells.

c.         Spread of the virus to other cells and organs.

d.         The immune response, both as a host defense and as a contributing cause of certain diseases.

e.            Persistence of the virus in some instances.

2.            Transmission

a.         Viruses are transmitted to the individual by many different routes.

b.         Person-to-person spread occurs by transfer of respiratory secretions, saliva, blood, or semen and by fecal contamination of water of food.

c.            Transmission can also occur between mother and offspring in utero across the placenta, at the time of delivery, or during breast feeding.

d.         Animal-to-human transmission can take place either directly from a bite of a reservoir host as in rabies or indirectly through the bite of an insect vector, such as a mosquito.

e.            Activation of a latent, nonreplicating virus to form an active, replicating virus can occur within the individual, with no transmission from an external source.

3.         Routes of Entry

a.         To infect its host, a virus must first attach to and infect cells of one of the body surfaces, unless they are bypassed by parenteral inoculation via a wound, needle, or bite of an arthropod or vertebrate.

b.         Skin:

i.          the outer surface proper, the skin, has a relatively impermeable, dry, outer layer of dead cells.

ii.          as such, it provides a tough and impermeable barrier to the entry of viruses.

iii.            however, after entry through minor abrasions or by artificial puncture, some viruses replicate in the skin to produce local lesions, for example, papillomaviruses and poxviruses.

iv.         the most efficient way by which viruses are introduced through the skin is via the bite of an arthropod vector, such as a mosquito, tick, or sandfly.

v.         viruses that are transmitted and replicate in arthropod vectors are called arboviruses.

vi.            introduction of a virus by skin penetration may be iatrogenic as a result of human intervention, such as transmission of hepatitis B and C viruses by contaminated needles or blood transfusion.

c.            Respiratory Tract:

i.            although lined by cells that are susceptible to infection by many viruses, the respiratory tract is ordinarily protected by effective cleansing mechanisms.

ii.          a mucus blanket and ciliated cells line the nasal cavity and most of the lower respiratory tract.

iii.         inhaled virus particles deposited on this surface are trapped in mucus, carried by ciliary action from the nasal cavity and airways to the pharynx, and then swallowed or coughed out.

iv.         all viruses that infect the host via the respiratory tract do so by attaching to specific receptors on epithelial cells.

d.         Viruses that initiate infection of Humans via the Respiratory Tract:

e.            Alimentary Tract:         

i.          many viruses are acquired by ingestion.

ii.          they may either be swallowed or infect cells in the oropharynx and then be carried to the intestinal tract.

iii.         the virus is rarely infected, because of its tough stratified squamous epithelium and the rapid passage of swallowed material over its surface.

iv.         the intestinal tract is partially protected by mucus, which may contain IgA, but the constant movement of the contents provide opportunities for virions to attach to specific receptors.

v.         virions may also be taken up by specialized M cells that overlie Peyer’s patches in the ileum, from which they are passed to adjacent mononuclear cells in which they may replicate.

vi.         from the stomach downward, acid, bile, and proteolytic enzymes may inactivate viruses.

f.          List of viruses that initiate infection of Humans via Alimentary Tract:

g.            Urogenital Tract:

i.          the urogenital tract, where urine and sexual products are secreted and released into the environment, constitutes another discontinuity in the protective covering of the skin.

ii.          it is the route of entry of many important pathogens such as herpes simplex viruses, HIV and hepatitis B and C.

h.            Conjunctiva:

i.          in the eye the skin is replaced by a transparent layer of living cells to form the conjunctiva.

ii.          it is constantly cleansed by the flow of tears and is wiped by the eyelids.

iii.         it is a rare route of entry for some adenoviruses and a few enteroviruses.

I.          Viruses that initiate infection of Humans via Skin, Genital tract, or Eye:

4.            Mechanisms of Spread in the Body

a.         Viral infections are either localized to the portal of entry or spread systemically through the body.

b.            Localized infection: influenza is localized primarily to the upper and lower respiratory tracts.

c.            Systemic viral infection:

i.          after poliovirus is ingested, it infects the cells of the small intestine and then spreads to the mesenteric lymph nodes, where it multiplies again.

ii.          it then enters the bloodstream and is transmitted to the central nervous system, where damage to the anterior horn cells occurs, resulting in characteristic muscle paralysis.

d.         Local spread on Epithelial surfaces:

i.          many viruses replicate in epithelia cells at the site of entry, produce a localized or spreading infection in the epithelium, and are then shed directly into the environment.

ii.            infection within the host spreads by sequential infection of neighboring cells – papillomaviruses initiate infection in the basal layer of the epidermis, but maturation of virions occurs only in keratinized cells (long incubation period).

iii.         viruses that enter the body via the intestinal or respiratory tract can spread readily in the layer of fluid that can transport virions over the most epithelial surfaces (shorter incubation period).

iv.            restriction of infection to an epithelial surface cannot be equated with lack of severity of clinical disease – large areas of intestinal epithelium may be damaged by rotaviruses, causing severe diarrhea.

e.            Subepithelial invasion and Lymphatic spread:

i.          after traversing the epithelium to reach the subepithelial tissues, virions are exposed to tissue macrophages and can enter the lymphatics that form a network beneath the skin and all mucosal epithelia.

ii.          virions that enter lymphatics are carried to local lymph nodes; as they enter, they are exposed to macrophages lining marginal sinuses and may be engulfed.

iii.         virions may be inactivated and processed and their component antigens presented by macrophages and dendritic cells to adjacent lymphocytes in such a way that an immune response is initiated.

iv.         some viruses replicate in cells of the monocyte/macrophage lineage; others infect lymphocytes.

v.         some virions may pass through lymph nodes to enter the bloodstream.

vi.         there is often a local inflammatory response, the extent of which depends on the extent of tissue damage.

f.          Spread by Bloodstream: Viremia:

i.          the blood is the most effective and rapid vehicle for the spread of virus through the body.

ii.          once a virus has reached the bloodstream, usually via the lymphatic system, it can localize in any part of the body within minutes.

iii.         the first entry of virus into the blood is called primary viremia – it is clinically silent and is known to have taken place only because of the invasion of distant organs.

iv.         further replication in these sites leads to the sustained liberation of much high concentrations of virus, producing a secondary viremia, which can in turn lead to the establishment of infection in other parts of the body.

v.         in the blood, virions may be free in the plasma or may be associated with leukocytes, platelets or erythrocytes.

vi.         viruses carried in leukocytes are not cleared as readily as viruses circulating free in the plasma; being protected from antibodies and other plasma components they can be carried to distant tissues.

vii.            macrophages and vascular endothelial cells play a special role in determining the viruses’ subsequent fate in the plasma.

g.         Types of interactions between Viruses and Macrophages:

i.            macrophages may fail to phagocytose virions; in Venezuelan equine encephalitis virus infection this is an important factor favoring prolonged viremia.

ii.          virions may be phagocytosed and destroyed; because the macrophage system is so efficient, viremia with such viruses can be maintained only if virions enter the blood as fast as they are removed.

iii.         virions may be phagocytosed and then passively transferred to adjacent cells (hepatocytes in the liver) – if the virus replicate in these cells, as in hepatitis B virus, it can cause clinical hepatitis.

iv.         virions may be phagocytosed by macrophages and then replicate in them.

v.         in yellow fever, virus replicates in both macrophages and hepatic cells, producing severe hepatitis.

h.         Role of Vascular Endothelial cells:

i.          the vascular endothelium with its basement membrane and tight cell junctions constitutes the blood-tissue interface and a barrier for viruses.

ii.            parenchymal invasion by circulating virions depends on localization in the endothelial cells of capillaries and venules, where blood flow is slowest and the barrier the thinnest.

iii.         virions may move passively between or through endothelial cells and basement membrane, or they may infect endothelial cells and ‘grow’ through this barrier.

I.            Maintenance of Viremia:

i.            because virions circulating in the blood are continuously removed by macrophages, viremia can be maintained only if there is a continuing introduction of virus into the blood from infected tissues, or impairment of macrophages.

ii.            circulating leukocytes constitute a site for viral replication.

iii.         viremia is usually maintained by infection of the parenchymal cells of organs – liver, spleen, lymph nodes and bone marrow and partly by infection of endothelial cells.

iv.         striated and smooth muscle cells may be an important site of replication of some enteroviruses, togaviruses, and rhabovirsues.

5.            Invasion by of Skin

a.         As well as being the site of initial infection, the skin may be invaded via the bloodstream, producing erythema and often a generalized rash.

b.         The individual lesions in generalizing rashes described as macules, papules, vesicles, or pustules.

c.         A lasting local dilation of subpapillary dermal blood vessels produces a macule, which becomes a papule if there is also edema and infiltration of cells in the area.

d.         Primary involvement of the epidermis or separation of epidermis from dermis by fluid pressure results in vesiculation.

e.         Erosion or sloughing of the epithelium results in ulceration and scabbing, but prior to ulceration a vesicle may be converted to a pustule by polymorphonuclear cell infiltration.

f.          More severe involvement of the dermal vessels may lead to petechial or hemorrhagic rashes, although coagulation defects and thrombocytopenia may also be important in the genesis of such lesions.

6.            Invasion of the Central Nervous system

a.         Viruses can spread from the blood to the brain either:

i.          after localizing in blood vessels in meninges and choroid plexus, with invasion of the neurons then occurring from the cerebrospinal fluid, or

ii.          more directly after localizing in blood vessels of the brain and spinal cord.

b.         Most viruses that invade the central nervous system cross the vessels that constitute the blood-brain barrier.

c.         Spread of virus:

i.          some viruses infect the vascular endothelial cells prior to infection of vessels.

ii.          others appeared to be transported across the capillary walls without endothelial cell infection.

iii.            subsequent spread in the central nervous system can take place via the cerebrospinal fluid or by sequential infection of neural cells.

iv.            enteroviruses which cause meningitis may traverse the blood-cerebrospinal fluid junction in the meninges or may grow in the epithelium of the choroid plexus – in such cases virions are found in the cerebrospinal fluid.

d.         The most important route of infection of the central nervous system is via the peripheral nerves, as in rabies, varicella, and herpes simplex.

e.         Viruses may pass either:

i.            centripetally from the body surface to the sensory ganglia or

ii.            centrifugally from the ganglia to the skin, as in the reactivation of herpes simplex or varicella (as zoster).

f.          Lytic infections of neurons are characterized by marks of encephalitis:

i.            neuronal necrosis.

ii.            phagocytosis of neurons by phagocytic cells.

iii.            perivascular infiltration of mononuclear cells.

7.            Infection of the Fetus

a.         Most viral infections of the mother have no harmful effect on the virus, but some blood-borne viruses cross the placenta to reach the fetal circulation, sometimes after establishing foci of infection in the placenta.

b.         Severe cytolytic infections of the fetus cause fetal death and abortion, as in smallpox.

c.            Maternal rubella contracted in the early months of pregnancy often leads to congenital abnormalities in the baby – deafness, blindness, and congenital heart and brain defects.

d.            Cytomegalic inclusion of disease of the newborn results from infection acquired congenitally from mothers suffering an inapparent cytomegalovirus infection during pregnancy – hepatosplenomegaly, hepatitis, jaundice, mental retardation.

e.         Some congenital Viral infections:

8.         Virus Shedding

a.            Shedding of infectious virions is crucial to the maintenance of infection in populations.

b.         Exit usually occurs from one of the body openings or surfaces that are involved in the entry of viruses.

c.         With localized infections the same body openings are involved in both entry and exit.

d.         In generalized infections a greater variety of modes of shedding is recognized, and some viruses are shed from multiple sites – hepatitis B virus, HIV in semen, cervical secretions, milk and saliva.

e.            Concentration of virus:

i.          the amount of virus shed in an excretion or secretion is important in relation to transmission.

ii.          very low concentrations may be irrelevant unless very large volumes of infected material are transferred.

iii.         some viruses occur in such high concentrations that a minute quantity of material can transmit infection.

f.            Respiratory and Oropharyngeal secretions:

i.          many different viruses that cause localized disease of the respiratory tract are shed in mucus or saliva expelled from the respiratory tract during coughing, sneezing, and talking.

ii.          viruses are also shed from the respiratory tract in several systemic infections, such as measles, chickenpox, and rubella.

iii.         a few viruses, the herpesviruses, cytomegalovirus, and EB virus, are shed into the oral cavity, often from infected salivary glands, or from the lung or nasal mucosal, and are transmitted by salivary exchange in kissing.

g.         Feces:

i.          enteric viruses are shed in the feces, and the more voluminous the fluid output the greater is the environmental contamination they cause.

ii.          they are in general more resistant to inactivation by environmental conditions than are enveloped respiratory viruses, especially when suspended in water, and such viruses can persist for some time outside the body.

h.         Skin:

i.          the skin is an important source of virus in diseases in which transmission is by direct contact via small abrasions – warts, genital herpes.

ii.          several poxviruses may be spread from animals to humans by contact with skin lesions – coxpox, vaccinia.

iii.            although skin lesions are produced in several generalized diseases, virus is not shed from the maculopapular skin lesions of measles, nor from the rashes of flavivirus and picornavirus infections.

iv.         herpes virus infections produce vesicular lesions in which virus is plentiful in the fluid of the lesions.

I.          Urine:

i.          viruria is lifelong in arenavirus infections of rodents and constitute the principal mode of contamination of the environment by these viruses.

ii.          a number of human viruses – mumps virus and cytomegaloviruses, replicate in tubular epithelial cells in the kidney and are shed in the urine.

j.          Milk: several species of viruses, e.g. cytomegalovirus, are excreted in milk, which may serve as a route of transmission to the newborn infant.

k.         Genital secretions:

i.          many viruses can be found in semen or vaginal secretions.

ii.          viruses shed from the genital tract depend on mucosal contact for successful transmission.

l.          Blood:

i.          viremia is a most important vehicle, not only of viral spread within host, but also for transmission between hosts.

ii.          blood is usual source from which arthropods acquire viruses by inserting their proboscis into a capillary, and blood may also be the route of transfer of viruses to the ovum or fetus.

m.        No Shedding:

i.          many sites of viral replication do not communicate with the outside world e.g. the brain and therefore the virus is not shed.

ii.          the stepwise augmentation of the virus by replication in cells located in internal organs may be an important prerequisite for shedding from another site, or for infection by blood-sucking arthropods.