Innate Immune Response: Mechanisms, Cells, and HIV Pathogenesis

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Innate Immune Response

Overview of Immunity

The immune system protects the body from pathogens such as viruses, bacteria, and fungi through a combination of physical, chemical, and cellular mechanisms. Immunity is broadly divided into innate (nonspecific) and adaptive (specific) responses.

Innate immunity: Immediate, nonspecific defense against pathogens.
Adaptive immunity: Specific, acquired response involving lymphocytes and memory.

Learning Outcomes

Understand the role of the innate immune system.
Describe physical and cellular aspects of protection from disease.
Explain phagocytosis and mechanisms used to kill pathogens.
Provide examples of microbial evasion of innate immunity.
Distinguish between cellular and non-cellular innate immune responses.
Compare and contrast roles of various innate immune cells.
Explain HIV replication, genome organization, and treatment trends.

Physical Barriers to Infection

Physical Factors

Physical barriers are the first line of defense, preventing pathogen entry.

Skin: Acts as a physical barrier; contains antimicrobial peptides and acidic pH.
Mucous membranes: Line the gastrointestinal, respiratory, and genitourinary tracts.
Mucus: Viscous glycoproteins trap microbes and prevent tract desiccation.
Lacrimal apparatus: Drains tears, washing eyes.
Stomach acid: Low pH destroys pathogens.
Flushing of urinary tract: Prevents colonization.
Ciliary elevator: Moves mucus and trapped particles out of the respiratory tract.

Ciliary Elevator

The ciliary elevator is crucial for respiratory defense. Ciliated cells move mucus containing trapped microbes upward for expulsion. Disorders such as cystic fibrosis and primary ciliary dyskinesia impair this function, increasing infection risk.

The Blood and Lymphatic Systems

Circulation and Immune Surveillance

Blood and lymphatic systems transport immune cells and facilitate surveillance for pathogens.

Blood capillaries: Allow immune cells to pass in and out of circulation.
Lymph capillaries: Collect fluid and immune cells from tissues.

Innate Immune Cells and Their Functions

White Blood Cells (WBCs)

Innate immunity relies on several types of WBCs, each with specialized functions.

Phagocytes (e.g., macrophages, neutrophils): Ingest and degrade pathogens; present antigens to trigger adaptive immunity.
Granulocytes (basophils, eosinophils, neutrophils): Contain granules with enzymes/toxins; stimulate inflammation.
Natural Killer (NK) cells: Detect and destroy unhealthy cells using activating/inhibitory receptors.

Table: Major Innate Immune Cells

Cell Type	Recognition	Function
Neutrophil	Phagocytic	Engulf and destroy bacteria; acute inflammation
Macrophage	Phagocytic	Antigen presentation; phagocytosis; cytokine production
Eosinophil	Granules	Combat parasites; modulate allergic responses
Basophil	Granules	Release histamine; mediate allergic responses
NK cell	Receptors	Lyse virus-infected and tumor cells

Granulocyte Cells

Basophils: Release histamine and other mediators; involved in allergic reactions.
Eosinophils: Combat multicellular parasites; modulate inflammation and allergy.
Neutrophils: Most abundant; first responders to infection; phagocytose bacteria.

NK Cells

Detect healthy vs. unhealthy cells via activating/inhibitory receptors.
Induce apoptosis in infected or transformed cells.

Mechanism of Phagocytosis

Phagocytosis Steps

Phagocytosis is a multi-step process by which immune cells ingest and destroy pathogens.

Chemotaxis: Chemical signals attract phagocytes to infection site.
Adherence: Phagocyte attaches to pathogen surface.
Ingestion: Opsonization (coating with serum proteins) enhances ingestion.
Digestion: Pathogen is destroyed inside a phagolysosome.

Phagocyte Enzymes and Toxic Oxygen Compounds

Phagocytes generate reactive oxygen species (ROS) to kill engulfed microbes.

Key reactions include production of superoxide (), hydrogen peroxide (), and nitric oxide ().
Enzymes involved: NADPH oxidase, myeloperoxidase, nitric oxide synthase.

Microbial Evasion of Phagocytosis

Strategies Used by Pathogens

Some microbes have evolved mechanisms to evade destruction by phagocytes.

Mechanism	Example Organisms
Inhibit adherence (M protein, capsules)	Streptococcus pyogenes, S. pneumoniae
Kill phagocytes (leukocidins)	Staphylococcus aureus
Lyse phagocytes (membrane attack complex)	Listeria monocytogenes
Escape phagosome	Shigella, Rickettsia
Prevent phagosome-lysosome fusion	HIV, Mycobacterium tuberculosis
Survive in phagolysosome	Coxiella burnetii

Pathogen Recognition and Signal Transduction

PAMPs and Pattern Recognition Receptors

Innate immune cells recognize pathogens via pathogen-associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs).

PAMPs: Conserved microbial structures (e.g., peptidoglycan, flagellin, dsRNA, LPS).
PRRs: Host receptors (e.g., Toll-like receptors) that detect PAMPs and initiate immune responses.

Toll-Like Receptors (TLRs)

TLRs are a family of PRRs that recognize specific microbial ligands.

TLR	Ligand
TLR1/2	Lipoproteins, lipopeptides
TLR3	Double-stranded RNA
TLR4	Lipopolysaccharide (LPS)
TLR5	Flagellin
TLR7/8	Viral RNA
TLR9	Unmethylated CpG DNA

Inflammation and Fever

Inflammation

Inflammation is a protective response to infection or injury, characterized by redness, heat, swelling, and pain.

Activation of acute-phase proteins by the liver.
Release of mediators: histamine, kinins, prostaglandins, leukotrienes, cytokines.
Results in vasodilation and increased vascular permeability.

Fever

Fever is an elevation of body temperature in response to infection.

Triggered by pyrogens (e.g., LPS, cytokines) acting on the hypothalamus.
Enhances immune cell activity and inhibits pathogen growth.

Complement System

Pathways and Outcomes

The complement system consists of plasma proteins that enhance immune responses.

Activation pathways: classical, alternative, lectin.
Outcomes: cytolysis (membrane attack complex), opsonization (enhanced phagocytosis), inflammation.

Antiviral and Antimicrobial Mechanisms

Interferons (IFNs)

Alpha and beta interferons are cytokines produced in response to viral infection.

Induce antiviral states in neighboring cells.
Activate immune cells and inhibit viral replication.

Iron-Binding Proteins

Iron-binding proteins limit microbial growth by sequestering iron.

Transferrin: Blood and tissue fluids.
Lactoferrin: Milk, saliva, mucus.
Ferritin: Liver, spleen, bone marrow.
Hemoglobin: Red blood cells.
Bacteria produce siderophores to compete for iron.

Antimicrobial Peptides

Short peptides produced in response to microbial molecules.

Inhibit cell wall synthesis.
Form pores in plasma membrane.
Broad spectrum of activity against bacteria, fungi, and viruses.

HIV and AIDS: Pathogenesis and Immune Evasion

HIV Overview

Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS).

HIV infects cells expressing CD4 surface protein (macrophages, T-helper cells).
Interacts with coreceptors on target cells.
Worldwide impact: millions infected and deaths since 1981.

HIV Infection and Replication

HIV binds to CD4 and coreceptors, fuses with host cell membrane, and releases viral RNA.
Reverse transcription produces viral DNA, which integrates into host genome.
Viral genome integration favors active transcription units (high GC content, open chromatin).
HIV replication cycle includes entry, reverse transcription, integration, transcription, assembly, and budding.

HIV Genome Organization

HIV-1 genome encodes structural (gag, pol, env) and regulatory proteins.
Mature virion contains envelope glycoproteins, capsid, and RNA genome.

Progression of HIV Infection

Decline of CD4 T lymphocytes leads to immune deficiency.
Progression from asymptomatic to severe immune dysfunction and AIDS.

HAART (Highly Active Antiretroviral Therapy)

Combination therapy reduces viral load and increases survival.
Regimens include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside RTIs (NNRTIs), and protease inhibitors.

HIV Incidence Trends

Recent years show a decline in new HIV infections in the US.

Summary: Complexity of the Immune System

The immune system involves numerous cell types, signaling molecules, and regulatory pathways. Effective defense requires coordination between innate and adaptive responses, with many factors influencing the outcome of infection.

Example: The interplay between phagocytes, complement, and interferons is critical for controlling viral and bacterial infections, while pathogens like HIV have evolved sophisticated mechanisms to evade these defenses.

Additional info: Some diagrams and tables have been expanded for clarity and completeness based on standard microbiology textbook content.