Salam Mustafa Pathogenesis of Infectious Diseases Mohammad Shakeeb Final 1 6/12/2015 0
If anyone is interested in going through the book, this is chapter 14 page 238. This is a long lecture so roll your sleeves up, get your hot drink ready and get on with it! Pathogenesis: It is the steps or mechanisms involved in the development of an infectious disease. The terms 'Infection' and 'Infectious Diseases' are usually used as synonyms. However, in microbiology, an infection usually refers to colonization by a pathogen. This pathogen then may or may not cause a disease. That is, a person might be infected by a pathogen but yet not develop the disease (has an infection but not the infectious disease) *Why doesn't a pathogen always cause a disease? 1. The microbe may land at an anatomic site where it is unable to multiply. For example, when a respiratory pathogen lands on the skin, it may not be able to grow. Streptococcus pneumonia causes bacterial pneumonia in the lungs. In the skin however, it causes neither an abscess nor does it cause a wound infection. 2. Many pathogens must attach to specific receptor sites before they can multiply and cause damage. Absence of certain receptors for specific pathogens in the human tissue results in the absence of that specific disease. 3. Antibacterial factors that destroy or inhibit the growth of bacteria may be present at the site where the pathogen lands (For example, lysozymes present in tears and saliva). These prevent colonization by pathogenic bacteria. 1
4. Normal flora of that site (where the pathogen lands) may inhibit the growth of the foreign microbe (for example, normal flora in the skin, vagina and intestine). This is known as Microbial Antagonism. -Reminder; microbial antagonism is where one microbe or group of microbes causes the removal of another microbe. 5. Certain indigenous microflora produces bacteriocins (antibacterial factors) which inhibit the growth of the pathogen. -This is another example of microbial antagonism. 6. The individual's nutritional and overall health status also influences the growth of the pathogen. It may inhibit the growth of the pathogen. 7. Vaccination against a certain pathogen and prior infection with that pathogen may prevent recurrence of that infection (The body is immune against that pathogen). 8. Phagocytes that engulf and destroy pathogens would prevent recurrence of infections. *The doctor didn't really stick to the difference between the terms 'Infection' and 'Infectious Disease', but I did, since the subject was about that... (And because she's awesome -Alina) Phases/Periods in the Course of an Infectious Disease After the exposure to the pathogen, there is: 1. Incubation period 2. Prodromal period 3. Period of illness 2
4. Convalescent period/disability/death (the final outcome could be either one of these) Incubation Period: It is the time that elapses between the arrival of the pathogen and the onset of symptoms. It is influenced by several factors: - Nutritional status and overall health of the host - Immune status of the host - Virulence of the pathogen - The number of pathogens that enter the body Prodromal Period: It is the time during which the patient is feeling out of sorts but is not yet experiencing actual symptoms. Out of sorts means that the patient doesn t feel well. He feels like he s about to get sick. Period of Illness: It is the time during which the patient is experiencing the typical symptoms of the disease. For example, a patient with pneumonia will be experiencing fever, productive cough, sputum production and sometimes night sweats. Communicable diseases are most easily transmitted during this period. Convalescent Period: It is the time during which the patient recovers. Even though the patient may recover from the illness itself, permanent damage may be caused (a disability). -For example, brain damage may follow encephalitis or meningitis. )شلل االطفال( -Paralysis may follow poliomyelitis -Deafness may follow ear infections. 3
These are examples for the disabilities that may occur as a result of certain disease. But of course, the likelihood of these disabilities to occur differs, that is, it is not a necessity that each meningitis disease would cause brain damage. It may or may not cause this disability. *An infection is different from cancer. An infection might end up causing cancer. This is why the last stages of cancer are different from the ones we just discussed. Not an important point but a student asked the doctor something concerning this subject (how cancer has a different last stage) and the Doctor cleared it with this statement Localized versus Systemic Infections An infection may remain localized to one site or it may spread becoming a systemic or a generalized infection. Wound infections, abscess and pneumonia are examples for localized infections. If the pathogens are not contained at the original site of infection, they may be carried to other parts of the body via lymph (that is, the pathogen travels through the lymphatic system), blood or even in some cases macrophages (phagocytic cells in general). Bacterial pneumonia for example, may spread from the lung to the blood causing systemic or generalized pneumonia. Acute, Subacute, and Chronic Diseases A disease could be acute, subacute, or chronic depending on the length of its incubation period and duration. 4
An Acute Diseasehas a rapid onset followed by a relatively rapid recovery. Examples for acute diseases are: measles influenza. and )النكاف ) mumps,)الحصبة( A Chronic Disease has an insidious (slow) onset and lasts for a long time. For example: leprosy (Hansen disease) and syphilis. A Subacute Disease is a disease that has a faster onset than a chronic disease but slower than that of an acute disease. An example would be: subacute bacterial endocarditis (SBE). Latent Infections A Latent Infection is an infectious disease, where it goes from being symptomatic to asymptomatic. Sometimes later on, it may go back to being symptomatic. The word latent was derived from the Greek work latens which means to lie hidden. The two most important examples for latent infections are: Herpes virus infection and Syphilis. Herpes Virus Infections: A herpes virus is a double stranded DNA virus. This virus is of 8 types. Type 1 can cause cold sores which may occur متقطع( intermittently,)بشكل but the patient continues to harbor the herpes virus between cold sore episodes. This is the reason for the recurrence of the infection. Stress acts a trigger that causes the recurrence. Stressful triggers could be fever, extreme cold, or emotional stress. 5
Type 3, also known as Varicella zoster virus infects only humans and causes chickenpox. A person who had chickenpox as a child may harbor the virus throughout his life. Later on in life, as the immune system weakens, that person may develop الناري( shingles )الحزام. Both lesions are caused by the same virus (varicella zoster); however, shingles is the recurrent form of chickenpox. It is considered a latent manifestation of chickenpox. Another example for latent infections is Syphilis. Syphilis is caused by a spirochete bacterium called Treponema Pallidum. If not successfully treated, syphilis can progress through several stages, including the latent stage. The several stages include primary, secondary, latent and tertiary stages. These stages occur when syphilis isn t treated appropriately. - During the primary stage, an open lesion called a chancre is formed (chancre is a specific type of ulcer). So chancre is the characteristic feature of primary syphilis. This happens during the first month (more specifically after 3 weeks) after which the spirochete entered the bloodstream. - 4 to 6 weeks later, the chancre curls or becomes wrinkled and might disappear. The chancre curls inwards and a rash appears. The symptoms then disappear within weeks to 12 6
months (that is, this stage is 1 year maximum). This is the second stage. - In the latent stage, there are no symptoms. It lasts for weeks to years. - Latent syphilis results in tertiary syphilis, the spirochetes cause destruction of the organs in which they have been hiding (the brain, heart and bone tissue). It sometimes leads to death. Primary versus Secondary Infections A primary infection is caused by one pathogen and can be followed by a secondary infection caused by another pathogen. The most common example is bacterial pneumonia. Serious cases of this infectious disease frequently follow mild viral respiratory infections. -During the primary infection (mild viral respiratory infection), the virus causes damage to the ciliated epithelial cells that line the respiratory tract. The function of these cells is to move foreign materials up and out of the respiratory tract (it clears the tract) -While coughing, the patient may inhale some saliva containing opportunistic bacterial pathogens such as Streptococcus pneumoniae, Haemophilus influenzae or Klebsiella pneumonia. -Because the ciliated epithelial cells were damaged by the virus, they are unable to clear the bacteria from the lungs. -Hence, the bacteria then multiply and cause pneumonia. Long story short; due to the primary infection (viral respiratory infection), ciliated epithelial cells in the respiratory tract were damaged and now can no longer function properly (can t clear 7
the tract). When pathogens enter the tract, they are not removed, and so cause another infection (bacterial pneumonia which is the secondary infection). Steps in the Pathogenesis of Infectious Diseases Pathogenesis follows the following sequence: 1. Entry of the pathogens into the body. 2. Attachment of the pathogen to some tissues (via specific receptors) within the body. 3. Multiplication of the pathogen. 4. Invasion or Spread of the pathogen. 5. Evasion of host defenses (some pathogens develop certain mechanisms to evade our immune system). 6. Damage to host tissues Virulence Virulence is the ability of the pathogen to cause a disease. The Virulent Strain of a microbe is capable of causing a disease, whereas the Avirulent Strain is not. For example, toxigenic strains of the bacterium Corynebacterium diphtheriae (those strains that produce diphtheria toxin) are virulent, whereas nontoxigenic strains are not (i.e., the pathogenesis of the bacteria is related to its ability 8
to produce diphtheria toxin). So, it isn t necessary the each C. diphtheria strain is virulent. Another example is the bacterium S. pneumoniae. Encapsulated strains of the bacterium are virulent and can cause a disease, whereas non-encapsulated strains are avirulent and can t cause diseases (loss of the capsule leads to the loss of pathogenicity of the bacterium). Some strains of a given pathogen can be more virulent than other strains. The term Virulence is sometimes used to express a measure or degree of pathogenicity. All pathogens cause disease; however, some are more virulent than other. -For example, it only takes about 10 Shigella cells to cause shigellosis, but it takes between 100 and 1000 Salmonella cells to cause Salmonella. Therefore, Shigella is considered to be more virulent than Salmonella. A smaller infectious dose of shigella can cause an infection when compared to salmonella. The term Virulent can be used for comparison between different organisms or different species of the same organism such as Corynebacterium diphtheriae. Another example is the bacterium Streptococcus pyogenes. Flesh-eating strains of this bacterium are more virulent than other strains because they produce certain necrotizing enzymes unlike the other strains. There is also Staphylococcus aureus. Strains of this bacterium that produce toxic shock syndrome toxin-1 (TSST-1) are considered more virulent than the strains that do not produce this toxin. 9
Virulence Factors Virulence factors are phenotypic characteristics (or physical attributes) of pathogens that enable them to escape various host defense mechanisms and cause disease. These include: 1. Attachment a) Receptors and Adhesins: Presence of receptors on the surface of host cells. A particular pathogen can attach only to those cells bearing those receptors. -S. pyogenes cells have an adhesion on their surfaces, called protein F. This enables this pathogen to adhere to a protein (fibronectin) that is found on many host cells. -HIV is able to attach to cells bearing a surface receptor called CD4. T-helper lymphocytes are CD4+ cells (they have those receptors on their surface) -These molecules on the pathogen s surface that are able to recognize and bind to a particular receptor on a host cell s surface are called adhesins or ligands. -Protein F on S. pyogenes is the ligand and fibronectin is the receptor. The adhesin present on the HIV is a certain glycoprotein molecule and the receptor is CD4. b) Bacterial Fimbriae (Pili): These are long, thin, hairlike, flexible projections composed primarily of an array of proteins called pilin. These enable the bacteria to attach to surfaces. -Fimbriated strains of Neisseria Gonorrhoeae cause urethritis, whereas the nonfimbriated strain doesn t. -Fimbriated strains of E. coli is able to attach to the urinary bladder and hence cause cystitis. 10
-Fimbriae of group A, beta-hemolytic streptococci (S. pyogenes) contain molecules of M-protein. These M- proteins adhere to pharyngeal cells and cause pharyngitis. -So, fimbriae are important in the attachment of the pathogen and initiation of infection. 2. Obligate Intracellular Pathogens -Pathogens of this type like:rickettsia and Chlamydia must live within host cells to survive. -Rickettsia invades and lives within endothelial cells and vascular smooth muscle cells. -Different species and serotypes of Chlamydia invade different types of cells like conjunctival epithelial cells, and cells of the respiratory and genital tracts. 3. Facultative Intracellular Pathogens -These are pathogens that are capable of living in both, outside and inside the host cell. -Phagocytes play an important role in our defenses against pathogens. The two most important categories of phagocytes are Macrophages and Neutrophils. -Once phagocytized by these (macrophages and 11
neutrophils), most pathogens are destroyed by hydrolytic enzymes, hydrogen peroxide and superoxide anions. -However, certain pathogens are able to survive and multiply within phagocytes after being ingested, and this is what we mean when we talk about facultative intracellular pathogens. -Some pathogens (such as the bacterium M. tuberculosis) have a cell wall composition that resists digestion. Mycobacterial cell walls contain waxes which are thought to protect the organisms from digestion. This is a virulence factor against phagocytes. The doctor didn t really say any of the info in that image up in the corner, but he said he ll talk about it for the final, and umm this is our final material so I m not sure what to make of this... 4. Capsules -They have an anti-phagocytic function, i.e. they protect encapsulated cells from being phagocytized. -Examples for encapsulated bacteria are S. pneumoniae, Klebsiella pneumoniae, H. influenzae, and N. meningitides. -The most common example for encapsulated yeast is Cryptococcus neoformans. 5. Flagella -These are important in the invasion process. -They help invade areas of the body that non-flagellated bacteria can t reach. 6. Exoenzymes -These along with toxins are the major mechanisms by which pathogens cause diseases. Other virulence factors 12
do not really explain how pathogens actually cause a disease. -There are 7 types of exoenzymes. These are: Necrotizing Enzymes a) Flesh-eating strains of S. pyogenes produce proteases and other enzymes (collectively called necrotizing enzymes) that cause very rapid destruction of soft tissue, leading to adisease called necrotizing fasciitis. b) Various Clostridium species that cause gas gangrene (myonecrosis) produce a variety of necrotizing enzymes, including proteases and lipases. Coagulase -An identifying feature of S. aureus is its ability to produce the protein coagulase. -Its function is that it binds to prothrombin, forming a complex called staphylothrombin. -The protease activity of thrombin is then activated in this complex. -This causes the conversion of fibrinogen to fibrin. 13
-In the body, coagulase my enable S. aureus to clot plasma and thereby to form a sticky coat of fibrin around themselves. -This sticky coat is to protect themselves from phagocytes, antibodies and other host defense mechanisms. Kinase -It has the opposite effect of coagulase (it dissolves clots). -Enables pathogens to escape from clots. -Streptokinase is the kinase produced by streptococci. -Staphylokinase is the kinase produced by staphylococci. -S. aueus produce both coagulases and kinases. Hyaluronidase -A spreading factor. -Enables pathogens to spread through connective tissue. -This is done by breaking down hyaluronic acid which is the polysaccharide cement that holds tissue cells together. -Pathogenic species secreting hyaluronidase include: Staphylococcus, Streptococcus, and Clostridium. Collagenase -Breaks down collagen (the supportive protein found in tendons, cartilage and bones). -Enables pathogens to invade tissues. 14
-Clostridium perifringens secrete collagenase (hyaluronidase as well). Hemolysins -Damages the host s red blood cells. -By doing so, it provides the pathogen with a source of iron from the hemoglobin from the damaged red blood cell. Lecithinase -Produced by Clostridium perifrengins. -It breaks down phospholipids that are collectively called lecithin. -By doing so, it destroys the host s cell membrane (since it s made of phospholipids). 7. Toxins The two major categories of toxins are Endotoxins and Exotoxins. Endotoxins are integral parts of the cell walls of Gram negative bacteria. They can cause several adverse physiologic effects. Exotoxins are those that are produced within the cell and are then released outside the cell. 15
-As you can see, endotoxins cause fever and septic shock. However, there are several types of exotoxins: 1. Neurotoxins, which affect and damages the central nervous system, like tetanospasmin (produced by Clostridium tetani causing tetanus) and botulinal toxin (produced by Clostridium botulinum causing botulism, which is a flaccid type of paralysis). 2. Enterotoxins, cause gastrointestinal diseases. Bacterial pathogens that produce these are Vibrio cholerae, Shigella species, certain types of E. coli, and Clostridium defficile toxin B. Clostridium defficile toxin B leads to a condition called pseudomembranous colitis (it s pretty important to remember this disease). S. aureus toxic shock syndrome toxin-1 causestoxic Shock Syndrome. 3. Erythrogenic toxins produced by some strains of S. pyogenes (notice that only some produce it, not all) cause scarlet القرمزية( fever.)الحمى Remember that S. pyogenes also cause the disease Necrotizing fasciitis. 4. Diphtheria toxin produced by toxigenic strains of Corynebacterium diphtheriae causes diphtheria. 5. Leukocidins mainly produced by S. aureus cause destruction of leukocytes. 6. Exfoliative toxin produced by some strains of S. aureus causes scalded skin syndrome. Okay yes this lecture is too damn long, but here comes the last part that the doctor asked us to study by ourselves from the book.. 16
Mechanisms by which Pathogens Escape Immune Responses There are many ways by which pathogens avoid being destroyed by immune responses. Several mechanisms are: - Antigenic Variation: Antigens are foreign molecules that evoke an immune response (stimulates the immune system to produce antibodies). Some pathogens however, are able to periodically change their surface antigens, a phenomenon known as antigenic variation. So by the time that the host has produced antibodies specific to these antigens present on the pathogen s surface, those antigens are shed (destroyed) and new ones appear in their place (the antibodies are useless now). Pathogens capable of antigenic variation are Influenza viruses, HIV, Borrelia recurrentis, N. gonorrhoeae and the trypanosomes that cause African trypanosomiasis. - Molecular Mimicry: Pathogens cover their surface antigens with host proteins, so the pathogens will not be recognized as being foreign. - Destruction of Antibodies: Pathogens producing enzymes that destroy IgA antibodies (these enzymes are known as IgA protease). Some of these bacterial pathogens producing these enzymes are H. influenzae, N. gonorrhoeae, and streptococci. This is your first Microbiology lecture for the final material, you should study this thoroughly and don't forget why you started this journey. 17
Some tips would be to: study this lecture once, study something else and then revise it for the information to stick. Don't ignore the examples (we've seen what that did to us before) Marks aren't everything but how would you be okay with yourself if you get a low one when you're studying to be a doctor? Wasn't edited by Alina because Salam doesn't need an editor (a strong independent woman who needs no editor) mashii? "Maybe mashi will be our forever " 18