Cellular Receptors for Microbes Products of Damaged Cells and Foreign Substances

Slide 1 · Cellular Receptors for Microbes, Products of Damaged Cells, and Foreign Substances

Pattern recognition, danger sensing, and early innate immune responses

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish microbial PAMPs from host-derived DAMPs.

Locate major pattern-recognition receptor families in cellular compartments.

Explain TLR, inflammasome, RLR, STING, and surface-receptor responses.

Connect sensing pathways with selected inflammatory and immune disorders.

Slide 3 · Innate immunity detects danger before clonal antigen recognition

Microbial invasion or tissue injury

Cellular pattern recognition

Inflammation or antiviral defense

The initiating signal need not be an antigen recognized by a T- or B-cell receptor.

Early recognition is distributed across phagocytes, dendritic cells, and epithelial cells.

Slide 4 · A receptor converts a molecular signature into a response

Shared microbial or injury signal

Pattern-recognition receptor

Intracellular signaling

Effector response

Receptor specificity determines which danger signals are sensed.

The signaling pathway determines cytokine production, chemotaxis, or uptake.

Slide 5 · PAMPs are shared microbial molecular patterns

Pathogen-associated molecular patterns (PAMPs) occur in related microbes.

They are frequently important for microbial infectivity or survival.

Recognition is directed at conserved features rather than unique antigen clones.

Microbe

Conserved component (PAMP)

Innate detection

Slide 6 · Conservation makes PAMP recognition robust

Conserved pattern

Shared across multiple microbes

May be constrained by microbial function

Supports broad early recognition

Highly variable feature

More easily altered by microbial evolution

Not the defining target of PRRs

Not needed to explain this mechanism

A PRR recognizes a class of danger-associated structures—not every possible microbial epitope.

Slide 7 · DAMPs signal injury without requiring infection

Damage-associated molecular patterns (DAMPs) are released or exposed by injured and necrotic cells.

They provide evidence of disrupted host tissue integrity.

ATP and uric acid are source-described examples of danger-associated signals.

Tissue injury / necrosis

Released or altered host molecules

Inflammatory sensing

Slide 8 · PAMPs and DAMPs differ in origin—not in the need for sensing

PAMP

Source: Microbes

Biological meaning: Infectious threat

Example category: Microbial nucleic acids

DAMP

Source: Injured host tissue

Biological meaning: Tissue damage

Examples: Extracellular ATP, uric acid

Both can initiate innate immune signaling through appropriate receptor pathways.

Slide 9 · Localization organizes pattern recognition

Plasma membrane

Samples extracellular microbes and their surface products.

Endosomal membrane

Samples nucleic acids of internalized microbes.

Cytosol

Detects cytoplasmic nucleic acids and damage-related perturbations.

Slide 10 · Surface receptors detect material outside the cell

Plasma-membrane TLRs recognize selected microbial products.

C-type lectins bind fungal glycans.

Leukocyte G protein–coupled receptors detect N-formylated bacterial peptides.

Mannose receptors promote microbial uptake.

Extracellular molecular pattern

Surface receptor

Cellular response

Slide 11 · Endosomal receptors sample internalized material

Microbe taken into vesicle

Microbial nucleic acids in endosome

Endosomal TLR sensing

The membrane-bound compartment creates an additional surveillance site.

Compartmentalization enables recognition after microbial uptake.

Slide 12 · Cytosolic sensing covers intracellular invasion

NOD-like receptors

Microbial products, injury signals, and ionic disturbance.

RIG-like receptors

RNA from viruses replicating in the cytosol.

DNA sensing → STING

Cytosolic microbial DNA or mislocalized self DNA.

Slide 13 · Receptor families occupy distinct cellular compartments

Extracellular space

Surface TLR

C-type lectin

Mannose receptor

Peptide GPCR

Plasma membrane

Cytosol

NOD-like receptors

RIG-like receptors

Cytosolic DNA sensors

Endosome

Endosomal TLR

Inflammasome

Type I IFN

Type I IFN

Slide 14 · Innate sentinel cells express overlapping receptor sets

Phagocytes

Sense and ingest microbes; Macrophages can also sustain inflammation.

Dendritic cells

Detect danger and produce cytokines in addition to antigen presentation.

Epithelial cells

Participate in sensing at barrier surfaces.

Slide 15 · Five principal recognition systems in this section

System

Recognized signal

Main response

Toll-like receptors

Various microbial molecules

NF-κB / IRF signaling

NOD-like receptors

Cell damage / microbial cues

Inflammasome–IL-1 pathway

RIG-like receptors

Cytosolic viral RNA

Type I interferons

Cytosolic DNA sensing

Cytosolic DNA

STING–type I interferons

Surface lectin / other receptors

Glycans, peptides, sugars

Inflammation, movement, uptake

Slide 16 · Toll-like receptors are a major PRR family

The Toll family was first linked to development in Drosophila.

Related mammalian Toll-like receptors are essential to host defense.

A family of 10 mammalian TLRs.

Microbial ligand

TLR activation

Antimicrobial gene programs

Slide 17 · TLRs are distributed across membranes

Plasma-membrane TLRs

Face extracellular microbial products

Recognize selected ligand classes

Can trigger inflammatory transcription

Endosomal TLRs

Face contents of internalized vesicles

Detect microbial nucleic acids

Can induce antiviral gene programs

Location influences the material available for detection.

Slide 18 · Extracellular microbes can activate surface TLRs

Extracellular microbial product

Surface Toll-like receptor

Transcriptional activation

Inflammatory response

This is a compartment-based schematic, not a complete catalog of TLR–ligand pairs.

Slide 19 · Microbial nucleic acids can activate endosomal TLRs

Microbial uptake

Endosomal nucleic-acid recognition

TLR-dependent signal

Host defense genes

Vesicle localization permits detection of nucleic acids from ingested microbes.

Slide 20 · NF-κB drives the inflammatory arm of TLR signaling

TLR engagement

NF-κB activation

Cytokines + adhesion molecules

Leukocyte recruitment

Cytokine production and adhesion-molecule expression are both central to inflammation.

Slide 21 · IRFs initiate the type I interferon arm

Relevant TLR signaling

Interferon regulatory factors

Type I interferon production

Antiviral defense

IRFs are transcription factors; Type I IFNs are secreted antiviral cytokines.

Slide 22 · TLR signaling yields two major effector programs

NF-κB program

Inflammatory cytokine secretion

Adhesion molecule expression

Recruitment and activation of leukocytes

IRF program

Type I interferon production

Antiviral cytokine signaling

Restriction of viral threat

Pathway usage depends on the receptor and stimulus; This is a functional summary, not a claim that every TLR equally engages both arms.

Slide 23 · Receptor signaling translates into tissue inflammation

Pattern recognition

Cytokines / adhesion molecules

Leukocytes move into tissue

Microbial or debris clearance

The tissue outcome follows coordinated signaling and cellular recruitment.

Slide 24 · Defective TLR signaling can impair host defense

Inherited loss-of-function variants in TLRs or their pathways can cause rare severe immunodeficiency.

A normal receptor–signal axis is necessary for appropriate early defense.

The textbook does not specify a universal clinical phenotype for all such defects.

Loss of pathway function

Reduced innate signal

Susceptibility to infection

Slide 25 · Type I IFN defects heighten viral vulnerability

Inherited or acquired impairment of type I IFN production/function may cause severe viral disease.

The source explicitly cites severe SARS-CoV-2 infection as an example.

IFN insufficiency and IFN overactivation have distinct pathological consequences.

Reduced type I IFN

Weakened antiviral response

Severe viral infection risk

Slide 26 · NOD-like receptors survey intracellular danger

NOD-like receptors (NLRs) are cytosolic pattern-recognition proteins.

The family name derives from NOD2: Nucleotide-binding oligomerization domain-containing protein 2.

Family members respond to multiple microbial and host injury-related cues.

Cytosolic danger signals

NLR sensing

Inflammatory machinery

Slide 27 · NLRs respond to diverse signs of cellular damage

Microbial products

Intracellular microbial structures can be recognized.

Injury-related molecules

Extracellular ATP and uric-acid-associated signals are examples.

Ionic disturbance

Reduced cytosolic K⁺ is another detectable danger state.

Slide 28 · K⁺ efflux is a danger-associated cellular change

Stimulus or membrane perturbation

Loss of intracellular K⁺

NLR-associated sensing

Inflammasome response

The textbook recognizes loss of K⁺ as a signal; Its molecular recognition details remain incompletely understood.

Slide 29 · The inflammasome is a multiprotein signaling platform

Several NLR family members signal through cytosolic inflammasome complexes.

An inflammasome couples danger sensing to protease activation.

Its key downstream enzyme is caspase-1.

Danger detection

Multiprotein assembly

Caspase-1 activation

Slide 30 · The NLRP3 inflammasome contains distinct components

Sensor

NLRP3 recognizes or responds to activating danger states.

Adaptor

Links signaling components within the complex.

Effector protease

Caspase-1 is activated within the assembled complex.

Slide 31 · Inflammasome activation couples synthesis with processing

Inflammatory receptor signals

Pro–IL-1β is produced

Inflammasome activates caspase-1

Mature IL-1β released

The source figure depicts receptor-induced pro–IL-1 production and subsequent proteolytic processing.

Slide 32 · Caspase-1 converts inactive precursor into active IL-1

Pro–IL-1β (precursor)

Active caspase-1 cleavage

Mature IL-1β

Inflammatory effects

Proteolytic activation is distinct from transcriptional induction of the precursor.

Slide 33 · IL-1 promotes recruitment of inflammatory cells

Mature IL-1β secretion

Local inflammatory signaling

Leukocyte recruitment

Removal of damaged material

Inflammatory signaling is protective when appropriately regulated, but injurious if excessive.

Slide 34 · IL-1 signaling can produce fever

IL-1 is an important endogenous inflammatory mediator.

Cytokine release links cellular danger recognition with a systemic febrile response.

Repeated inappropriate activation provides a mechanistic explanation for periodic fever syndromes.

Inflammasome activation

IL-1 released

Fever / inflammation

Slide 35 · Inflammasome dysregulation causes autoinflammation

Gain-of-function changes in NLRs or related proteins can amplify responses.

Loss of inhibitory regulators can also permit excessive pathway activity.

The resulting disorders may present with periodic fever and other inflammatory symptoms.

Excess inflammasome activity

High IL-1 signaling

Recurrent inflammation

Slide 36 · Autoinflammation is not synonymous with autoimmunity

Autoinflammatory syndromes

Primary abnormality in innate inflammatory pathways

May feature periodic fever

Inflammasome / IL-1 pathway may be central

Autoimmune diseases

Driven by reactions of T and B cells to self antigens

Adaptive immune specificity is pivotal

Different initiating pathobiology

Clinical manifestations can overlap; The mechanistic distinction concerns the dominant initiating immune system.

Slide 37 · IL-1 antagonism targets the effector pathway

Dysregulated inflammasome

Excess IL-1 activity

IL-1 pathway blockade

Reduced inflammatory manifestations

Inflammasome-related autoinflammatory syndromes respond well to IL-1 antagonists.

No specific drug, regimen, or response rate is asserted.

Slide 38 · Urate crystals link inflammasome sensing to gout

Urate crystal deposition

NLR-related inflammasome activation

IL-1-mediated inflammation

Gout-associated tissue response

The core principle is sterile crystal-induced inflammation rather than microbial invasion.

Slide 39 · Cholesterol crystals may amplify atherosclerotic inflammation

Excess cholesterol crystals in tissue

Innate danger sensing

Inflammatory response

Contribution to atherosclerosis

The textbook uses qualified language: This pathway may contribute to atherosclerosis.

Do not interpret this mechanism as the sole cause of the disease.

Slide 40 · Crystals can provoke sterile inflammation through a shared route

Urate crystals

Clinical association: Gout

Activates inflammasome-related inflammation

Established example in source

Cholesterol crystals

Present when tissue cholesterol accumulates

Can elicit receptor-associated inflammation

Possible contribution to atherosclerosis

Both illustrate how nonmicrobial material may engage innate immune injury pathways.

Slide 41 · RIG-like receptors detect cytosolic viral RNA

RIG-like receptors (RLRs) occur in the cytosol of many cell types.

They were named for RIG-I: Retinoic acid-inducible gene I.

They recognize RNA associated with viruses replicating inside the cytosol.

Viral RNA in cytosol

RLR sensing

Type I IFN production

Slide 42 · Viral replication places RNA within the sensing compartment

Virus infects cell

Viral RNA appears in cytosol

RIG-like receptor activation

Antiviral cytokines

RLRs recognize the intracellular molecular context of infection.

Slide 43 · Cytosolic DNA can signal microbial or host danger

Microbial DNA

May derive from viruses present within the cell.

Mislocalized self DNA

Accumulation of host DNA in cytosol can also trigger sensing.

Common outcome

DNA sensors engage the STING pathway for type I IFN generation.

Slide 44 · STING links cytosolic DNA recognition to interferons

Cytosolic microbial / self DNA

Cytosolic DNA sensing

STING pathway

Type I interferons

STING denotes stimulator of interferon genes; It is a signaling pathway component, not a synonym for every DNA sensor.

Slide 45 · Excess STING pathway activity causes interferonopathies

Antiviral signaling must be controlled in magnitude and duration.

Excessive STING signaling can produce systemic inflammatory conditions.

The textbook groups these conditions as interferonopathies.

Overactive STING pathway

Excess interferon-associated response

Systemic inflammation

Slide 46 · RNA and DNA sensing converge on type I interferons

RIG-like receptor system

Trigger: Cytosolic viral RNA

Sensor: RIG-like receptor

Product: Type I IFN

Cytosolic DNA system

Trigger: Cytosolic DNA, microbial or host

Signal: DNA-sensor → STING

Product: Type I IFN

Distinct upstream sensors can engage an overlapping antiviral effector program.

Slide 47 · C-type lectin receptors recognize fungal glycans

C-type lectin receptors (CLRs), including Dectins, are expressed on macrophages and dendritic cells.

They are located at the plasma membrane.

Fungal glycans trigger inflammatory responses through these receptors.

Fungal surface glycans

C-type lectin recognition

Antifungal inflammatory signaling

Slide 48 · Fungal glycans provide a recognizable surface signature

Fungal carbohydrate structures

C-type lectin on innate cell

Innate activation

Inflammatory defense

CLRs are an additional surface-sensing system; They are not the same receptor family as TLRs.

Slide 49 · Leukocyte GPCRs detect bacterial N-formyl peptides

Neutrophils and macrophages express receptors for short N-formylmethionyl bacterial peptides.

These are plasma-membrane G protein–coupled receptors.

Detection provides directional information about the source of bacterial products.

N-formyl bacterial peptides

Leukocyte GPCR

Chemotactic movement

Slide 50 · Chemotaxis links bacterial detection to cell movement

Bacterial peptide gradient

Leukocyte GPCR sensing

Directional migration

Movement toward bacterial source

This pathway primarily explains movement toward a signal source, not direct microbial digestion.

Slide 51 · N-formylmethionine distinguishes many bacterial proteins

Bacterial proteins

Initiation commonly involves N-formylmethionine

Provide N-formyl-containing peptides

Recognized by leukocyte chemotactic receptors

Mammalian proteins

Most cytosolic proteins lack this initiation feature

Mitochondrially synthesized proteins are a notable exception

Recognition is not perfectly exclusive to bacteria

The mitochondrial exception is important when interpreting specificity.

Slide 52 · Mannose receptors support microbial phagocytosis

Microbial terminal mannose-rich sugars

Mannose receptor binding

Microbial internalization

Phagocytosis

Microbial glycosylation patterns differ from typical mammalian glycoproteins.

Slide 53 · Different receptors produce different cellular actions

Receptor / pathway

Signal

Teaching endpoint

TLRs → NF-κB

Microbial products

Cytokines / adhesion molecules

TLRs or nucleic acid sensors → IFN

Microbial nucleic acids

Antiviral defense

NLR / inflammasome

Cell damage and selected stimuli

Caspase-1 → IL-1

N-formyl peptide GPCR

Bacterial peptide

Chemotaxis

Mannose receptor

Microbial sugars

Phagocytosis

Slide 54 · Matching ligand, location, and receptor improves reasoning

Where is the signal?

What is being sensed?

Likely system

Outside cell

Fungal glycans

C-type lectin receptors

Endosome

Nucleic acids of ingested microbes

Endosomal TLRs

Cytosol

Viral RNA

RIG-like receptors

Cytosol

DNA

DNA sensors / STING

Cytosol

Damage / K⁺ disturbance

NOD-like pathway

Slide 55 · Innate receptor pathways diverge into distinct responses

Microbial products

TLR → NF-κB / IRFs

Cytokines / IFNs

Damage or crystals

NLR inflammasome

Mature IL-1β

Cytosolic viral RNA

RIG-like receptor

Type I IFN

Bacterial N-formyl peptide

Leukocyte GPCR

Chemotaxis

Microbial terminal mannose

Mannose receptor

Phagocytosis

Slide 56 · Clinical reasoning: Acute crystal-associated inflammation

Crystals are deposited in tissue, followed by a marked inflammatory response without a pathogen being necessary.

Which innate pathway best connects the particulate danger signal to IL-1 activity?

NLR-related inflammasome activation → caspase-1 → mature IL-1.

This is the mechanistic association used explanation of gout.

Slide 57 · Clinical reasoning: Severe viral disease with impaired interferons

An inherited or acquired defect reduces type I interferon production or function during viral infection.

Which immune consequence follows directly from the source-described mechanism?

Impaired early antiviral defense with increased risk of severe viral infection.

Type I IFN deficiency is associated with severe viral infections, including SARS-CoV-2 infection.

Slide 58 · Clinical reasoning: Extracellular fungus and bacterial peptides

A macrophage encounters fungal glycans; A nearby neutrophil detects a concentration gradient of bacterial N-formyl peptides.

Which receptor function explains each response?

C-type lectin receptor → fungal inflammatory sensing; N-formyl peptide GPCR → chemotaxis.

Recognition of glycans and directed migration are distinct receptor outputs.

Slide 59 · Frequent conceptual errors to avoid

Incorrect inference

All PRRs reside at the cell surface.

Every PRR recognizes microbial material only.

STING and RIG-like receptors have identical upstream ligands.

Correct interpretation

PRRs span surface, endosomal and cytosolic compartments.

Host damage and crystals can trigger innate sensing.

Cytosolic RNA and DNA engage different proximal systems.

A useful organizing question is: What ligand, in which compartment, activates what response?

Slide 60 · Five outputs integrate receptor biology with pathology

Inflammation

NF-κB, cytokines and adhesion molecules recruit leukocytes.

Antiviral defense

IRFs and cytosolic nucleic-acid pathways produce type I IFNs.

IL-1-driven pathology

Inflammasomes link danger to caspase-1 and fever.

Directed migration

N-formyl peptide receptors guide chemotaxis.

Particle uptake

Mannose recognition helps microbial phagocytosis.

Slide 61 · Primary reading

Robbins, Cotran & Kumar: Pathologic Basis of Disease.

11th edition (2026).

Section: Cellular Receptors for Microbes, Products of Damaged Cells, and Foreign Substances.

Conceptual schematics are original editable PowerPoint objects; they are not reproduced textbook figures.