Mechanism of microbial infection.

PROFESSOR MD AYUBA

CONSULTANT ANATOMIC PATHOLOGIST

DEPARTMENT OF HISTOPATHOLOGY

JUTH, JOS

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• Pathogenicity = ability to cause disease
• Virulence = degree of pathogenicity
• -pathogens must first gain access to the host:
• -must adhere and penetrate before infection
• is established
• -then must continually evade host defenses
• -infection usually causes host damage: disease

To cause disease a pathogen must

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• 1. gain access to the host
• 2. adhere to host tissues
• 3. penetrate or evade host defenses
• 4. damage the host, either:
• - directly
• - accumulation of microbial wastes

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Entry Into Host

1. Portals of Entry

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A. Mucous membranes (moist mucosa)

• -most common route for most pathogens
• -entry through mucus membranes:
• 1. respiratory tract
• (most common)
• 2. gastrointestinal tract
• 3. urinary/genital tracts
• 4. conjunctiva

B. Skin (keratinized cutaneous membrane)

• -some pathogens infect hair follicles and
• sweat glands
• -few can colonize surface
• -unless broken, skin is usually an
• impermeable barrier to microbes

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C . Parenteral route

• -penetrate skin: punctures, injections,
• bites, cuts, surgery, etc.
• -deposit organisms directly into deeper tissues

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• most microbes must enter through their preferred portal of entry in order to cause disease
• -some can cause disease from many routes of Entry

-most usually also exit the host from the same original portal to spread disease

Numbers of Invading Microbes�

• -likelihood of disease increases as the
• number of invading pathogens increases
• ID50 (Infectious Dose) = number of
• microbes required to produce infection in
• 50% of the population
• -different ID50 for different pathogens
• -different ID50 for different portals of
• entry for the same pathogen
• LD50 (Lethal Dose) amount of toxin or
• pathogen necessary to kill 50% of the
• population in a particular time frame

Adherence�

• = attachment to the host by the microbe at portal of entry
• -usually necessary for virulence
• -blocking adhesion can prevent disease
• -pathogen has surface molecules called
• adhesions or ligands that bind specifically
• to the host surface receptors
• -most microbial adhesions are glycoproteins

• or lipoproteins located on the glycocalyx, capsule, capsid, pili, fimbriae or flagella
• -most host receptors are typically proteins (for virus) or carbohydrates (for bacteria) in the wall or membrane of host cell

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Biofilms:

• -formed when microbes adhere to a surface
• that is usually moist and contains organic matter
• -each microbe secretes Glycocalyx allowing other microbes to adhere; a large mass is formed the biofilm is resistant to disinfectants and antibiotics (outer layer protects inner layers)
• -problem for catheters and surgical implants:serves as chronic reservoir

Penetration of Host Defenses

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1. Capsules

• = organized glycocalyx layer
• (carbohydrates) outside cell wall
• -impairs phagocytosis: prevents engulfment and destruction by leukocytes
• -if present, is usually required for virulence -some nonantigenic

2. Cell Wall Components

• A. M protein of Streptococcus pyogenes:
• -heat and acid resistant
• -mediates attachment of bacterium to epithelial cells
• -resists phagocytosis by leukocytes

• B. Fimbriae + Opa (membrane protein) used
• by Neisseria gohorrhoeae:
• -promote attachment and uptake by host
• epithelial cells and leukocytes
• -Neisseria then grows inside these cells
• C. Mycolic acid (waxy) of Mycobacterium
• Tuberculosis
• resist digestion by
• phagocytes
• -Mycobacterium then
• grows inside phagocyte

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3. Enzymes (exoenzymes)

• A. Coagulases: clot fibrin in blood to create
• protective barrier against host defenses
• B. Kinases: dissolve clots (fibrinolysis) to
• allow escape from isolated wounds e.g.
• Streptokinase (Streptococcus pyogenes)
• Staphylokinase (Staphylococcus aureus)

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• C. Hyaluronidase: hydrolyzes hyaluronic
• acid (‘glue’ that holds together connective
• tissues and epithelium barriers) allowing
• deeper invasion
• e.g. Clostridium
• species: allows
• them to cause
• gangrene
• (tissue necrosis

• D. Collagenase: breaks down collagen
• (fibrous part of connective tissue) for
• invasion into muscles and organs
• e.g. Clostridium species
• E. IgA proteases: destroy host IgA
• antibodies found in mucous secretions
• to allow adherence and passage at
• mucus membranes
• e.g. Neisseria species that infect CNS

4. Antigenic Variation

• -pathogen alters its surface antigens to escape
• attack by antibodies and immune cells
• e.g. Neisseria gonorrhoeae
• -has many versions of the Opa gene
• -can alter which one is being expressed
• e.g. influenza virus
• -constant genetic
• recombination
• between flu
• viruses: always
• new spike proteins

• 5. Penetration into Host Cytoskeleton
• -use actin of host cell to penetrate and move
• within the cell
• A. Invasins: surface proteins produced by
• bacteria to control actin
• e.g. Salmonella
• -rearrange actin:
• cause the cell
• membrane to
• wrap around the
• microbe and take it

• into the cell (endocytosis)
• -allows Salmonella to penetrate intestinal
• epithelium
• e.g. Shigella and
• Listeria
• -trigger
• endocytosis
• -polymerize
• actin behind
• bacterium to propel through host cell
• B. Cadherin: allows penetration between cells at intercellular junctions e.g. Shigella and Listeria: move between cells at cell junctions.

• Damage to Host Cells
• 1. Using Hosts Nutrients
• e.g. iron
• -required for all cells (electron transport chain: cytochromes) both host and pathogen
• -host usually does not have free iron available (free iron leads to easy colonization by pathogens) -humans bind unused iron to transport
• proteins: transferrin
• -pathogens can produce siderophores: secreted by bacteria to compete iron from
• host proteins, siderophore iron complex then absorbed by bacteria

• Direct Damage To Colonized Area
• -growth and replication in host cells: results
• in host cell lysis
• -penetration through host cells (mucosa,
• organs) causes damage
• -lysis of host cells to obtain nutrients
• 3. Production of Toxins
• Toxins = poisonous substance produced by
• Microbes -tend to cause widespread damage/disease in host -may be necessary for virulence

• A. Exotoxins
• -produced inside the bacteria and either secreted or released following microbe lysis
• -toxin genes are often found on plasmids or via lysogenic phages -most are enzymes
• -function to destroy certain host cell parts or inhibit particular metabolic functions
• -damage from toxin results in the particular signs or symptoms of a disease
• -can be named for the disease, type of cell attacked or organism that produces it e.g. tetanus toxin: causes tetanus (contraction) of muscle

• -three types of exotoxins:
• 1) A-B toxins Two parts: A is the enzyme that disrupts some cell activity B binds surface receptors to bring A into the host cell e.g. botulinum & tetanus toxin
• 2) Membrane disrupting toxins -cause lysis of the host cell by

disrupting the plasma membrane

• e.g. leukocidins: make protein channels in phagocytic leukocytes
• e.g. hemolysins: make protein channels in RBCs (!-hemolysis: Steptococcus pyogenes)
• 3) Superantigens
• -bacterial proteins that cause proliferation of T cells and release of cytokines
• -excessive cytokines can cause fever, nausea, vomiting, diarrhea, shock and death (septic shock) e.g. toxic shock syndrome
• (Staphylococcus)
• e.g. enterotoxins: Staphylococcal food poisoning

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• B. Endotoxins
• -part of the outer membrane portion of the cell wall of gram negative bacteria: Lipopolysaccharide (LPS)
• -released when dead cells lyse -in blood, causes macrophages to release high levels of cytokines resulting in chills, fever, weakness, aches, small blood clots, tissue necrosis, shock and death e.g. endotoxic shock: critical loss of blood
• pressure due to bacterial endotoxins (LPS) Sterile solutions can contain LPS: bacteria dies in sterilization but LPS is unaltered Due to serious consequences at very low levels of LPS, it is essential to test medical devices and solutions for endotoxin

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Pathogenic Properties of Virus�

• 1. Mechanisms to evade host defenses
• A. Grow inside host cells to hide from immune defense
• B. Kill immune cells
• e.g. HIV – TH Cells
• 2. Cytopathic effects
• = visible effects of viral infection on
• host cell: some effects will kill the cell, some will just change the cell

• A. stop DNA, RNA and/or protein synthesis
• e.g. Herpes virus block mitosis
• B. lysosomal autolysis of host cells
• e.g. Influenza: bronchiolar epithelium
• C. production of inclusion bodies (visible
• viral parts inside the cell)
• can identify
• a particular virus
• e.g. Rabies virus: Negri bodies

• D. syncytium formation (neighboring cells fuse together) e.g. Varicella Zoster virus
• E. change in cell function
• e.g. Measles
• F. production of interferons by host cell
• (triggers host immune response)
• G. induce antigenic changes on host cell surface (triggers destruction of infected
• cell by host immune response)
• H. induce chromosomal changes
• I. cell transformation: may activate or
• deliver oncogenes resulting in loss of contact inhibition (cancer) e.g. Papilloma virus

fungi

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• -produce toxins causing allergies or disease e.g. -chronic sinusitis (black molds) -Stachybotrys: headaches, vomiting, mental disturbance -invasive systemic mycosis in immune compromised patients
• e.g. Candida -mushrooms: mycotoxins may be hallucinogenic or deadly

• 2. Protozoa:
• -can grow inside host cells causing lysis e.g. Malaria (Plasmodium) -use host cells as food source
• -produce wastes that cause disease
• 3. Algae
• -produce neurotoxic substances e.g. shellfish poisoning

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