Discuss the ligands and molecular signaling pathways relevant to Toll-like Receptors (TLRs). List defects in TLR signaling pathways that are known to result in human disease.

Question

Discuss the ligands and molecular signaling pathways relevant to Toll-like Receptors (TLRs). List defects in TLR signaling pathways that are known to result in human disease.

(25 marks)

Answer 1

Toll-like receptors (TLRs) are a class of pattern recognition receptors (PRRs) that play a crucial role in the innate immune system. They are responsible for recognizing conserved molecular patterns associated with pathogens, known as pathogen-associated molecular patterns (PAMPs), as well as endogenous danger signals, called damage-associated molecular patterns (DAMPs). Upon activation, TLRs initiate signaling pathways that lead to the production of inflammatory cytokines, type I interferons, and other molecules involved in immune responses.

Some of the ligands of toll-like receptors include:

1. Microbial Components: TLRs recognize a variety of microbial components, including lipopolysaccharides (LPS), lipoproteins, peptidoglycans, flagellin, and nucleic acids (DNA and RNA) from bacteria, viruses, fungi, and other pathogens.
2. Endogenous Ligands: TLRs can also recognize endogenous molecules released from damaged or dying cells, such as heat shock proteins, high-mobility group box 1 (HMGB1), and various host nucleic acids.

Some common molecular signaling pathways:

1. MyD88-Dependent Pathway: Most TLRs signal through the myeloid differentiation primary response 88 (MyD88) pathway. Upon ligand binding, TLRs recruit adaptor proteins such as MyD88, leading to the activation of downstream signaling cascades involving interleukin-1 receptor-associated kinases (IRAKs), tumor necrosis factor receptor-associated factor 6 (TRAF6), and mitogen-activated protein kinases (MAPKs). This culminates in the activation of transcription factors such as nuclear factor-kappa B (NF-κB) and the production of pro-inflammatory cytokines.
2. TRIF-Dependent Pathway: TLR3 and TLR4 can also signal through the Toll/interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon-β (TRIF) pathway. This leads to the activation of interferon regulatory factor 3 (IRF3) and the production of type I interferons (IFNs), which play a crucial role in antiviral responses.

Defects in TLR signaling can lead to a magnitude of defect including but not limited to

1. Primary Immunodeficiencies: Mutations in genes encoding TLRs, their signaling adapters (e.g., MyD88, TRIF), or downstream signaling molecules can lead to primary immunodeficiency disorders characterized by increased susceptibility to recurrent infections. For example, mutations in MyD88 or IRAK4 result in defective signaling through the MyD88-dependent pathway and predispose individuals to severe bacterial infections.
2. Autoimmune Diseases: Dysregulated TLR signaling has been implicated in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel diseases (IBD). Aberrant TLR activation by endogenous ligands may contribute to chronic inflammation and autoimmunity.
3. Chronic Inflammatory Disorders: Defects in negative regulators of TLR signaling can lead to chronic inflammatory disorders characterized by excessive cytokine production and inflammation. For example, mutations in TOLLIP or SIGIRR have been associated with increased susceptibility to inflammatory bowel disease and other inflammatory conditions.
4. Cancer: Dysregulated TLR signaling has been implicated in cancer development and progression. TLR activation in tumor microenvironments can promote tumor growth, invasion, and metastasis by inducing pro-inflammatory cytokines, angiogenesis, and immunosuppressive pathways.

I know this is long but I hope this answered your question in depth! Please feel free to reach out if you want me to simplify it for you!

Answer 2

TLRs recognize a range of molecules derived from microbes or damaged host cells, known as PAMPs and DAMPs. These ligands bind to the extracellular domain of TLRs, triggering downstream signaling pathways that initiate immune responses. Here are some key ligand categories:

Gram-positive & Gram-negative bacteria: LPS from Gram-negative bacteria, lipoproteins, flagellin

Viruses: Viral RNA, ds RNA, viral DNA

Fungi: Beta-glucan, zymosan

DAMPs: HSPs, S100 proteins, HMGB1

Molecular Signaling Pathways: Upon ligand binding, TLRs undergo conformational changes and recruit intracellular adaptor molecules, mostly MyD88 and TRIF. These adaptors activate downstream pathways leading to the production of inflammatory mediators, co-stimulatory molecules, and type I interferons

MyD88-dependent pathway: This pathway is common to all TLRs except TLR3. It leads to the activation of NF-κB and MAP kinases, which ultimately induce the expression of pro-inflammatory cytokines and co-stimulatory molecules.

TRIF-dependent pathway: Primarily used by TLR3 and TLR4, this pathway activates IRF3, leading to the production of type I interferons. These interferons then activate the JAK-STAT pathway, further amplifying the immune response.

To answer the second question- Mutations or dysregulation in TLR signaling pathways can lead to various human diseases, impacting different aspects of the immune response:

Increased susceptibility to infections: Mutations in TLRs or their adaptor molecules can impair the recognition of pathogens, leading to increased susceptibility to infections, such as recurrent bacterial and viral infections.

Autoimmune diseases: Inappropriate activation of TLRs by DAMPs can trigger autoimmune responses, contributing to the development of diseases like lupus erythematosus and rheumatoid arthritis.

Chronic inflammatory diseases: Dysregulated TLR signaling can lead to chronic inflammation, playing a role in diseases like inflammatory bowel disease and asthma.

Cancer: Altered TLR signaling can be seen in some cancers, affecting tumor growth and immune evasion by cancer cells.

Sources: TLR3 contributes to persistent autophagy and heart failure in mice after myocardial infarction (www.ncbi.nlm.nih.gov/pmc/articles/PMC5742674/); Talin1 controls dendritic cell activation by regulating TLR complex assembly and signaling (www.ncbi.nlm.nih.gov/pmc/articles/PMC7398162/)