Pathogens, Virulence, and Immunity

• A healthy human system relies on "normal" microbiota and disease resistance mechanisms. Failure in either can cause disease.
• Disease resistance has intrinsic/innate and adaptive immunity

Innate Immunity

• The body's natural, non-specific defense present from birth
• Provides immediate protection against infections and harmful substances

Pathogens & Virulence

• A pathogen is a disease-producing microorganism
• Pathogens determine severity of disease with virulence factors
• Virulence is a pathogen's ability to overcome host defenses
• Virulence is determined by quantitative measures (ID50 and LD50)
• Pathogens can lose or gain genes for virulence factors and adapt to immune responses upon exposure
• LD50 (Lethal Dose) is the number of pathogens needed to kill 50% of an experimental group of hosts
• ID50 (Infectious Dose) is the number of pathogenic particles to cause infection in 50% of experimental hosts

Adhesins & Colonization

• Adhesins are virulence factors in bacterial pathogens
• Adhesins facilitate attachment to host cells or surfaces
• Colonization is when pathogens establish a persistent presence without causing overt disease symptoms
• Colonization can happen in healthy carriers
• MRSA is a pathogen that can colonize healthy carriers
• Colonization increases a healthy carrier's risk of infection
• Colonization assists transmission of pathogens to others
• Healthy carriers can develop an active infection when pathogens colonize in other places

Infection & Disease

• Infection is when a microbe colonizes and establishes itself
• This leads to disease, and refers to invasion by a pathogen
• Disease is damage or injury to the host
• Disease occurs if there is any damage at all

Microbial Attachment

• Attachment happens first before colonization
• Otherwise, the microbes will be shed from the system
• Loose associations are weak attachments that shed microbes daily, as with the bowel and skin
• Specific cell-to-cell interaction is when microbial cells firmly attach to carbohydrates, lipids, or proteins on host cells
• Specific cell-to-cell interactions make resident microbes harder to shed
• Specific cell-to-cell interactions are area-dependent, as receptors differ throughout the body
• Methanogens adhering to receptors in the gut are an example of normal specific cell-to-cell interactions
• E. coli 0157:H7 use fimbriae to attach to receptors in the gut, can result in infection

Normal Flora

• Refers to microbes normally found at an anatomical site
• Commensals provide benefit to one partner, and the other partner is not harmed, situational
• Normal flora help shape and train the immune system and its responses
• Normal flora prevents attachment/colonization by pathogens
• Normal flora may produce molecules that kill or inhibit pathogen growth
• Different commensals control each other's growth in biofilm

Commensalism & Opportunistic Behavior

• Commensals can be opportunistic, which can aid pathogens or cause disease arise
• Overgrowth of commensals (UTIs, bronchitis) or pathogens attaching to commensals and entering the human system are examples of commensalism
• Skin is a strong physical barrier that is routinely shed, which controls resident microbe populations
• Skin commensals are mostly Gram-positive bacteria attaching within microscopic crevices in the skin and are not easily removed
• Sweat and follicular sebaceous glands are major skin colonization sites
• Microbial populations on the skin fluctuate due to weather, age, hygiene, and hormones
• Most transient bacteria on exposed skin are Gram-negative
• Gram-negative bacteria cannot grow as well in the dry skin environment
• Staph. epidermidis and Corynebacteria are skin commensals that are Gram-positive facultative anaerobes
• These can be found on exposed skin, in sweat glands, and in dry areas
• Proprionibacterium is a Gram-positive anaerobe that colonizes skin glands
• Proprionibacterium breaks down lipids secreted by the host
• Proprionibacterium produces volatile compounds and body odors and can cause acne
• Proprionibacterium takes advantage of hormonally controlled overproduction of sebum
• Gram-negative skin commensals are found in moist areas of the skin, such as the groin and armpits
• Yeast skin commensals are found on the scalp

Nose & Respiratory Tract Commensals

• Staph. epidermidis and Staph. aureus are commensals that can be found in the nostrils
• The nostrils are cooler and have lots of oxygen and many receptors
• Anaerobes can be found in the tonsillar crypts (nasopharynx)
• 5-15% of healthy carriers harbor many pathogens in the tonsillar crypts
• Streptococcus, Corynebacteria, Neisseria, and Haemophilus are microbes found in the tonsillar crypts
• Alpha-hemolytic Streptococcus (normal flora) and Beta-hemolytic Streptococcus are microbes found in the oropharynx
• Beta-hemolytic Streptococcus causes strep throat, is not normal flora, but it can be carried by healthy individuals
• The lower respiratory tract is sterile with no known normal flora
• Microbes are removed by the mucociliary blanket and phagocytic cells that reside in respiratory tract
• The mucociliary blanket moves particles upward
• Cough reflex dislodges particles
• Phagocytic cells phagocytize foreign particles

Oral Microbiome

• The mouth is heavily colonized within hours of birth
• It consists of many unknowns and specialized environments
• It facilitates complex communication between resident microbes
• Biofilms aid colonization of mouth commensals by using extracellular polysaccharide (dextran) to adhere to gums and teeth
• Plaque on teeth is a hardened biofilm
• The biofilm is due to calcium and magnesium encrustation
• It contains a complex assortment of aerobic, anaerobic, and facultative microbes
• Strep. mutans and Lactobacillus cause dental caries
• Bacteroides and Campylobacter cause periodontal disease

Stomach & Gut Microbiome

• Unculturable normal flora is found in the mucous lining of the stomach and upper intestines
• Some are the cause of Peptic Ulcer Disease
• Helicobacter pylori is a stomach commensal that colonizes about 50% of the world's population
• Helicobacter pylori produces urease
• Urease allows it to survive in the stomach at very low pH
• Most transient microbes are killed by the stomach acidity
• Transient microbes can survive stomach acidity by passing through quickly
• Transient microbes can survive stomach acidity by embedding in fatty food particles or ingestion in bulk
• The colon has the largest microbial population in the body (>10^14) at 60% unknown and 80% unculturable
• Microbiome diversity in the colon varies between individuals, ethnic groups, cultures, etc.
• The core group of microbes in the microbiome is the group everybody has in their colon
• Bacteriocins are antimicrobial peptides produced by normal flora of the colon
• Bacteriocins kill or inhibit the growth of pathogens
• E. coli commensal in the colon generates bacteriocins that can kill clostridia
• Bowel microbes are usually anaerobic or facultative
• Constant shedding and rapid replacement of populations is present in the bowel
• Populations are self regulating in the bowel but can be disturbed by stress, antibiotics, illness

GU Microbiome

• No resident bacteria, but viruses are present in the kidneys
• The bladder also has a microbiome
• The female urinary microbiota (FUM) differs from the male urinary microbiota (MUM)
• The upper male genital tract is typically microbial free
• The lower male genital tract contains an assortment of different Gram-positives and Gram-negatives
• Continuous flushing action in lower male GU promotes self-limiting infections
• In the female genital tract, acid-tolerant lactobacilli predominate
• Lactobacilli produces bacteriocins that kill pathogens in the female genital tract
• Numbers change in response to hormone cycle in the female genital tract
• The female genital tract is sensitive to stress, hormonal changes, and antibiotics

Benefits of Commensals

• A healthy microbiome prevents chronic kidney disease and cardiovascular complications
• A healthy microbiome prevents abnormal immunity
• Commensals occupy physical space
• This limits pathogen attachment
• Commensals secrete products and regulatory metabolites
• These affect other members of the microbiome and the host

The Immune System

• Large network of cells, tissues, organs, cytokines, and receptors and more
• The Immune system creates in both innate and adaptive immunity
• Immunity occurs when the body has the ability to resist a particular disease or infection
• An antigen is anything that can raise an immune response against it
• Antigens aid in self versus non-self recognition
• Non-self recognition is the ability to recognize foreign objects not related to the host
• Adaptive immunity is a specialized defense mechanism that protects against pathogens
• Adaptive immunity is characterized by specificity, diversity, memory, and the ability to distinguish between self and non-self
• Intrinsic immunity is always on
• Innate immunity is stimulated by inflammation
• Intrinsic and innate immunity create generalized resistance and do not have memory
• They do not improve with repeated exposure
• Adaptive immunity improves with repeated exposure to the antigen
• Intrinsic immune mechanisms are cell-based proteins constantly expressed
• Defensins and lysozymes degrade the cell wall of Gram-positives
• Defensins and lysozymes are produced and concentrated in mucus
• Mucus layers create a physical/chemical barrier that contain defensins and lysozymes to degrade the cell wall of gram positives
• Innate immunity is based off pattern recognition receptors (PRRs) recognize pathogen associated molecular patterns (PAMPs)
• Pattern recognition leads to early non-specific detection of foreign molecules
• Examples include LPS, peptidoglycan, lipoteichoic acid, flagella, and nucleic acids
• Stimulation of pattern recognition receptors (PRRs) causes cells to produce pro-inflammatory molecules such as cytokines and chemokines
• White blood cells (leukocytes) in innate immunity are present in blood, lymphatics, lymph nodes and all have PRRs on their surfaces but their responses differ
• Dendritic cells are white blood cells and leukocytes that are phagocytic cells
• Dendritic cells play a major role in innate immunity
• Dendritic cells produce cytokines present in immunogenic substances to other cells
• Dendritic cells serve as a bridge between the innate and the adaptive immune response
• The adaptive immune response is triggered when the number of PRRs and cytokines reach a certain level
• Mast cells are white blood cells (leukocytes) are associated with of innate immunity
• Mast cells release pharmacoactive and antimicrobial molecules
• Neutrophils are white blood cells and leukocytes, are associated with innate immunity and release extracellular traps
• Natural killer cells are white blood cells and leukocytes, are associated with innate immunity and produce bacterial permeability increasing protein which can kill microbes
• The lymphatic system shadows the circulatory system
• The Lymphatic system is used as a highway for cells involved in innate and adaptive immunity
• Lymph nodes are like hotels for cells
• The complement system is composed of 9 soluble factors found in the blood and is considered part of the innate immune response
• It includes a series of proteins that work together in a cascade to eliminate pathogens
• The C3 factor spontaneously cleaves after binding to the cell walls of bacteria. This starts a chain reaction cleaving other complement factors
• If the last 4 complements generate a pore in the bacterial cell, it can result in death
• The membrane attack complex (MAC) forms that pore in the cell
• Intrinsic cell defense mechanisms and affected cells produce inflammatory chemical messengers
• These inflammatory chemicals call in the innate response via phagocytic cells
• These phagocytic cells initiate additional inflammatory chemical messengers
• Eventually the amount of inflammatory cytokines reaches a certain threshold
• This ultimately triggers the adaptive/acquired immune response

Additional Notes on Adaptive Immunity

• Artificial acquired immunity does not come in contact naturally or in the wild with pathogens
• Artificial acquired immunity is typically injected and can be active or passive
• Active artificial acquired immunity occurs when antibodies are produced as a result of immunization with a vaccine
• Passive artificial acquired immunity occurs with antibodies that have been produced in another animal in vitro, only antibody exposure
• Natural acquired immunity occurs when the body develops long-lasting protection against specific pathogens via natural exposure
• Active natural acquired immunity occurs when antibodies or activated lymphocytes are produced as a result of direct contact with pathogen
• Passive natural acquired immunity occurs when antibodies are passed to a fetus through a placenta/colostrum, only exposed to antibodies
• Immune system environmental sampling occurs primarily in association with M-cells
• M-cells are found in epithelial lining of the GI and respiratory tracts
• M-cells serve as channels of information between the lumen of intestines and respiratory tract
• M-cells have nerves, immune system cells, and are connected to lymph nodes
• They have very diverse immune-related functions
• M-cells can take samples of what's in the intestines and lungs
• M-Cells transport these to the lymph nodes to present/show other cells
• Cytokines and chemokines are produced by immune system cells associated with M-cells and they can diffuse
• Cytokines and chemokines stimulate more cells and amplify the signal
• M-cells signal the brain to produce a chemical messenger to control M-cell behavior
• This will controls M-cell behavior and stimulates the growth of protective bacteria lining the walls of the GI or respiratory tract
• M-cells line intestinal cells
• M-cells sample GI tract of bacteria for the immune system and alerts immune system of pathogens if detected
• The cell-to-cell attachment pathogen ruffles M-cell which then transcytoses the microbe
• Peyer's patches are found just below the M-cells in the Gl tract, lead to connection to the lymph node
• In the respiratory tract M cells rapidly deliver bacterial antigens to the draining lymph nodes with no Peyer's patches
• Pain-sensing neurons wired to M-cells in the gut release neuropeptides
• The release of neuorpeptides can change the density of filamentous bacteria lining the walls of intestines
• The neuropeptides can also change the density of M-cells to limit entry of pathogens

Functions of Adaptive Immunity

• Recognition of non-self, response to non-self, and specific memory of response to non-self -Adaptive inmunity leads to elimination, or neutralization, of foreign material
• Memory in adaptive inmunity leads to the ability to memorize response to specific foreign material
• Memory include specific memory T-cells and B cells
• Specific memory T-cells are generated in first infection
• Specific memory T-cells reactivate when exposed to the same infectious agent
• Specific memory B-cells reactivate and produce antibodies in first infection with the help of T-cells
• Specific memory B-cells occur the individual is re-exposed to the same infectious agent
• Humoral immunity in the adaptive acquired immune response and antibody mediated immunity
• Clearace of infection occurs through plasma B-cells activated by T-cells to produce specific antibodies
• Plasma B-cells are activated by T-cells
• B cells help produce specific antibody against surface antigens on foreign agents
• Cell-mediated immunity in the adaptive immune response causes T-cells to specifically kill infected cells
• Includes two classes of T-cells, T-helper and T-cytolytic
• T-helper cells produce chemical messages
• T-helper cells allow B-cells to produce large amounts of specific antibody
• T-cytolytic cells receive chemical messages from T-helper cells to kill infected cells
• Antigens are being recognized of foreign agents adaptive immunity
• Antigens are defined as molecules that induce/cause the production of antibodies
• Attached antibodies are a signal to the immune response
• Antibodies recognize specific antigen (epitope)

Notes on Antigens

• Autoimmunity can be caused by "shared motifs" or molecular mimicry between antigen and host
• Some antigens generate better responses than others
• Antigen formation in complex molecules or cells (like bacteria) consists of many different antigens that can induce the formation of many different antibodies
• The Clonal Selection Theory refers to every increasing arms race between pathogen and host
• Antigens selects for those cells that make antibody and for cell mediated activity
• Antigens select which B-cells will make antibody against it
• Antigens select for which T-cells will react against it
• Microbes have evolved mechanisms that evade or manipulate this process

Arms Race

• The reaction and counter reactions between pathogens and the immune response is the ever increasing arms race in the Clonal Selection Theory
• How repertoires or assortments of specific antibody producing cells and T-cells are produced and maintained in the body is the Clonal Selection Theory
• Sustained antibody production requires T-cell help
• Antibodies are also called Immunoglobulin (Ig)
• Immunoglobulins (antibodies) are made and secreted by plasma B-cells in response to antigen
• Receptors on cell's surface can recognize and bind antigen
• Plasma B-cells are activated to produce immunoglobulins (antibodies) when a critical threshold of receptors have been engaged by antigen on the cell's surface
• CD4 T-cells (T-helper cells help push B cells to produce more specific antibody with each round of cell division
• Antibodies are compose of two or more FABs (bind antigens) and Fc (tail, special function)
• Antibodies contain two or more and they are binding sites antigens
• The Fc structure in antibodies is the tail of the molecule, which has special functions
• Receptors on the surface of other cells can use antibody to now bind antigens or other cells and respond
• Glycosylation (addition of sugar residues) of Fc can distinguish human, dog, cat antibodies from each other
• The five classes of antibodies or immunoglobulins (Ig) are IgM, IgG, sIgA, IgD, and IgE, all made by immune system
• IgM immunoglobulins (antibodies) are produced first and are the largest, recognize many things
• IgG immunoglobulins undergo Second response and can cross the placenta, they are most specific, also systematic
• sIgA immunoglobulins (antibodies) are secreted across mucus membranes and breast milk and they prohibit attachment of pathogens to specific areas
• IgD immunoglobulins (antibodies) are found on all cells and their exact function is unknown
• IgE immunoglobulins (antibodies) are involved in allergic responses and also parasitic infections like worms, blocked by antihistamines

Fuctions of Antibiodies

• Neutralization, molecular tag, agglutination of antigens, and activation of complement
• Neutralization, molecular tag agglutination and precipitation of antigen, and activates compliment system
• Antibodies function by Neutralizing attachment infectious agent
• Molecular Tagging means antibodies tag microbes for phagocytosis
• Compliment Activation, involves nine soluble protein factors in classical complement pathway activated by antibody attaching to antigen
• Specific targeting in Compliment Activation happens do to the major activity is forming a hole in the target from a Membrane Attack Complex (MAC)
• Agglutination is is when binding occurs, they are creating visible complexes or aggregates that are easier for the immune system to recognize and eliminate

Primary vs Secondary Response

• First exposure to antigen generates primary response and re-exposure generates specific secondary response (recall)
• Primary Response includes H1N1 with 14 days needed for IgG response to develop with T-cells and is a longer process
• Secondary Response occurs with H1N1 and generates in four days, is specific without T-cells making it a shorter process
• The adaptive immune system needs antigen presentation from the host
• T-cells are activated after tiny pieces of antigen nestled
• These molecules are called MHC class 1 or MHC class 2 with the T cell receptor recognizing antigen

MHC Classes

• MHC class 1 molecules exist on nucleated body cells and present intracellular pathogens to CD8 T-cytotoxic cells
• If the receptor on CD8 recognizes infected, after signaling from T-helper cells, it deystorys infected
• Major Histocompatibility molecules are are cell surface proteins that present peptides to T cells
• Cells present antigen via MHC allowing the immune system to identify and respond to foreign antigens
• Class 2 Molecule sites are used by profession phagocytic antigen presenation
• Class 2 molecules broken antigens fragments to bits for activation of helper T class
• helper T activates Secrete chemical messengers activated B-cells, cytotoxic with releases
• toxic kills them CD4 -helper target and can do so again

Activation and Regulation

• Helper activated help and killer humoral cell activity for best protection
• Unchecked, immune responses can be an , or post-infection problems occur. Complete immune is off infection host must heal
• Mechanisms with adaptive systems must be turned antibody, signal
• Stimulation can affect immune re- response is allows response

Immunity Control

• Antigens cause responses

Types

• T is immunity location

Measles, Mumps,

RSV Respiratory Syncytial

Infections

-Is a disease from spread from spread to air and requires test such

Fungal Infections

Viral

• Viral skin-like small clusters, with virus.
• Viral of which. Not viral for for years

Bacterium

• bacteria causes cells not of
• bacterial. Are not all bacteria. Has that

Parasites

Worms

• Many

Prions

Treatments

• Are given help help disease

Factors for All for All Immunity