PATH*3610 - Unit 5-6
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True or False: when Parenchymal cells (the functional cells of an organ) are lost, the adjacent surviving cells may undergo division to replace them
TRUE: → The extent of regeneration depends on the ability of that cell type to divide, the # of surviving cells, and whether or not there is a surviving connective tisssue “framework” to allow the normal tissue structure.
What are the three different type of cells in which their regenerative capacity ?
Labile cells, Stable cells, and Permanent cells
Describe labile cells
Normally divide actively through life, to replace cells which are normally lost.
have short intermitotic (resting) phase
Familiar examples include the epithelial cells of the skin and mucosal surfaces
(e.g. those cells lining the gastrointestinal and respiratory tracts)
Hematopoietic cells of the bone marrow also fit the category (blood stem cells that develop into all types of blood cells, including red blood cells, white blood cells, and platelets.)
Injury to these tissues will be rapidly followed by regeneration
epithelial cells occur from the basal germinative layers, and from the bone marro stem cells in the case of the bone marrow
A prerequisite for refeneration is that a sufficient # of labile cells have survived the initial injury
Describe Stable Cells
Long lived and have a low rate of division
remain in intermitotic (resting) phase for years but can divide if necessary
E.g. parenchymal cells of solid organs → liver, kidney, and pancreas
((hepatocytes, renal tubular epithelial cells and pancreatic acinar cells, respectively)
→ also included fibroblasts and endothelial cells
Cells of organs, such as the liver can regenerate after necrosis → provided some cells have survived and there is the connective tissue framework to support the regeneration
Describe permanent cells
Can’t divide after fetal life.
Examples include nervous system (both central and peripheral cells), and cardiac muscle cells.
Injury to these cells can only heal by scarring of the tissue
The “functional” cells of these tissues cannot be replaced
extensive injusry to nervous or cardiac muscle tissue will thus lead to a functional deficit
What determines the rate of cell proliferation?
The primary motivators for cell replication are proteins called cyclins
interact with cyclin-dependent kinases within the nucleus → control the entry and progression of cells through the cell cycle
What are the variety of factors that modify the rate of cyclin activity?
A variety of external growth factors
include epidermal growth factors, platelet-derived growth factor, insulin-like growth factors, fibroblast growth factor, and interleukins.
A variety of systemic hormones also promote cell replication, including thyroid hormone and growth hormone.
These factors most commonly act through interactions with cell surface or nuclear surface antigens to indirectly upregulate cyclin activity
Cell proliferation is in part regulated by inhibitory signals and include those which normally regulate cell proliferation healthy cells
(including those involved in contact inhibition, which regulates cell proliferation in the context of the cells’ relationship with its neighbouring cells),
those that monitor cells for abnormalities and have a variety of effects, including impaired proliferation and induction of apoptosis.
What is the net rate of cell proliferation dependent on?
The ability to replicate, post mitotic cells and those that have reached a state of senescence, have previously proliferated to a point that they are no longer capable of replication.
The balance between proliferative and inhibitory signals (cyclin activity).
The balance between the rate of cell proliferation and cell loss secondary to apoptosis.
Describe Rotaviruses
Common cause of diarrhea in a variety of species, including humans
(not really that important I just thought to put it lol)
What exactly is scarring?
Defined as replacement of normal tissue by dense collagenous connective tissue after insult or injury,
it is the result of healing by fibrosis
Contrasts with regeneration as scarring results in local loss of normal tissue parenchymal cells and architecture
When does scarring occur?
When regeneration is not possible
Either because of injured cells are permenant cells; or because the injurious process caused sufficiently widespread necrosis to affect both the supportive connective tissue framework, and the labile or stable cell population
When an acute inflammatory process is not resolved, or there is ongoing tissue necrosis in chronic inflammation
True or false: When scarring develops, it involves several different processes that occur in steps.
FALSE: Although they’re separated into different categories, in reality they are to some degree occuring concurrently
Describe Inflammation and debridement
Scarring development
Immediately following an injury
hemostatic lug forms, allowing a scaffold for inflammatory cells, especially neutrophills, to migrate to the area
neutrophills release lysosomal enzymes which liquefy the debris → can be more readily removed by lymphatics and macrophages
Next phase occurs with the flux of M1 and M2 macrophages.
remove debris, which include inflammatory exudate, blood, nectrotic tissue) or debride the area
The cleanup which allows scar formation to occur
Debridement → the medical removal of dead, damaged, or infected tissue from a wound to promote healing —> may occur naturally via macrophages or if the inflammation is extensive surgically, in each case there is loss of tissue and little regeneration. Note that debridement also occurs with resolution and regeneration but to a lesser degree.
Describe granulation tissue formation
Scarring development
an important component of scar formation
acting to fill the injured area until more mature scar tissue can develop
Granulation tissue is highly vascular immature connective tissue
consists of proliferating fibroblasts, newly formed capillaries, and some inflammatory cells
It appears as pink, soft, and “granular” because of the many new capillaries
Granulation tissue formation is the result of two concurrent processes → angiogenesis and the migration and proliferation of fibroblasts
Describe Angiogenesis
Scarring development
The formation of new blood vessels occur
newly formed vessels are ‘leaky’ which contributes to the edema of healing wounds
a variety of growth factors stimulate both fibroblasts and endothelial cells; integrins (structural proteins in the extracellular matrix) also influence vessel growth.
Describe collagenization
Scarring development
the process by which collagen is laid down in the area
collagen is synthesized by fibroblasts, via the production of the precursor, procollagen.
collagen is an insoluble fibrillary (consisting of fibrils or strands) protein
gives much of the tensile strength to scar tissue
Describe maturation
Scarring development
the process by which granulation tissue is gradually replaced by mature connective tissue
content of collagen increases as the number of capillaries and inflammatory cells decreases
a mature scar is a poorly cellular mass of collagen
strength of scar increases as amount of collagen increases, as the type of collagen changes from type III to type I, and there is increased cross-linked between collagen molecules
scar tissue is not as strong as the initial tissue.
contraction of the scar occurs as it matures, decreasing its size.
actomyosin filaments in certain fibroblasts (myofibroblasts) cause early contraction
later contraction is due to increased presence of collagen
Describe Abrasions
Commonly called a “graze” or “scrape” - when epidermal cells of the skin are removed, the mildest form of skin injury. This is the type of injury that occurs when you fall on cement or asphalt and “skin” your knee; mechanical force is involved. As the basal layers of epidermal cells are not affected, regeneration occurs from below the abrasion.
Describe Lacerations
The result of tearing of tissues, especially over bony surfaces. They affect both the epidermis and dermis.
Describe Incision
The cutting of tissues by a sharp-edged object. As with a laceration, both the epidermis and dermis are affected. Both lacerations and cuts cause minimal loss of basal epidermal (germinative) cells so healing generally occurs without loss of tissue.
Describe contusions
A bruise produced by blunt trauma; there is blood vessel damage and hemorrhage into tissue.
Describe Avulsion
The tearing away of a part due to severe trauma.
Describe Crush injuries, burns and large lacerations
All cause extensive loss of the epidermis.
Describe a puncture wound, or a “stab”
The result of penetration by an object, usually of relatively small diameter, into the skin or other tissues. Such penetrating wounds cause deep injury to tissues. Perforating wounds go right through the tissue, so both entry and exit wounds are present.
What is a scab?
Reddish-brown, that develops over a wound
composed of clotted blood and some inflammatory cells.
acts as a “bandage” to protect the wound from infectious agents
in small wounds, which are healing by first intention, the epidermal cells rapidly grow under the scab to re-establish the integrity of the skin
scab will separate when the new epidermis matures and starts shedding its superficial keratinized layers.
Describe Healing by first intention
SCABS!
It is important that wound edges are approximated, brought close together, to allow healing by first intention. This is usually accomplished surgically in large wounds by using sutures or ’stitches’, in smaller wounds with tissue glue or adhesive sutures.
The benefits of healing by first intention are that healing occurs more quickly and scarring is minimized. Sutures are commonly removed after 7-10 days. Although at this time the tissue has not regained all of its normal strength if the sutures are left longer the risk of wound infection and scarring is increased.
Describe healing by second intention:
Is necessarily slower than healing by first intention, as the defect which must be healed is much larger, as would occur with lacerations or cuts which are not sutured, and any wound causing a large epidermal defect.
granulation tissue (proliferating capillaries and fibroblasts), is important in healing both by first and second intention
however, it is less prominent in healing by first intention than it is in second
covered by regenerating epidermis much earlier
KELOID formation, consisting of abnormal nodular masses of collagen, can result from even minor skin wounds.
keloid formation demonstrates a familial tendency
Ultimately, many factors can influence the extent and effectiveness of wound healing. These include:
Nutritional factors – vitamin C, protein or zinc deficiency may lead to defective collagen synthesis.
Drugs – patients on corticosteroids (often used to suppress immune-mediated diseases) will show delayed wound healing.
Foreign material – material such as fragments of wood, dirt etc. in wounds, as well as the presence of necrotic tissue or large clots will delay the rate of healing. The presence of foreign material in tissue will lead to chronic inflammation.
Blood supply – if blood supply to the area is compromised, healing will be delayed. This can occur in diabetes mellitus, due to the presence of microvascular disease that impairs blood flow to tissues.
Age – advanced age may lead to less effective wound healing.
The size and shape of the wound, the nature of the injured tissue, the degree of immobilization, as well as the presence of infection are all factors which will also influence the rate of healing.
Describe the order of increasing structural complexity
In order of increasing…
prion viruses (agent causing mad cow)
the intraceullular bacteria (rickettsia and chlamydia)
the mycoplasma (‘simple’ form of bacteria
the bacteria, fungi, protozoa,
and then finally the metazoa
How can viruses be classified?
RNA or DNA based viruses
based on the type of nucleic acid in their genomes
How can bacteria be classified?
classified by shape → cocci, rods (bacilli), and spirochetes
By their reaction on gram staining (Gram-positive or Gram-negative)
by their oxygen requirement for growth (aerobic or anerobic)
How can fungi be classified
Can be classified as either yeasts or molds, or as dimorphic
Describe the basis of the site of multiplication of various organisms
viruses are obligate intracellular organisms
as are prions and two types of bacteria → (rickettsiae and chlamydiae)
require host cells to grow and mulitply, using the hosts’ metabolic machinery for growth
tend to infect parenchymal cells
culture of such organisms thus requires living cell systems, such as tissue cel culture or embryonated eggs
Extracellular organisms can multiply outside of cells - these include most of the other pathogens
can be cultured on artificial media (with the exception of protozoa and metazoa)
Facultative intracellular organisms (such as mycobacteria and some fungi) can grow both inside (usually in macrophages) and outside of cells
can be cultured either on specialized artificial media or in cell culture
Describe infectivity and pathogenicity
Infectivity refers to the ability of an organism to colonize tissues, whereas pathogenicity refers to the ability of an organism to cause disease. Pathogenic organisms can be classified as either low-grade or high-grade, on the basis of their ability to cause disease. Low-grade pathogens will only cause disease in immunocompromised hosts – these are termed opportunistic infections. High-grade pathogens (virulent pathogens) may cause disease even in healthy hosts.
How do organisms get passage into the body?
Most organisms gain entry to the body via natural passages, that is, any tissue of the body that is “exposed” to the external environment. These are termed the primary portals of entry. These portals are typically mucosal or epithelial barriers.
Organisms can also gain entry to the tissues via trauma and direct inoculation.
Other than by trauma, the tissues of internal organs such as the heart, bones, brain and muscles can only be infected via the blood
What are the four principal methods of the spread of infection?
Physical contact
Either direct or via fomites (intermediate objects, such as utensils, clothing, doorknobs, needles, external parasites, etc.)
Airborne infection
Transmission through the air via dust or droplets (an estimated 20,000 droplets – containing potential pathogens – can be expelled by one sneeze)
Food-borne infection
Contamination of food or water is a primary mode of spread of enteric disease
Insect-borne infection
Insects can transmit viral, bacterial, and protozoal disease
What are the results of an infection?
When a micro-organism invades a tissue, one of three things may happen:
The invader dies (most likely) due to the actions of both nonspecific defenses (including inflammation) and more specific immune responses.
The invader may survive without giving rise to obvious clinical disease but causing an immune response.
The invader survives, multiplies, and produces clinical disease.
Many factors will influence the outcome of host exposure to a pathogen; three primary components that may contribute are:
the pathogen itself, the host, and the environment.
The host and environment are often lumped together, as ultimately the effects of environmental conditions manifest as changes in the factors above (such as the effects of cold on the immune system, the effects of air quality on lung and mucus membrane defenses).
Questions include:
Pathogen
1. the virulence (the severity or harmfulness of a disease or poison.) of the pathogen
2. the dose of pathogen exposure
The host/Environment
1. the status of the primary defenses of the host (nonspecific protective mechanisms)
2. the immune status of the host (ability to mount an appropriate immune response, ability to recognize the pathogen from previous exposure)
True or False: infection does not necessarily imply disease
TRUE:
Some infections can remain latent for long periods.
When the infectious agent has led to the development of an immune response (i.e., the development of antibodies and/or cellular immunity) but disease is not clinically apparent, subclinical infection is said to occur.When the infectious agent has survived and multiplied in the host, producing tissue damage, then clinically apparent infectious disease occurs.
Once the organism has infected the host tissue, disease may result from both the effects of the organism on the host tissue and the effects of the host response to the organism (both the inflammatory response and the immune response).
Describe in general the impacts of infection in the blood stream:
The presence of micro-organisms in the blood is of clinical significance. Depending on the type of organism, this finding is termed viremia, bacteremia, fungemia or parasitemia (“-emia” meaning of the blood).
The first three conditions can be diagnosed using blood cultures and serology, but more commonly molecular techniques such as PCR (polymerase chain reaction), ELIZA (enzyme-linked immunosorbent assay), DNA fingerprinting and proteomics are used.
Whereas parasitemia is typically diagnosed by identifying the parasite in blood smears. In the blood, organisms may be carried free in the plasma, or attached to or within blood cells or leukocytes, however some organisms are difficult to find on a smear, as a result PCR, ELIZA or serologic tests may be needed.
Describe Bacteremia:
Refers to the presence of viable bacteria within the bloodstream, and ranges from transient bacteremia (such as you get from brushing your teeth),
in which the body removes small numbers of bacteria in the bloodstream, preventing their multiplication, to severe bacteremia where large numbers of bacteria in the bloodstream are capable of overwhelming the body’s defenses.
Transient bacteremia may be of significance in immunocompromised hosts, and in those with chronic cardiac valve disease or with valve prostheses (the bacteria may grow in the damaged valves).
Describe toxemia:
refers to the presence of toxins produced by bacteria within the bloodstream
Describe sepsis/septicemia:
refers to the disease state that arises from the presence of bacteria, or their toxic byproducts, within the bloodstream,
resulting in a clinical syndrome characterized by fever, vasodilation and decreased blood pressure. In these cases, the subsequent shock and DIC may result in death.
What general structure do viruses commonly share?
A central core of nucleic acids that encode the genome of the virus. In a proportion of viruses, this genome is encoded with DNA; the remainder are encoded with RNA.
A well-structured protein coat or capsid,
An outer lipid envelope, only found in a limited proportion of viruses
The host cell supplies the energy, substrates and synthetic machinery for viral growth. The viral life cycle can be summarized as:The virus must find susceptible cells, with appropriate receptors on their cell membranes which are “recognized” by proteins on the virus surface (ligands)
the virus binds to receptors on the cell via viral surface ligands
the virus penetrates the cell – fusion to cell membrane, receptor –mediated endocytosis, or translocation of virus across cell membrane
virus is uncoated inside the cell; genome separates from structural elements
virus initiates cycle of nucleic acid transcription and translation, using specific enzymes
new viral proteins are synthesized and new viral genomes replicated
new virions are assembled and released directly (unencapsulated viruses), or by budding (encapsulated viruses)
Why do viruses only infect certain cell types?
The presence of appropriate cell receptors for the virus determines the organotropism of the virus – certain viruses preferentially affect specific parenchymal cells.
For example, the poliomyelitis virus has a tropism for the motor neurons of the central nervous system; the Hepatitis A virus has a tropism for cells of the liver. The clinical signs of different viral infections are the result of the type of cell infected and the type of cell injury resulting from the virus.
How do cells mediate the injury caused by viruses?
Viral-mediated cell necrosis
Viral-mediated cytopathic cell injury
Upon viral infection of a target cell, the virus may impair normal cell functions directly, resulting in sublethal or lethal cell injury, by several means:Cell lysis may occur during virus replication and release (as a means of dispersion of virions). Viral replication will often interfere with normal cell functions, resulting in cell death.
Inhibition of host cell DNA, RNA or protein synthesis functions, which may result in either subtle cell dysfunction or cell death (particularly when critical enzyme paths are involved).
Damage to cell membranes by direct insertion of viral proteins into the cell membrane, which can alter membrane function and/or integrity (resulting in cell swelling and/or lysis). Some viral proteins may promote fusion of neighbouring cells, resulting in formation of syncytial cells or giant cells.
As you will recall from Unit 01, apoptosis is a path by which cells may undergo programmed suicide when faced with loss of integrity. With some viral infections, host cells may undergo self-directed apoptosis as a mechanism to control viral infection and eliminate infected cells.
However, some viruses are noted to encode genes that are capable of impairing apoptosis, in such a way as to promote persistent viral infection (but in doing so favouring neoplastic transformation and the development of cancers).
Describe inclusion bodies
Inclusion body formation occurs in some viral infections. Inclusion bodies are formed during the process of viral replication and consist of either assembled viral particles or parts of viral nucleic acid synthesis.
Inclusion bodies can occur in the cytoplasm or the nucleus (or both), and useful diagnostically in the microscopic identification of specific viral infections. For instance, rabies virus infection produces characteristic eosinophilic inclusion bodies within the cytoplasm of infected neurons.
What are cytopathic viruses?
viruses that result in cell death!
Cell death may occur rapidly causing extensive necrosis of target cells. Good examples include the effects of influenza viruses on respiratory epithelium, yellow fever virus on hepatocytes, and polioviruses and rabies virus on neurons.
A good example of this type of virus is Ebola
a filovirus that has caused outbreaks of disease in Africa
particularily virulent and often leads to the death of the host
causes necrosis and preferentially affects endothelilal cells → resulting in widely-disseminated hemorrhage (and shock) and disseminated intravascular coagulation
a condition where the body's normal blood clotting process goes into overdrive, leading to the formation of small blood clots throughout the bloodstream
Filoviruses are filamentous, enveloped, RNA viruses that are highly cytopathic and generally result in cytolysis
What are persistent or chronic viral infections?
Some viruses result in slow and progressive cell death over a protracted period of time
Chronic viral hepatitis (B and C)
Describe Cirrhosis
Refers to the loss of normal lobular architecture of the liver as a result of necrosis followed by scarring fibrosis and nodular regeneration
it is the result of profound or chronic injury to the liver
may occur with chronic intoxication or viral injury and will lead to diminished liver function
Viral infection of a host may result in what? in terms of the antiviral immune response?
The expression of viral proteins on the surface of the host cell, which are recognized as foreign by CD8+ (cytotoxic) T-lymphocytes, inducing a cell-mediated immune response and cytolysis.
Similar to apoptosis, this is an important mechanism by which the body attempts to eliminate virally-infected cells; however, the host response may also result in significant cell death and associated illness.
The body also responds to virus infection by producing the glycoprotein cytokine Interferon (IFN). IFN is produced by CD4+ T-lymphocytes in the Th1 response.
Besides being a potent macrophage activator and enhancer of NK cell activity, IFN has antiviral effects. These antiviral effects are due to interference of viral translation. Interferon is also secreted by other cells (fibroblasts, macrophages) following exposure to a virus.
What does the lack of a neutrophil response signify?
Increased numbers of lymphocytes in tissues are suggestive of a response to a viral pathogen, rather than a bacterial pathogen. Additionally, the peripheral blood may show an increased number of lymphocytes (lymphocytosis), whereas neutrophils numbers are more often normal or decreased.
True or False: infection with some viruses may result in “tranformation” of those cells
TRUE!!
causes them to become immortal and to grow independently of growth-regulating signals, resulting in cancer.
EPV is a good example (Epstein-Barr Virus)
Describe Latent Viral infecitons
results when viral genes remain in surviving target cells for long periods, often for the life of the host, but are not expressed
may result in later reactivation, leading to disease later in life
more commonly associated with neoplastic transformation
HERPES! s a good example
large, double-stranded DNA viruses with a protein capsid and a lipid envelope
acquired when virions bud out from infected cell
What are some outcomes of a viral infection?
As one might predict, the outcome of viral infection varies quite dramatically with the severity of infection and the target cells affected. Acute cytolysis or necrosis of target cells with a particularly virulent virus may result in organ death or severe dysfunction (such as might be seen in the heart, brain, or liver).
The outcome of less severe infection is more likely to be survival, but the outcome (regeneration or scarring) varies as discussed in the unit od healing and repair. Recovery from viral infection is often associated with the development of an appropriate immune response that is capable of neutralizing the virus.
A major complication that may occur with viral infection is secondary bacterial infection; cell death or dysfunction results in impairment of important immune mechanisms, providing ‘fertile soil’ for other pathogens or opportunistic microorganisms to take root. For example, viruses that injure the epithelium of the upper airways can cause paralysis or loss of surface cilia, impairing normal ciliary clearance mechanisms and making the host more susceptible to secondary bacterial infections.
Describe Chlamydiae (there are also other terms to remember!)
obligate intracellular bacteria (reproduce inside cells)
The body also responds to these organisms in much the same way as it responds to viruses – the cellular response is typically mononuclear (lymphocytes, plasma cells, macrophages).
the major cause of non-gonococcal urethritis (inflammation of the urethra – recall that “-itis” refers to inflammation).
Chlamydial cervicitis (inflammation of the cervix) can lead to neonatal ophthalmia when an infant pass through the birth canal. It is purulent inflammation of the conjunctiva of the eyes of newborns and is also a major infectious cause of female sterility.
Trachoma, caused by a different serotype of C. trachomatis, is endemic in tropical countries, and on a worldwide basis, is the leading cause of blindness. A severe conjunctivitis leads to eventual scarring and opacification of the cornea.
Chlamydophilia psittaci is the causal agent of psittacosis, a zoonotic disease which can be passed from birds to man.
Avian species that can be affected include pigeons, chickens and turkeys, and various pet bird species, including finches and a variety of psittacines (budgies, parrots, etc. – the parrot family) – thus the name of the disease. The disease in birds varies greatly, ranging from outbreaks with high mortality to subclinical cases. Birds can act as a reservoir of infection for man, with transmission largely by infected droplets. Outbreaks of disease in man have led to many of the strict importation controls and quarantine requirements for psittacine birds.
In man, the organism causes an acute illness characterized by fever and flu-like symptoms, and interstitial pneumonia (similar to viral pneumonias), which causes a dry, non-productive cough. It is treatable with antibiotics, but severe cases can lead to death.
What are zoonotic diseases?
diseases which can be transmitted from animals to man
Describe the Rickettsiae
obligate intracellular bacteria (reproduce inside cells)
The rickettsiae require arthropod vectors for transmission; these include lice, ticks, and mites.
R. prowazeckii, the causal agent of typhus (spotted fever) is transmitted by the bites of fleas, ticks and lice, with the rat being the primary reservoir of infection. The organism injures the vascular endothelium, leading to thrombosis and hemorrhage (a hemorrhagic vasculitis). Through history typhus has been a major cause of epidemics in association with war and famine, as discussed in Hans Zinsser’s Rats, Lice and History. Other rickettsial diseases include Rocky Mountain spotted fever, and Q fever.
Describe facultative intracellular organisms
→ such as mycrobacteria and fungi
can also lead to disease, but the mechanisms by which these organisms cause cell damage are not well understood.
Probably the host response to these organisms, both the inflammatory and the immune response, leads to much of the tissue injury seen in such diseases as M. leprae (discussed in Inflammation).
Many mycobacteria (such as M. tuberculosis) and some fungi can remain asymptomatic and dormant in tissue macrophages, due to the organisms being controlled by the immune system. Immune suppression will lead to reactivation of these infections, similar to the reactivation of latent viral infections.
Describe Prions
A group of obligate intracellular pathogens (reproduce inside cells)
Differ from viruses as they lack nucleic acid.
Prions are the causal agents of a variety of spongiform encephalopathies, recognized in both man and several other mammals.
The term ‘spongiform’ refers to the characteristic vacuolar degeneration seen in the brain
Disease may be sporadic, inherited, or transmitted
Examples of these “slow” neurologic diseases include scrapie of sheep, BSE of cattle, chronic wasting disease (CWD) of elk and mule deer, and Kuru, both sporadic and ‘new-variant’ cases of Creutzfeldt-Jakob disease (CJD) and the inherited Gerstmann- Straussler syndrome (GSS) of man.
Prion associated diseases develop when normal prion protein (PrPc) undergoes a conformational change, to form an abnormal protein (PrPsc).
What can occur with the accumulation of these abnormal prion proteins?
it leads to dysfunction of the affected brain tissue and neuronal loss.
There is no inflammatory response to the organism. All of these diseases are slow, degenerative neurologic diseases, characterized by progressive loss of function ending in death.
Prions can be considered subviral transmissible agents, consisting of protein only. There is much yet to be learned about the mode of transmission.
Describe opportunistic bacteria
Under normal circumstances, normal flora is beneficial, but in certain situations, they can cause disease. They will behave in an “opportunistic” fashion if the host is immunosuppressed, or if they gain access to a part of the body where they are not normally resident.
Describe Antibacterial agents
Bacteria outside of a host can be killed by a variety of “antibacterial” agents, which exert their effect by either denaturing bacterial protein, or interfering with bacterial metabolism.
Bacteriostatic agents are those which inhibit the growth or multiplication of bacteria.
Bactericidal agents are those that kill bacteria.
A broad-spectrum antibiotic is one which is effective against a wide variety of bacteria. The indiscriminate use of broad spectrum antibiotics has the undesired effect of also killing many desired, commensal bacteria.
Finally, once a course of antibiotics is begun, it should be continued for the full period which will depend on the bacteria and disease process. If therapy is stopped earlier, the surviving (more resistant) organisms may lead to the growth of larger numbers of similarly resistant organisms, which will subsequently be more difficult to treat.
Describe how antibiotics can be used and missused
Within the body, it is more difficult to kill bacteria, as many agents toxic to bacteria are also toxic to host cells. Antibiotics are substances that were initially prepared from fungi. They were found to have specific activity against certain bacteria, either inhibiting their growth or killing them. The first antibiotic to be derived from fungi was penicillin (from the fungus Penicillium notatum). Many modern “second and third generation” antibiotics have been synthetically derived.
The development of antibiotic-resistant strains of bacteria is a major problem of modern medicine.
Because of their mode of reproduction and their ability to multiply extremely rapidly, bacteria have an enormous capacity to mutate and adapt to change.
Through the use of antibiotics for purposes such as promoting weight gain in livestock, or the use of antibiotics in treating “nonspecific” diseases, we have selected bacterial strains which are resistant to many of the commonly used antibiotics. Additionally, genetic material that codes for resistance, plasmids can be transferred between bacteria. These resistant strains are becoming increasingly difficult to treat and are a particular problem in hospital acquired infection or “nosocomial infections”.
When using an antibiotic, it is of the utmost importance to ensure that, firstly, the disease being treated is of bacterial origin. A great many of the sore throats, colds and similar complaints which physicians see on a daily basis are of viral origin, and antibiotics are not indicated. Secondly, once the disease has been identified as bacterial in origin (preferable by culture), the sensitivity of the organism to specific antibiotics should be determined. This ensures that the appropriate antibiotic is used as not all organisms are sensitive to all antibiotics; it is preferable to use the antibiotic that is most specific for the particular organism.
What does bacteria virulence depend on?
adhering and colonizing host cells
invading the cell to release locally acting as well as remotely acting toxins- endotoxins, exotoxins, enterotoxins
the production of local vasculitis
The extent and severity of tissue injury caused by bacteria depends on their ability to attach to and enter host cells or to produce toxins. The bacterial genes that encode adherence proteins and toxins are often coregulated by specific environmental conditions. Gram positive cocci also have fibrillar surface ‘M’ proteins, which prevent phagocytosis by macrophages.
Facultative intracellular bacteria have a restricted tropism, to infect epithelial cells and/or macrophages; they generally bind to host cell plasma membrane integrins or extracellular matrix proteins (e.g. fibronectin, collagen).
What are some bacterial virulence factors?
Bacteria have a number of defenses that increase virulence, a few of these are plasmids, bacteriophages, biofilms (commonly found on urinary and intravenous catheters) and quorum sensing.
Describe Bacterial Adhesins
Surface-attached molecules on bacteria that enable them to adhere to host cells or other surfaces,
Mycoplasmas spp. are unique extracellular bacteria that are epitheliotropic or hemotropic, and lack a cell wall, as a result they can evade the immune system. There are several pathogenic species that can cause a wide variety of disease such as pneumonia, infertility, abortion to name a few.
Mycoplasma hemofelis (hemo - blood, felis - cat) is an example of one of these organisms in cats. The bacteria become parasitic and lives adhered to the erythrocyte by a P1 membrane associated protein. As the bacteria multiply, changes occur in the red blood cell that cause macrophages in the spleen to phagocytose and destroy the red blood cell and hence the bacteria (an example of the immune system at work!). This can cause severe anemia and eventually death.
Describe Bacterial Endotoxins
Endotoxins are the lipopolysaccharide (LPS) component of the cell walls of Gram-negative bacteria, and are released into the blood of the host following death and lysis of bacterial. Response to LPS can be beneficial, as it activates protective immunity through the release of cytokines and chemokines activating T –lymphocytes.
But LPS can induce excessive levels of cytokines (a broad category of small proteins that act as signaling molecules in cell communication) such as TNF and result in disease. They exert their effects on small blood vessels, causing:
Generalized peripheral vasodilation, progressing to shock;
Endothelial injury and activation of the coagulation cascade, leading to DIC and acute respiratory distress syndrome; and
Massive cytokine release (including interleukin-1 from macrophages), producing a systemic acute phase response and fever.
Some of these highly virulent bacteria can invade tissue and cause a local vasculitis resulting in thrombosis of small blood vessels (leading to ischemic necrosis of the area around the infection). Toxins produced by the bacteria may also cause vascular injury.
Describe Bacterial Exotoxins
Exotoxins are secreted proteins that directly cause cell injury. These can be subdivided into local acting and remotely acting exotoxins
Locally-acting exotoxins
These are typically enzymes (such as coagulase and proteases) that are secreted into their immediate environment. These enzymes have a role in breaking down complex food materials into smaller, more assimilable units (amino acids, peptides, etc.) to be used for bacterial metabolism. These enzymes are also useful for tissue invasion; in a host, these enzymes can cause local tissue injury and permit deeper entry into the host.Staphylococcus aureus → produces the enzyme coagulase, which converts fibrinogen to fibrin.
Coagulase production is correlated with pathogenicity, with coagulase- negative staphylococci (such as S. epidermidis) having low virulence. Coagulase is believed to cause the bacterium to become coated with a layer of fibrin, which helps it resist phagocytosis.
The staphylococci tend to form pus in tissues (perhaps due to this ability to resist phagocytosis), causing a wide range of lesions (pimples, boils, styes, wound infections, osteomyelitis). It is an important cause of secondary bacterial pneumonia, following primary viral respiratory illness.
Clostridium perfringens, a Gram-positive anaerobe, is widely found in the soil and in the intestinal tract of both man and nearly all warm-blooded animals. After death, with release from the intestinal tract it frequently invades tissues, causing bloating of cadavers. It is the most frequent isolate from cases of gas gangrene in man.
Remotely-acting exotoxins
These are secreted by living bacteria, absorbed into the bloodstream, and often mediate their effects at distant sites in the body. They are highly-antigenic proteins and will induce the formation of specific antibodies (termed antitoxins). Because of their protein nature, they are heat-labile, and can be destroyed by cooking – this can be useful knowledge, as many exotoxins are the causes of food poisoning.
Toxic Shock syndrome → prolifferation of staphylococci aureus in vagina
Necrotizing Fasciitis → flesh-eating disease Caused by virulent strains of group A streptococci, which secretes an exotoxin, NF causes a rapidly advancing necrotizing process which spreads in the subcutaneous tissues and may extend to deep fascia. Fascia refers to the meshwork of connective tissue which lies subcutaneously and which separates muscles; hence the name necrotizing fasciitis. Thrombosis of vessels and secondary cutaneous gangrene also occur.
Tetanus → is a Gram-positive anaerobe. The C. tetani bacillus can survive for long periods as spores. Tetanus is usually acquired by contamination of wounds. C. tetani produces an exotoxin, tetanospasmin, which travels along nerves from the wound to the spinal cord.
Botulism - disease is acquired by ingesting the pre- formed toxin, which is one of the most potent known toxins.
Clostridium botulinum is an anaerobic bacillus with highly resistant spores, which is found primarily in the soil; it also is found in the intestine of domestic mammals. It is of concern as a cause of food poisoning, as it will grow in a variety of foods (preserved meats, canned goods), if the temperature employed in canning is insufficiently high to kill the spores.
Describe Bacterial Enterotoxins
exotoxins that exert their effect on intestinal mucosal cells (termed enterocytes). They are produced by bacteria during multiplication, either within the gut lumen (e.g., Vibrio cholerae, certain E. coli strains), or in foods (e.g., Staphylococcus aureus) that are then eaten.
attach to gut mucosal cell receptors, causing either structural damage or functional alteration (increased fluid secretion by intestinal epithelial cells). Enterotoxins thus variably cause diarrhea (sometimes hemorrhagic), cramping, and abdominal pain.
Cholera → caused by Vibrio cholerae, which secretes an enterotoxin. This enterotoxin leads to isosmotic fluid secretion by the intestinal epithelial cells (through increased cAMP generation). Voluminous diarrhea leads to extensive loss of water and electrolytes; death can result from dehydration, electrolyte imbalance, and shock. The provision of a clean water supply is of great importance in preventing cholera.
Hamburger disease → acquired through the consumption of improperly cooked ground beef. The organism is carried in the intestine of cattle and can contaminate the carcass at the time of slaughter. It can also be acquired from a variety of other food sources, such as milk products or vegetables, if fecal contamination has occurred.
Describe food poisoning and the two different types of it
Acute gastroenteritis (causing severe vomiting and diarrhea) caused by the action of bacterial toxins, due to bacterial contamination of food or drink. Food poisoning can be caused by a variety of different bacterial organisms.
Infection type
Bacteria in the contaminated food multiply, and produce their toxins in the bowel (e.g., Traveler’s diarrhea, caused by E. coli; Salmonella sp.)
Signs appear 12-24 hours following ingestion of contaminated food
Toxin type
Bacteria in the food produce toxins, which are then ingested. Signs appear earlier (2-6 hours).
The classic example is staphylococcal food poisoning, when food contaminated during preparation (Staphylococci spp are commonly found on the skin) is stored at temperatures that allow bacterial multiplication and toxin production.
Describe Supperative inflammation in terms of the body’s response to bacterial infections
Acute inflammation (with pain, redness, heat and swelling, as well as the systemic fever response) accompanies many acute bacterial infections.
There is increased vascular permeability, and the cell response is characterized by the presence of large numbers of neutrophils.
There may also be an increased number of neutrophils in the blood. The neutrophils are attracted by chemotactic factors, many released by the bacteria at the site of infection.
Suppurative inflammation (both acute and chronic) is thus characteristic of many bacterial infections – there is liquefactive necrosis and the formation of pus. Abscesses may form. (Refer back to the unit on inflammation to review abscess formation). The ‘pyogenic’ bacteria evoke this response (mostly extra-cellular Gram-positive-cocci, and Gram-negative rods). Suppuration is particularly likely to occur when anatomical factors inhibit drainage and the resolution of acute inflammation.
Describe Koch’s Postulates
criteria necessary to establish an etiologic associated between the presence of a microorganism and the presence of disease
A causal organism can be found in disease lesions.
The organism can be grown and isolated in culture.
Secondary inoculation of the purified organism from culture causes the same lesions in experimental animals.
The organism can be recovered from the experimental animal.
True or False: Many fungal infections are caused by opportunistic invaders that can either become systemic or spread locally
TRUE!
Given the correct conditions, normal flora such as Candida spp can also cause systemic disease.
What are systemic fungal diseases?
those that affect the “deeper” tissues such as histoplasmosis, coccidioidomycosis, and blastomycosis
The fungal spores come from soil, plant material, bird droppings, etc.
Systemic fungal diseases are a particular problem in immunosuppressed individuals, such as AIDS patients, and in patients treated with immuno-suppressive drugs (i.e., cancer patients, transplant patients, or patients with immune-mediated diseases).
Many fungal infections can thus be considered opportunistic infections.
What can fungi exist as?
In hosts both as single cell forms (yeasts), being either intracellular or extracellular, or as hyphae (long filaments).
Yeasts are microscopic; hyphae may also be identified microscopically in tissues. Special stains will improve the visibility of fungi in tissue sections. If hyphae form large enough colonies (mycelia) in or on tissues, they may be grossly apparent.
What does fungi growth require?
high humidity, warmth and oxygen; the requirement for warmth and humidity mean that fungal diseases are generally more prevalent in certain geographical regions, particularly in tropical climates.
True or False: Antibiotics have the misconception that they affect fungal infections when they don’t necessarily have any affect on them
FALSE (in a sense)
The use (and abuse) of antibiotics has led to an increased incidence of fungal infections because normal bacterial flora, which has a role in limiting fungal growth, is disrupted
Additionally, immunosuppressive therapy for transplantation and chemotherapy for cancer favours opportunistic fungal infections, by suppressing cell-mediated immunity. Fungal infections can be serious in AIDS patients for the same reason. Fungi cause tissue injury by inducing DTH hypersensitivity responses to fungal antigens. This hypersensitivity to fungal antigens is useful diagnostically.
Describe Superficial fungal diseases
These are likely better known to most people, as they are considerably more common and include such diseases as athlete’s foot, ringworm, and vaginal yeast infections.
Describe Dermatomycoses
The dermatomycoses are highly contagious (readily passed from person to person) and may be difficult to treat.
Factors favouring transmission include crowded living conditions and poor hygiene. Dermatomycoses are characterized by patchy, reddened, scaling lesions, typically affecting skin between the fingers and toes (“athletes foot”) or in the groin area; ring like lesions on the scalp causes patchy hair loss (hence ringworm).
Describe Candidiasis
Candida albicans is the fungus that most often causes disease.
Candida is often a commensal organism on the mucous membranes, found in sites such as the oral cavity, genitalia and gastrointestinal tract.
It is rarely a problem, but in certain situations, such as in immunosuppressed individuals, or following antibiotic therapy which has disturbed the normal bacteria,
Candida can overgrow, in other words it is an opportunistic bacterium. Although normally a superficial infection, Candida fungemia can sometimes occur; this is termed ‘invasive candidiasis’, with bloodborne organisms disseminating to various tissues. It is the most common nosocomial yeast infection in the intensive care unit.
What is the difference between the definitive host and the intermediate host
The definitive host is the host of the adult (mature, reproducing) form of the parasite. The intermediate host is the host of the immature form(s) of the parasite. Some parasites may have more than one intermediate host.
Describe Protozoa
On a global basis, protozoal parasites “dominate” as causes of infectious disease.
The protozoa are one-celled organisms, several of which are important pathogens in man.
They can be either intracellular or extracellular parasites. Much of the difficulty in treating protozoal infections stems from the variety of forms they can assume within their host.
Transmission is either via insect vectors (as with malaria and sleeping sickness) or by ingestion (i.e., of feces contaminated water or food – as with toxoplasmosis). We will discuss two of these diseases in more detail.
MALARIA!!!
the one of the greatest infectious public health problem in the world. It is caused by the protozoal parasite, Plasmodium. This organism uses both man and specific species of mosquitoes to complete its life cycle. Malaria is endemic in Asia and Africa. There are four species of Plasmodium that cause malaria: P. vivax, P. malariae, P. ovale, and P. falciparum.
TOXOPLASMOSIS!!!
Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii.
The definitive hosts of Toxoplasma are members of the cat family, including domestic cats.
Cats excrete oocysts in their feces, which mature and become infectious after 1 to 21 days.
Human and other animals are the intermediate host and infection can lead to disease in some individuals following ingestion of infectious oocysts from meat or soil contaminated by feces.
Sporulated oocysts are ingested, encyst in the small intestine and release sporozoites into the intestinal lumen where infects villus enterocytes.
. The organism affects the fetal brain and retina, leading to extensive necrosis with calcification and scarring. Death can occur in utero, or the fetus can be born with a variety of defects.
Describe Helminths
Multicellular parasites → the helminths include the nematodes, cestodes and trematodes.
They have well-defined life cycles with intermediate hosts and may infect many different animal species as well as man.
Man can act either as a natural or accidental host – in which case the parasite can progress through its life cycle, or as an aberrant host, in which case further development of the parasite in the host is blocked, and it dies. The term “accidental” refers to the parasite developing in a host that is not its usual host.
The type of disease which develops (pathology and symptomatology) will depend on the stage of the life cycle of an individual parasite and the organ affected; systemic signs may develop (fever, anemia) if the parasites invade the bloodstream or cause blood loss. In many parasitic infections the signs of disease may be minimal.
In general, these organisms do not behave as opportunistic pathogens
Nematodes!
no intermediate hosts are required for completion of nematode life cycles
Pinworm disease, trichinosis and filariasis are also caused by nematodes.
Pinworms are a common parasite of the intestine of children; the primary sign of infection is anal irritation and itching.
Trichinosis (characterized by an acute myositis, inflammation of the muscles, caused by the larval forms) is now quite rare, owing to improvements in the inspection of pork and changes in its handling and cooking.
Filariasis is a tropical disease, requiring the Culex mosquito for transmission of infection. The adult worms live in the lymphatics (particularly of the groin and pelvis), where they can cause obstruction. Chronic edema and fibrosis leads to lymphatic obstruction and enlargement of the affected tissues, a condition referred to as elephantiasis.
hookworms → prevalent in tropical climates, where the larval form of the worm lives in moist soil. Hookworm infection is acquired when the larvae burrow through the skin of the bare feet and enter veins; they are carried in the blood to the lung, where they then cross into the small airways and travel up the trachea.
rom the trachea, they enter the pharyngeal area, are swallowed, and finally reach the small intestine. Here, in the duodenum and jejunum, the adult worms attach to the mucosa and feed by sucking blood.
Roundworms → are acquired when the eggs of the parasite are ingested, for example, on uncooked vegetables. Infection is common in children, who frequently put their fingers in their mouths. Once the eggs reach the intestine, larval forms penetrate the intestinal wall, and they undergo travels similar to hookworms before maturing as adult worms in the intestine once more.
Clinical effects of the adult worms include obstruction of the bowel (by large numbers of worms), and inflammation of the bile duct and pancreatic ducts, caused by parasitic migration. The migration of the larval forms through the lungs can lead to coughing and wheezing.
Cestodes/tapeworm
The tapeworms that cause disease in man spend part of their life cycle in man and part in another animal. They are long, flattened, segmented worms. The beef, pork and fish tapeworms exist as a cystic stage in their animal host; man becomes infected by eating inadequately cooked meat.
Once in the human host, the adult matures and reproduces sexually in the intestine, from which eggs are passed to eventually infect their animal host (i.e., when human waste contaminates pasture or water). They rarely cause disease signs in their human hosts.
Trematodes (flukes)
The trematodes are flatworms that require an intermediate host (often snails).
Schistosomiasis, which occurs primarily in Egypt and northern Africa, is the most common disease caused by flukes. The adult flukes live in the veins of the pelvis and bladder. The spiny eggs are laid in the wall of the urinary bladder, where they produce an intense inflammatory reaction,
Describe External Parasites
the ectoparasites: scabies, lice and fleas. These live on or in the skin
They can cause itching, with secondary scratching leading to traumatic injury to the skin; this may be complicated by secondary bacterial infection. Some individuals develop hypersensitivity reactions to the bites of arthropods (to the saliva which is deposited in the skin) and develop an extreme itching response.
the control of vectors is of major importance in the control of many diseases. As carriers of disease, arthropods can act in one of two ways:
1. Mechanical Vector
The arthropod ‘picks up’ the infecting agent and either deposits in on exposed foods or passes it on via the contamination of biting mouthparts.
2. Biologic Vector
The arthropod has an essential role in the completion of the life cycle of the infecting agent.
Flea allergy dermatitis is a common cause of skin problems in dogs and cats. The bite of even one flea can lead to a hypersensitivity response, which leads to an intense “itch” sensation.