Infectious Process, part I       Reading: pg. 113 – 141

• Background
• Obligatory steps to causing infection (fig. 12.1, pg. 113)
• Host defenses and microbial evasion strategies (fig. 12.2, pg. 114 – 116)
• Host-parasite relationships
  • Four types of infection
• Causes of infectious disease
  • Koch’s postulates
  • Modern day use of Koch’s postulates
• Biological response gradient (fig. 12.8, pg. 120)
• Entry, exit and transmission
  • Infection vs. shedding (fig. 13.1, pg. 123)
• Sites of entry
  • Skin (fig. 13.2, pg. 124)
  • Respiratory tract (fig. 13.4, pg. 125, fig. 13.5, pg. 126)
  • Gastrointestinal tract (fig. 13.6, pg. 127, fig. 13.9, pg. 128)
  • Urinogenital tract
  • Oropharynx
• Exit and transmission
  • Three factors affecting transmission
  • Types of infection and their role in transmission (fig. 13.12, pg. 131)
  • Types of transmission and their control (fig. 13.14, pg. 133)
• Transmission between humans
• Transmission from animals
  • Invertebrate vs. vertebrate

Infectious Process, part II, Immune Defenses in Action  Reading: pg. 143-156

• Antimicrobial peptides
  • Defensins
  • Dermicidins
  • Cathelicidins
  • Lysozyme
• Complement
• Acute phase proteins and pattern recognition receptors
• Fever
• Natural Killer cells
• Phagocytosis (fig. 14.7, pg. 147)
  • Non-oxidative mechanism
  • Oxidative mechanism
  • Nitric oxide
• Cytokines
  • Interferons (fig. 14.8, pg. 148, fig. 14.9, fig. 14.10, pg. 149)
  • TNF
• Anti-body mediated immunity (know antibody classes)
• Cell-mediated immunity
• Recovery from infection

Infectious disease

Part I

p. 113-141

Background

p   Race between host and microbes:

n   Host develop better defense mechanisms

n   Microbes rapidly evolve mechanisms to overcome host defenses

p   Microbes always steps ahead:

n   evolve much faster than host

n   multiply more rapidly

p  generation time of 1 hr or less

p  Human generation time  = 20 yrs

n   Genes passed laterally between microbes       

p  plasmids for antimicrobial resistance

Obligatory steps to causing disease

Fig. 12.2 Host defenses and microbe’s answer

p   Infectious microbes exploit weak points in the host’s defenses

Host-Parasite relationships

p   Race between:

n   microbe’s capacity to multiply, spread and cause disease

n    host’s ability to control and get rid of pathogen

p   host’s response is crucial - delay gives microbes advantage.

p   Adaptation à balanced relationship between microbes and host

Causes of infectious disease

p   When a person is sick, how do we determine which microbe is responsible for causing the disease?

p   Robert Koch

n   Koch’s postulates

n         Microbe must be present in every case of the disease

n    Microbe must be isolated from host and grown in pure culture.

n    When a pure culture is inoculated into a new host, it must produce the same disease

n     Microbe must be recovered from diseased experiment host

n   Modifications to Koch’s postulates:

p  Some microbe could not be grown in laboratory

p  Using human subjects is unethical

Modern day use of Koch’s postulates

p     Conclusion about causation made using common sense

n    some diseases do not appear for years after infection

n    Molecular techniques - identification of unculturable microbes

p    same problem they had in Koch’s days

n    Some diseases

p   caused by multiple microbes

p   only occur in genetically pre-disposed individuals

p   virus integrates genome into that of host à vertical transmission

p   microbe triggers disease and then disappears

The biological response gradient

p   disease caused by a microbe may not be exactly the same.

p   clinical disease depend on:

n   infecting dose and route

n   age

n   sex

n   presence of other microbes

n   nutritional status

n   genetic background.

Entry, Exit, and Transmission

p   Infection vs. Shedding

n   Body surfaces

p  Receptors – attachment à infection

p  shedding - microbes exit to be transmitted to fresh host.

Sites of entry: Skin

p    Protection: Normal flora and chemicals.

n    microbes enter by way of

p   hair follicles, sebaceous glands, nails, wounds, burns.

p   Conjunctiva

n    protected by flushing with tears

n    dirty fingers carry microbes to area

p   Biting arthropods

n    penetrate skin and introduce parasites into body

p    Fig. 13.2:

n    list of microbes that enter body through skin.

Sites of entry: Respiratory Tract

p    microbes trapped by

n    mucus, carried to throat by ciliary action

p    Microbes overcome cleansing mechanism by

n    Having molecules that allow microbe to attach firmly to cell surfaces à Fig. 13.4 examples

n    Fig. 13.5 different ways to interfere with ciliary activity

n    Avoiding destruction by alveolar macrophages – M. tuberculosis

Sites of Entry: Gastrointestinal Tract

p   Infecting microbes must:

n   attach to epithelial cells to

p  colonize and avoid being washed out

p  Fig. 13.6: mechanisms for attachment

n   counteract mucus, acids, enzymes and bile

p  Fig. 13.9:

Sites of Entry: Urinogenital Tract

p    Vaginal defenses:

n    Normal flora (Lactobacilli)

n    Low pH (5.0) inhibits colonization by pathogens

n    Invaders must attach to vaginal wall à STDs

p    Urethral and bladder defenses

n    Urinary tract - invaded via urethra

n    Defenses:

p   Flushing action of urine

p   Bladder

§    mucus layer

§    ability to produce inflammatory response

§    secretory Abs

§    immune cells

Sites of Entry: Urinogenital Tract

p    Mechanisms for invading urinary tract

n    Attachment mechanisms

p   Gonococci and Chlamydia

§    special peptides on flagella binds to urethral cell à induces engulfment of bacterium (parasite-directed endocytosis)

n    Foreskin

p   protects pathogen by keeping it moist

p   STDs common in uncircumcised males

p    Urinary tract infections:

n    commonly caused by intestinal bacteria (E. coli)

n    More common in females

p   urethra is shorter and closer to anus

Oropharynx

p   Defenses:

n   Flushing action of saliva (1L/day)

n   Secretory IgA

n   Lysozyme

n   Normal flora

n   Leukocytes in mucosal surface and saliva

p   Invasion mechanism

n   Attachment to teeth or mucosal cells

n   Changes in host defenses can lead to invasion

p  Vitamin C deficiency and thrush (Candida)

Exit and Transmission

p       Exit by way of:

n       Body surfaces

n       Blood-sucking vectors

p       3 factors affect transmission

n       Number of microbes shed

n       Microbes stability in environment

n       Number of microbes required to infect a fresh host

p      varies with microbe

§      to cause food poisoning

§      S. dysenteriae, 10 cells

§      Salmonella, 10^6 cells

p      Route of infection

§      rhinovirus in nasal cavity, 1 dose; 200 doses through pharynx

p   Fig. 13.12 Types of infection and their role in transmission

Types of transmission and their control

p        Microbes transmitted to humans in many ways

n        Respiratory or saliva spread

p       Nasal secretions, droplets

§       sneezing, coughing, talking

§       Common cold

p       Fomites

p       Not easy to control

n         Fecal-oral spread

n        Poor hygiene

n        fecal contamination of food or water

n        Control: public health measures

n         Venereal spread

n         STDs from sexual activities

n         Hard to control

Transmission between humans

p   Respiratory tract

p   Gastrointestinal tract

p   Urinogenital tract

p   Oropharynx – spread in saliva

p   Skin – shedding or direct contact

p   Milk – breast milk, cow’s milk

p   Blood – arthropods or needles

Transmission from animals

p   human infections from animals

n   Directly from vertebrates (zoonoses)

p  Contact, inhalation, bites, contamination of food and water, and ingestion as food

n   Indirectly from invertebrate vectors (via blood-sucking arthropods)

p  Insects, ticks and mites

Infectious process

Part II

Immune defenses in action

Innate immunity

p   Protects against microbes that have entered host

p   Less specific

Antimicrobial peptides

p      Proteins excreted by epithelial surfaces and PMN’s

p      Have antibacterial effects

n       Defensins – form ion channels in microbial membranes

n       Dermicidins – made by sweat glands

n       Cathelicidins – acts against group A Streptococcus

n       Lysozyme – most effective against Gram +; abundant in lung

Complement

p   Discussed earlier:

n   Induces inflammatory responses

n   Promotes chemotaxis, phagocytosis and vascular permeability

p   Activation by the alternative pathway

p   Action of complement in vivo restricted to Neisseria

Acute Phase proteins and pattern recognition receptors

p        C-reactive protein (CRP):

n        Antibacterial pentameric β-globulin

n        Produced by liver cells

n        Reacts with phosphorylcholine in cell wall à activates complement and phagocytosis.

n        Act as opsonins, antiprotease, pattern recognition receptors

p      Toll-like receptors

n      Surface receptors on macrophages

n      Bind conserved microbial molecules

p    LPS, bacterial DNA and flagellin, ds RNA

n      Recognizes bacteria as foreign through pattern recognition receptors à release of cytokines

p        Collectins:

n        bind to carbohydrate molecules on bacterial and viral surfaces

n        Activates complement and macrophages

Fever

p   Raise in body temperature

n   Kill microbes susceptible to high temperature

n   Others have adapted to episodes of fever

p   Immune mechanisms more active at high temperatures

n   Complement activation

n   Lymphocyte proliferation

n   Protein synthesis (antibody and cytokines)

Natural killer cells

p   Important early source of cytokines

p   Act as cytotoxic effector cells

n   Lyse bacteria- and virus-infected host cells

p  by producing cytotoxic granules and perforin

n   Not antigen specific

n   Provides a more rapid, less specific means of controlling infections

Phagocytosis

p   Macrophages in tissue

p   PMNs in blood

p   Engulf, kill and digest invading microbes

Phagocytosis

p   Intracellular killing

n   Oxidative killing

n   Nonoxidative killing

Oxidative killing

p        Fig. 14.4 “respiratory burst”

n        consumption of oxygen

n        generation of reactive oxygen intermediates (ROIs)

p      superoxide ion, hydrogen peroxide, and free hydroxyl radicals

Oxidative killing

p   ROI kills microbes due to

n   Direct damage

p  cell membrane, DNA, and proteins

n   Damage due to alteration in pH

n   Microbes killed only at acidic or at alkaline pH

p  Acid – E. coli and Candida

p  Alkaline - staphylococci

Oxidative killing

p   ROIs

n   Extremely short-lived

n   Toxicity prolonged by interactions with lipoproteins

Non-oxidative killing

p   Functions when oxygen is unavailable

p   Involves cytotoxic granules of phagocytes

n   PMNs

p  granules fuse with phagosome

p  fall in pH increases activity of cationic proteins and defensins

n   Eosinophils

p  contain cationic proteins

p  Causes damage to surface of worms

n   Macrophages

p  contain large amounts of lysozyme.

Non-oxidative killing

p   Nitric oxide

n   reactive nitrogen intermediates (RNIs)

n   generated during conversion of arginine to citrulline by arginase

n   Secreted by macrophages

n   Strongly cytotoxic

n   Arginase

p  cause damage by deprivation of arginine – essential amino acid

Cytokines

p   Chemical messengers

p   Has important role in infectious diseases

n   Contribute to:

p  control of infections - protection against infectious diseases (induction of antimicrobial processes)

p  development of pathology (production of tumor necrosis factor)

Interferons

p   acts against virus-infected cells

p   3 types (a, b, g)

n   IFNa and IFNb

p  produced in response to viral infection (within 24 hrs)

n   IFNg – produced later by T cells

p  interacts with specific receptors on cells

p  Induce antiviral state by generation of two enzymes

§    protein kinase

§    2’,5’ –oligoadenylate synthetase

§    Inhibit viral RNA translation (protein synthesis) and viral assembly

Interferons

p   Also active against

n   ricketssia, mycobacteria, and some protozoa

Other cytokines

p   TNF

n   Useful but can be dangerous if too much

n   Useful in inhibition of proliferation of B lymphocytes by Epstein-Barr virus

n   Initiation by Gram negative pathogens

p  Damage to blood capillaries à shock

p  Weakens blood-brain barrier

Anti-body mediated immunity

p   adaptive immunity

p   takes days to weeks to take effect

p   responsible for

n   recovery from infections

n   long term protection (immunity).

Antibody classes

p    Fc portion

n    responsible for differences in function of different Ab’s

n    Groups Ab’s into classes à subclasses

p    Examples:

n    IgG à   IgG1 – acts against protein

              IgG2 – acts against polysaccharides

p   Children under 2 more prone (low IgG2)

§    S. pneumoniae and H. influenzae - polysaccharide capsules

n    IgG1 and IgG3 – act against viruses

n    IgG4 and IgE – act against helminths, induce production of IgA

n    IgA – only Ab to function in protease-rich intestine

Antibodies

p   Bind to antigenic parts of microbes

n   Block attachment and entry

p  Neutralize microbe or its product

p  Immobilization and agglutination of microbes

n   Lysis of bacteria (result of complement fixation)

p  Limited to Neisseria and some viruses

n   Opsonization

p  Enhance phagocytosis

n   Antibody-dependent cellular cytotoxicity

p  Ab + eosinophils à damage to large parasites

Cell-mediated immunity

p   Second part of adaptive immunity

p   Activities:

n   Produce cytokines to induce activation of macrophages or antibody production

n   Direct cytotoxic action on infected cells

p   Recognizes specific peptides and MHC molecules

p   T cell immunity correlates with control of bacterial growth in leprosy

n   Spectrum of disease depends on ability to respond to M. leprae antigens

p   Cytotoxic T cells

n   kills pathogens by insertion of perforin

n   Induction of apoptosis by Fas/FasL interactions, granzymes and IFNa

n   Active against intracellular viruses, mycobacteria, and some protozoa

Recovery from infection

p   May take days to months but individual becomes immune to disease

n   Cell-mediated immunity responsible for recovery

n   antibodies responsible for maintenance of immunity.

p   Failures to recover due to:

n   deficient immune response

n   successful evasion mechanisms of pathogen.