Host Defenses Against Infectious Disease
Host Defenses Against Infectious Disease
Introduction to Host Defenses
Evolutionary Context: Vertebrates have undergone hundreds of millions of years of evolution, constantly exposed to microbial infections.
Consequences of Inadequate Defenses: Historically, inadequate host defenses led to disease or death.
Developed Defenses: Hosts have evolved highly efficient methods for:
Recognizing foreign invaders.
Mounting effective inflammatory and immune responses to control pathogen growth and spread.
Eliminating pathogens from the body.
Microbial Evolution: In response, microbes rapidly evolve mechanisms to overcome host defenses.
Microorganisms evolve with extraordinary speed compared to their hosts, multiplying much more rapidly.
Genes carried on plasmids contribute to this rapid evolution.
Host Response: The host has developed multiple defense systems with:
Overlapping mechanisms.
Various types of immune cells possessing duplicative and complementary actions.
Normal Flora
Microbial Antagonism: The normal flora of the body exhibits microbial antagonism against potential pathogens.
Commensal Organisms' Role: These organisms suppress the growth of potentially pathogenic bacteria and fungi by:
Already existing on epithelial surfaces, thus occupying ecological niches.
Outcompeting pathogens for essential nutrients.
Producing inhibitory substances such as acids or colicins.
Acquisition and Changes: Normal flora is established shortly after birth and dynamically changes throughout an individual's life.
Human Cell vs. Bacterial Count: Humans have approximately human cells in the body, but host approximately bacteria.
The majority of these bacteria reside in the bowel.
Internal organs and tissues are typically sterile.
Advantages of Normal Flora
Prevention of Pathogen Overgrowth: Prevents the proliferation of pathogenic species like Clostridium difficile, which causes pseudomembranous colitis.
This serious condition can arise after antibiotic therapy kills off beneficial normal flora.
Skin Bacteria: Produce fatty acids that discourage other species from invading.
Gut Bacteria: Commensal E. coli exhibit antibacterial activity.
They produce antimicrobial peptides called bacteriocins, which include colicins (proteins that kill other E.coli strains) and microcins (that can target pathogens like Salmonella).
Vaginal Lactobacilli: Maintain an acidic environment (pH approximately ) which inhibits the growth of other organisms.
Challenges Posed by Normal Flora
Potential for Spread: Normal flora can spread into previously sterile body parts, leading to infection under certain circumstances:
When the intestine is perforated or the skin barrier is broken.
During procedures such as dental extractions.
Organisms from the peri-anal skin ascending to the urethra and causing urinary tract infections.
Contributing to hospital-acquired (nosocomial) infections.
The Immune System Overview
Innate Immune System (Non-specific)
First Line of Defense: Activated first when a host is infected with a pathogen.
Components:
Physical Barriers: Skin, mucous membranes, etc.
Inflammation and Complement System.
Cellular Components:
White Blood Cells (Leukocytes).
Natural Killer Cells.
Mast Cells.
Eosinophils.
Basophils.
Phagocytic Cells: Macrophages, Neutrophils, Dendritic cells.
Adaptive Immune System (Specific)
Response Characteristics: Slower to activate, but highly specific and provides immunological "memory."
Components:
Humoral Immunity (Antibody-mediated immunity):
Mediated by macromolecules like secreted antibodies, complement proteins, and antimicrobial peptides found in extracellular body fluids.
Cell-mediated Immunity:
Involves the activation of phagocytes (e.g., macrophages) and Natural Killer Cells.
Features antigen-specific cytotoxic T-cells responding to a specific antigen (also known as T-cell immunity).
Innate Immunity (Rapid Response)
Physical Barriers Against Entry into the Body
Necessity for Overcoming Barriers: Before entering the body, microorganisms must overcome biochemical and physical barriers at the body surface.
Skin:
Normally impermeable.
Direct inhibitory effects from lactic acid and fatty acids in sweat and sebaceous secretions, resulting in a low pH environment.
Membranes Lining Inner Surfaces (e.g., mucous membranes):
Help prevent bacterial adherence to epithelial cells.
Microbial and other foreign particles can be trapped by adhesive mucus.
Flushing Actions: Tears, saliva, and urine provide a mechanical strategy to protect epithelial surfaces.
Secreted Body Fluids: Contain microbicidal factors.
Examples: Acid in gastric juice, spermine and zinc in semen, lactoperoxidase in milk, and lysozyme in tears, nasal secretions, and saliva.
Phagocytosis
Mechanism: Performed by cells called "phagocytes," which are immune cells capable of engulfing and killing microorganisms.
Types of Professional Phagocytes
Macrophages:
Originate in bone marrow as promonocytes, mature into circulating blood monocytes, and then into mature macrophages.
Widespread throughout tissues and the basement membrane of small blood vessels.
Found heavily in:
Lungs (alveolar macrophages).
Liver (Kupffer cells).
Lining of lymph node medullary sinuses.
Spleen.
Other locations: Brain microglia, kidney, osteoclasts in bones.
Polymorphonuclear Granulocytes (Polymorphs or Neutrophils):
Dominant white blood cell in the bloodstream, derived from the same stem cell precursor as macrophages.
Lack mitochondria and utilize cytoplasmic glycogen stores for energy.
Phagocytosis and Killing Mechanism
Recognition: Phagocytes recognize Pathogen-Associated Molecular Patterns (PAMPs).
Professional phagocytes use Pattern Recognition Receptors (PRRs) to detect conserved regions on microbes (PAMPs).
Examples of PAMPs include bacterial LPS, double-stranded RNA, and flagellin.
Engulfment: Binding of a PAMP to a PRR triggers engulfment by the phagocyte into a phagosome.
Killing: The phagosome fuses with the lysosome, forming a phagolysosome, which initiates the killing of the engulfed microorganism.
Extracellular Killing
Natural Killer (NK) Cells:
Large granular lymphocytes capable of killing infected host cells (cytotoxic).
Attach to virally-infected cells and differentiate them from normal cells before killing them.
Polymorphonuclear Leukocytes (PMNs):
Eosinophils:
Evolved to respond to larger pathogens too big for engulfment, such as helminths.
Many helminths activate the alternate complement pathway but are resistant to the resulting C9. However, their coating with C3b allows adherence to eosinophils, which possess a C3b receptor.
Once activated, the eosinophil attacks and damages the helminth.
Basophils:
Least abundant white blood cell (comprising - of circulating WBCs).
Responsible for inflammatory reactions during an immune response.
More commonly associated with allergic diseases.
Mast Cells:
Once thought to be type of basophil due to structural similarities and involvement in allergy and anaphylaxis, but are distinct cells developing from different hematopoietic precursor cells.
Note: Neutrophils are also PMNs but are primarily phagocytic.
Acute Phase Proteins (APPs)
Definition: Proteins in the plasma whose concentration increases in response to early 'alarms' like cytokines interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF).
These cytokines are small proteins used for cell signaling, released by immune cells such as macrophages, B lymphocytes, T-lymphocytes, and mast cells.
Examples: Mannose Binding Lectin and C-reactive protein dramatically increase during inflammation.
C-reactive protein (CRP):
An antibacterial agent produced by liver cells in response to IL-6 secreted from macrophages and T-cells.
Reacts with phosphorylcholine in the wall of dead or dying host cells (and some types of bacteria), activating the complement system and promoting phagocytosis.
Levels can rise -fold in hours.
Measured clinically to monitor inflammation in rheumatic disease.
Mannose Binding Lectin (MBL):
A type of collectin that recognizes carbohydrate patterns on a wide variety of microorganisms.
Collectins
Definition: Soluble Pattern Recognition Receptor (PRR) proteins that bind to oligosaccharide structures or lipids on the surface of microbes.
Functions: Result in cell recruitment, activation of the alternative complement cascade, and macrophage activation.
Types: Nine types of collectins have been defined, including mannose binding lectin.
Activation of the Complement System
Definition: Composed of a large number of distinct plasma proteins that react with one another.
Functions: Opsonize pathogens and induce an inflammatory response to fight infections.
Outcomes of Activation: Induction of the inflammatory response, promoting chemotaxis, phagocytosis, and vascular permeability.
Dendritic Cells
Phagocytic Nature: Like macrophages and neutrophils, dendritic cells are phagocytes.
Bridge to Adaptive Immunity: Unique in their role as messengers between the innate and adaptive immune systems.
Antigen-Presenting Cells (APCs):
After engulfment, they display antigens of the pathogen on their surface to T-cells.
Locations: Found in the skin (Langerhan's cells), inner lining of the nose, lungs, stomach, and intestines.
Activation and Migration: Once activated, they migrate to lymph nodes and interact with T cells and B cells to initiate the adaptive immune response.
Adaptive Immunity
Adaptive Immune Response Overview
Trigger: Organisms that overcome the innate immune system then encounter the adaptive immune response.
Humoral (Antibody-Mediated) Immunity
Antibodies: Immunoglobulin molecules synthesized by B lymphocytes in response to contact with a microbial antigen.
Specificity: Antibody molecules tightly bind to antigens of the microbe and are specific to that microbe.
Downstream Effects of Antibody Binding:
Activation of the complement cascade.
Inducing phagocytosis by macrophages and polymorphs (opsonization).
Antigen Marking: The antibody effectively marks specific pathogens that evaded innate responses, subjecting them to innate defenses (phagocytosis, complement).
Immune Memory: Antibodies "remember" a pathogen, allowing the adaptive immune response to mobilize more quickly upon re-exposure.
Structure of Antibodies
Two Main Regions:
Fc (Crystallizable) Region: Responsible for most differences in antibody function.
Fab (Antigen-Binding) Regions: Specific to an antigen.
Functional Adaptation: Switching from one Fc portion to another while preserving the same Fab portion allows the immune system to deploy different effector mechanisms against microbial pathogens.
Functions of Antibodies
Activation of Complement: Primarily through the "classical" pathway.
Note: Other mechanisms in the innate immune system can also activate classical and alternative pathways.
Activation of Phagocytic Cells (Opsonization):
The process by which a pathogen is marked for ingestion and destruction by a phagocyte.
Most important function of the antibody.
Rate of phagocytosis is enhanced by a -fold by antibody and complement acting together.
Blocking and Neutralizing Effects:
Simple binding of antibody molecules to a microbial surface is often sufficient to protect the host.
Can physically interfere with receptor interactions necessary for microbial entry or with toxin binding to host receptors; this is the basis of many vaccines.
Effective against organisms (viral, bacterial, protozoal) that use specific attachment sites.
Exception: For organisms that parasitize macrophages (e.g., Dengue fever), low levels of IgG can actually enhance infection by promoting binding to Fc receptors.
Immobilization and Agglutination:
Immunoglobulin antibodies are roughly the size of smaller viruses and larger than a bacterial flagellum, allowing physical attachment to restrict motile organisms.
The multivalent design of antibody molecules enables them to link together two or more organisms, causing agglutination.
Cell Mediated Immunity
T-cells (T-lymphocytes): Form the second main component of the adaptive immune response.
Defense Against Intracellular Organisms: Provide defense against intracellular organisms like viruses, certain bacteria, and protozoa.
Intracellular pathogens live inside cells, shielded from direct antibody attacks/binding.
Maturation: T-cells mature in the thymus gland.
Function of T-cells
Binding to Peptide Derived from Intracellular Organisms Complexed with MHC:
Microbe Processing: Microorganisms infecting a cell can die within it, and the host cell responds by breaking down the organism using enzymes ("processing"). Proteins from the organism are fragmented into peptides.
MHC Binding: The resulting peptides are incorporated into vacuoles and bind to a molecule in the Major Histocompatibility Complex (MHC).
MHC was discovered due to graft rejection in transplantation, but its key function is to act as cellular surface markers.
Class II MHC molecules are mainly found on macrophages and B cells.
T-cell Receptor (TCR) Recognition: A receptor on the T-cell functions similarly to an antibody in recognizing and binding to foreign antigens (resembles the Fab portion of an antibody).
Unlike antibodies, the TCR is designed to bind to MHC molecules, signaling to the T-cell that it has bound to a cell containing an intracellular microbe.
Activation: This binding activates the T-cell, triggering a downstream action.
Help Macrophages Kill Intracellular Parasites:
Specific T-cell Type: A specific type of T-cell (Th1, or T-helper cells) recognizes macrophages harboring intracellular microbes.
Activation Cascade: When the Th cell binds with an MHC molecule displaying microbial peptides on the surface of an infected macrophage, it triggers macrophage activating factors, specifically interferon gamma.
Microbe Killing: This triggers the infected macrophage to kill the infecting microbe.
Inhibit Intracellular Replication of Viruses:
Viral Peptide Presentation: Cells infected with a virus express MHC Class I molecules with virally derived peptides.
Cytotoxic T-cell Recognition: These are recognized by another type of T-cell, the Cytotoxic T-cell.
Killing Infected Cells: This recognition triggers the Cytotoxic T-cell to kill the infected host cell (the Cytotoxic T-cell performs both recognition and killing).
Killing Mechanism: Cytotoxic T-lymphocytes kill infected cells by inducing 'leaks' in the target cell.
The killing mechanism is non-specific, inducing leaks by inserting perforin, a kDa molecule.
Cell death occurs due to leakage and induction of apoptosis.
Disease Transmission
Four Types of Infections
Microorganisms with Specific Entry Mechanisms: Possess specific mechanisms for attaching to and penetrating the body surfaces of healthy hosts (e.g., most viruses, certain bacteria).
Arthropod-Introduced Microorganisms: Introduced into normal healthy hosts by biting arthropods (e.g., malaria, plague, yellow fever).
Wound/Bite Introduced Microorganisms: Introduced into normal healthy hosts via skin wounds or animal bites (e.g., Pasteurella multocida, rabies).
Opportunistic Microorganisms: Can only infect a host when normal defenses are impaired.
Entry, Exit, and Transmission Basics
Mammalian Host Surfaces: The mammalian host is a series of body surfaces (e.g., skin, mucous membranes).
Establishment: To establish themselves, microorganisms must attach to or penetrate these body surfaces.
Receptor Molecules: Specific molecules on microbes bind to specific molecules on the host.
Can be specific to certain cell types (%tropism%).
Examples: CD4 for HIV; C3d for Epstein-Barr virus.
Sites of Entry
Skin:
Microorganisms entering via skin may cause a skin infection or infection elsewhere.
On the skin, microbes (other than normal flora) can be inactivated by fatty acids and other substances secreted by sebaceous glands, and certain peptides formed by keratinocytes.
Skin bacteria may enter through hair follicles or sebaceous glands to cause styes or boils.
Wounds, abrasions, and burns are more common means of infection.
Bite of an Arthropod:
Mosquitoes, flies, ticks, and sandflies penetrate the skin during feeding and introduce infectious agents.
The arthropod transmits infection and is an essential part of the microorganism's lifecycle.
Conjunctiva:
Kept clean by the continuous flushing action of tears and blinking.
Organisms that infect the conjunctiva (e.g., chlamydia, gonococci) must possess efficient attachment mechanisms.
Respiratory Tract:
Cleaning Mechanisms: Inhaled particles are trapped in mucus and carried to the back of the throat through ciliary action, then swallowed.
Overcoming Defenses: Some microorganisms can overcome these cleaning mechanisms.
Interfering with Cleaning: Some organisms attach to cell surfaces, forming a mucociliary sheet. Specific molecules (adhesins) bind to receptor molecules on susceptible cells.
Inhibiting Ciliary Action: Microorganisms can inhibit ciliary action (e.g., Bordetella pertussis attaches to respiratory epithelial cells and interferes with cilia activity).
Avoiding Alveolar Macrophages: Inhaled microorganisms reaching the alveoli encounter alveolar macrophages; most are destroyed. Some pathogens have adapted to avoid phagocytosis (e.g., Tubercle bacilli survive in macrophages). Alveolar macrophages can also be destroyed by exposure to toxic substances like asbestos or certain dusts, increasing infection susceptibility.
Gastrointestinal Tract:
Attachment: Infecting bacteria attach themselves to the intestinal epithelium to avoid being carried through the alimentary canal and excreted.
Examples: Vibrio cholerae and rotaviruses specifically bind to receptors on the surface of intestinal epithelial cells.
Counteracting Defenses: Successful intestinal microbes must counteract or resist mucus, acids, enzymes, and bile.
Mucus: Acts as a mechanical barrier, contains molecules that bind to microbial adhesins, and includes secretory IgA antibodies.
Motility: Motile microorganisms (V. cholerae and Salmonella) can propel themselves through the mucus.
Enzyme Production: V. cholerae produces mucinase.
Urogenital Tract:
Microorganisms gaining entry can easily spread from one part of the tract to another.
Vaginal Defenses: During reproductive life, vaginal epithelium contains glycogen (due to estrogen) metabolized by certain Lactobacilli to produce lactic acid.
This results in a normal vaginal pH of approximately , inhibiting the colonization of many potential pathogens.
Urethral and Bladder Defenses: Include the regular flushing action of urine (bladder urine is normally sterile), a protective layer of mucus, and the ability to generate an immune response with secretory antibodies and immune cells.
Mechanisms of Urinary Tract Invasion: Nearly always invaded from the exterior via the urethra, with most organisms flushed out by urination.
Successful pathogens have developed special attachment mechanisms.
Example: %parasite-directed endocytosis% used by %Chlamydia%, where a peptide on bacterial pili binds to a carbohydrate polymer on the urethral cell, inducing the cell to engulf the bacterium.
Oropharynx (Throat):
Mechanisms of Invasion:
Specific Adhesion Factors: E.g., Streptococci attach specifically via lipoteichoic acid on their pili to the buccal (mouth) epithelium and tongue.
Reduced Mucosal Resistance: Factors that reduce mucosal resistance allow commensal and other bacteria to invade (e.g., gum infections caused by Candida infections, or thrush).
Protective Mechanisms:
Mucus.
Flushing action of saliva (humans produce about liter/day).
Secretory IgA (sIgA): Critical role in mucosal immunity, with two subclasses (IgA1 and IgA2) existing in a dimeric form. Main immunoglobulin in mucous secretions (tears, saliva, sweat, colostrum, genitourinary/gastrointestinal/respiratory secretions).
Lysozyme.
Exit and Transmission
Mechanisms: Microorganisms employ various mechanisms to ensure exit from the host and transmission to a new one.
Factors Governing Transmission:
The number of microorganisms shed.
The microorganism's stability in the environment.
The number of microorganisms required to infect a new host.
Types of Transmission Between Humans
Common Routes: The most common worldwide infections spread via respiratory, fecal-oral, or venereal routes.
Transmission from Respiratory Tract:
Respiratory infections spread rapidly in crowded indoor environments.
Increased nasal secretions with sneezing and coughing promote shedding.
A single sneeze can produce up to droplets, each containing many viral particles.
A smaller number of particles are expelled from the mouth, throat, larynx, and lungs during coughing.
Respiratory Spread and Droplet Size:
The size of inhaled droplets determines their initial localization.
Largest droplets fall to the ground after approximately meters.
Droplets of mm (micrometers) can be trapped in the nasal mucosa.
Droplets of - mm (micrometers) remain suspended indefinitely and can reach the lower respiratory tract.
Transmission from Gastrointestinal Tract:
Intestinal infections spread easily in conditions of poor public health and hygiene.
Historically, lack of sewage processing led to rampant fecal-oral transmission, which remains an issue in developing countries.
Adequate sewage systems and purified water effectively prevent most transmission of GI pathogens.
Transmission from the Urogenital Tract (Sexually Transmitted Diseases - STDs):
Microorganisms shed from the urogenital tract are often transmitted through contact with mucosal surfaces.
If the organism is present in discharge, it aids transmission (e.g., %Chlamydia%, %Gonorrhea%).
Can also be transmitted through open sores (e.g., %Syphilis%, %Herpes Simplex virus%).
STDs transmit with less speed than respiratory or intestinal infections.
Transmission from Oropharynx:
Saliva is the most common means of transmission.
Microorganisms reach saliva during upper and lower respiratory tract infections.
Certain viruses directly infect salivary glands and are shed in saliva (e.g., Paramyxovirus, HSV, Cytomegalovirus, Human Herpesvirus ).
Transmission from Skin:
Skin can spread infection via shedding or direct contact.
Humans shed skin at a rate of about skin scales per day.
Dermatophytes (fungi causing conditions like ringworm) are shed from skin, hair, and nails.
Transmission by direct contact or contaminated fingers is much more common.
Transmission from Blood:
Blood can spread via arthropods, needles, etc.
Sharing needles/intravenous drug use is a common spreading mechanism for bloodborne pathogens (e.g., HIV, HBV, HCV).
Not all infections can be spread by blood as the virus/bacteria may not be present in the bloodstream (e.g., HSV and Hepatitis A are not bloodborne).
Host/Parasite Relationships
Symbiotic Associations
Ubiquity: All living animals are used as habitats by other organisms, even bacteria are invaded by bacteriophages.
Colonization Complexity: The most complex bodies (birds, animals, humans) are the most colonized.
Constant Feature: Relationships between two species (symbiosis) are a constant biological feature.
Pathogenicity Variability: An organism may be pathogenic in one situation and harmless in another.
Types of Symbiosis: Commensalism, Mutualism, Parasitism.
Commensalism
Definition: One species lives harmlessly in or on the body of a larger species.
Characteristics: May acquire nutrients from the host, usually harmless, and can often benefit the host under normal circumstances.
Mutualism
Definition: Reciprocal benefits for both organisms.
Example: Bacteria and protozoa living in the stomachs of domestic ruminants play a critical role in cellulose digestion for the animal.
Distinction: Can be challenging to differentiate clearly between commensalism and mutualism.
Parasitism
Definition: A symbiotic relationship that benefits only the parasite.
Advantages for Parasite:
Metabolic, nutritional, and reproductive advantages.
Example: Viruses are completely dependent on their host for metabolic needs, using host machinery for transcription and translation while possessing their own genetic material.
Disadvantages for Parasite:
Host controls the development of the parasite.
No development is possible without a suitable host.
Adaptations to Counter Disadvantages: Parasites have evolved several adaptations to overcome this, such as virus particles, bacterial spores, protozoan cysts, and worm eggs.
Parasite Adaptations to Overcome Immune Responses
Evolutionary Pressure: Humans and mammals possess sophisticated inflammatory and immune responses due to constant infectious pressure.
Success Criterion: A successful parasite must overcome the host immune system.
Arms Race: The host-parasite relationship is never static; it is an ongoing arms race.
Host-Parasite Relationship Dynamics
Crucial Factor: The speed with which host adaptive responses can be initiated is crucial.
Consequences of Delay:
A delay in the host response can result in sufficient damage to cause disease.
From the microbe's perspective, a delay provides more time to be shed from the body, thereby spreading infection for a longer duration.