Question

7) Describe the signal transduction pathway that is activated when LPS binds to TLR-4. Chapter Section: 26.6

8) Predict the consequence for an individual of a deleterious genetic mutation in the gene for TLR-4. Chapter Section: 26.6

9) Briefly describe how a phagocyte engulfs and ingests a pathogen. Chapter Section: 26.6

10) How is immune memory beneficial to a host organism? Chapter Section: 26.1

11) Briefly describe the effect of deposition of antibody or complement on the surface of a pathogen or antigen in relation to opsonization. Chapter Section: 26.10

12) Briefly describe classical complement activation and cell damage. Chapter Section: 26.9

13) How do NK cells discriminate between normal, healthy cells and virus-infected or tumor cells? Chapter Section: 26.10

Answer 1

1. Signal Transduction Pathway when LPS binds to TLR4:

Toll-like receptor (TLR) are receptors expressed on the cells of innate immune system that are actively stimulated by the pathogen associated molecular patterns (PAMPs) expressed by bacteria, viruses and fungi. One such PAMP is Lipopolysaccharide (LPS) from Gram negative bacteria.

TLR 4 signal transduction:

When LPS is recognized by TLR4, signaling is divided into MyD88 dependent and MyD88-independent pathways. MyD88-dependent pathway results in activation of pro-inflammatory cytokines, while MyD88-independent pathway leads to induction of Type-I interferrons. MyD88 (myeloid differentiation primary response gene 88) is a critical adaptor in the interleukin-1 receptor (IL-1R) signaling pathway.  

a. MyD88-dependent pathway: TIRAP (TIR domain-containing adaptor protein, also known as Mal, MyD88-adapter-like) contains a phosphatidylinositol 4,5- bisphosphate (PIP2) binding domain. It mediates TIRAP recruitment to the plasma membrane. TIRAP helps in association between MyD88 and the TLR4 cytoplasmic domain to start MyD88-dependent downstream signaling.

MyD88 recruits and activates a death domain-containing kinase, IL-1 receptor-associated kinase-4 (IRAK-4). IRAK-4 kinase activity is important for transmitting TLR signals, including the induction of proinflammatory cytokines. IRAK-4 kinase activity may play a role in mRNA stability of certain cytokines and chemokines, such as TNF alpha and subsequent recruitment, activation and degradation of IRAK-1. Thereafter, TRAF6 (TNF receptor-associated factor 6) is an adaptor protein, which is important for downstream activation of TAK1 (transforming growth factor-b-activated kinase 1). TRAF6 forms a complex with UBC13 (ubiquitin-conjugating enzyme 13) and UEV1A (ubiquitin-conjugating enzyme E2 variant 1 isoform A) to activate TAK1. Thereafter, TAK1 activates IKK (I kappa B kinase) and MAPK (mitogen-activated protein kinase) pathways. Phosphorylation of I kappa B protein leads to its degradation and translocation of the transcription factor nuclear factor- kappa B (NF-kappa B), which controls the expression of proinflammatory cytokines. MAPK pathways leads to the induction of transcription factor AP-1, which induces expression of proinflammatory cytokines.

b. MyDD88-independent pathway: TRAM (TRIF-related adaptor molecule) mediate MyD88-independent signaling pathway. TRAM is essential for TLR4 signal transduction. It associates with the plasma membrane through myristoylation.

TRIF (TIR domain-containing adaptor inducing IFN-b) mediates MyD88-independent pathway. TRIF recruits TRAF3 (TNF receptor-associated factor 3) to activate interferon regulatory factor 3 (IRF3). In this activation process, TRAF3 associates with TANK (TRAF family member-associated NF-kappa B activator), TBK1 (TANK binding kinase 1) and IKKi to mediate downstream signaling. IRF3 along with NF-kappa B activates the transcription of Type I interferons genes.

On the other hand, TRIF also contains a Rip homotypic interaction motif (RHIM) that mediates the interaction with RIP1 (receptor-interacting protein 1). This RIP1 also activates transcription factors NF-kappa B and AP1. This further results in activation of Type I interferrons.

Thus, the stimulation of TLR4 by LPS leads to the release of important proinflammatory cytokines that are necessary to activate immune responses against invaded pathogens.