COMPREHENSIVE DATABASE ON TOLL LIKE

RECEPTORS

LITERATURE:

Essential to human survival is the ability to eradicate pathogenic

microorganisms. To ensure the efficient detection and removal of harmful
microbes, two effecter mechanisms have evolved: the innate and adaptive
immune systems; adaptive component consisting of specific T- and B-
lymphocytes that underwent clonal selection and expansion upon
presentation of a foreign antigen, as well as an innate component that was
characterized by its rapid mobilization and activation of effecter mechanisms
upon microbial challenge. Activation of innate immunity constituted the first
line of host defense against infection. The principal cellular components of
the innate immune system include polymorphonuclear leukocytes (PMNs),
tissue macrophages, dendritic cells (DCs), mast cells, and natural killer (NK)
cells (Qureshi et al., 2003). Far less attention has been directly towards
innate immunity, as it has been as a relatively nonspecific system, with its
main roles being to destroy pathogen and to present antigen to the cell
involved in adaptive immunity (Akira et al., 2004). The innate immune
system was a universal and ancient form of host defense against infection.
Innate immune recognition relied on a limited number of germline-encoded
receptors (Janeway et al., 2002) .These receptors evolved to recognize
conserved products of microbial metabolism produced by microbial
pathogens, but not by the host. Recognition of these molecular structures
allowed the immune system to distinguish infectious non-self from
noninfectious self (Janeway et al., 2002) .A molecular mechanism for innate
immune recognition of pathogens was established through identification of
the mammalian Toll-like receptor (TLR) gene family (Qureshi et al., 2003).
The discovery of TLRs has made us understanding of the mechanisms of
innate immune recognition.
Toll receptors were type I transmembrane proteins that were
evolutionarily conserved between insects and human. Toll was first
identified as an essential molecule for embryonic patterning in Drosophila
and was subsequently shown to play a key role in antifungal immunity
(Akira et al., 2001). Based on the similarity in the cytoplasmic portions
(designated the Toll-IL-1R, or TIR, domain), TLRs were related to IL-1
receptors (IL-1Rs) (Akira et al., 2001). By contrast, the extracellular region
of the TLRs and IL-1Rs differed markedly: the extracellular region of the
TLRs contained leucine-rich repeat (LRR) motifs, whereas the extracellular
region of the IL-1Rs contained three immunoglobulin-like domain (Akira et
al., 2004) .Within the TIR domain, the regions of homology comprised three
conserved boxes, which were crucial for signaling. The extracellular domain
of the TLRs contained 19-25 tandem copies of the LRR motifs. The repeats
comprised a -strands and an α-helix connected by loops. The LRR domains
of TLRs formed a horseshoe structure, and it was thought that the concave
surface of the LRR domains was involved directly in the recognition of
various pathogens. After ligand binding, TLRs/IL-1Rs dimerized and
underwent the conformational change required for the recruitment of
downstream signaling molecules. These molecules included the adaptor
molecule myeloid differentiation primary-response protein 88 (MyD88), IL-
1R-associated kinases (IRAKs), and tumor-necrosis factor (TNF)-receptor-
associated factor 6 (TRAF6). (Akira et al., 2004) Innate immunity provided
a rapid response to invasive stimuli (e.g. bacteria) mediated through pattern-
recognition receptors such as the toll-like receptors (TLRs). TLRs were the
critical signalling proteins for bacterial lipopolysaccharides (LPS; TLR4),
bacterial LPS/lipoproteins (TLR2) and bacterial DNA (TLR9) (Sabroe et al.,
2002), that played an important role in innate immune recognition of
pathogens. Recognition of conserved molecular patterns found on microbes
by these invariant, germline–encoded receptors led to a signal transduction
cascade that results in cellular activation and cytokine releases in both
immune and non-immune cells (Hayashi et al., 2003) .TLRs functioned as
sensors of microbial infection and were critical for the initiation of
inflammatory and immune defense responses. Stimulation of TLR signaling
pathways in tissues resulted in the rapid generation of an inflammatory
response and the production of pro-inflammatory cytokines, such as IL-1,
TNF-αand the chemokines (Sabroe et al., 2002).
Although 11 members of the TLR family have been identified in
mammals, the role of toll-like receptors on innate immunity have not been
well clarified yet (Akira et al., 2004).
In between these 12 years of the TLR discovery scientists have explored
it in organism as well as tissue level. Over the past few years, several
excellent reviews, literature articles, experimental data from gene knockout
studies detailing the many aspects of TLR biology have been published.
Most interesting part is in-between these 12 years the TLR related
publications has crossed a handsome 12,000 .That means 1000 papers in
average per year!!!!!!
 The past eight years have yielded substantial insight into the ligand
specificities, structure, and signaling cascades of TLRs, although many
fundamental questions remain(see below). Ultimately, the continued
characterization of TLR- and adaptor-deficientmice, in combination with in-
depth biochemicalanalysis of signaling pathways, will benecessary to round
out the knowledge of TLR biology. A complete understanding of the
molecular mechanisms governing TLR recognition and signaling will allow
development of therapeutic approaches that target responses from certain
TLRs while leaving the greater innate immune response intact, thus allowing
modulation of potentially harmful disorders such as sepsis and chronic
inflammation.Also there are currently 24 drugs in preclinical development,
with a further 18 in clinical trials (Graph 1). Aptly-named Innate Pharma is
developing IPH- 32XX, a series of TLR7 modulators for the treatment of
cancer, autoimmune and infectious diseases. Also in Innate's pipeline is IPH-
31XX, a double-stranded RNA which is the natural ligand of TLR3, usually
detected during viral infection. Activation of the TLR3 pathway leads to the
activation of NFkB and the production of type I interferons, and it is hoped
that this will be an effective method of destroying cancerous cells present in
melanoma and breast cancer. Both of Innate's TLR candidates are in the very
early stages of development, so it will be interesting to see how they perform
in the clinic.
So, the TLR bilogy is attracting the research to put their focous on it
and also the industrialist to lunch the products that to be used in TLR
research.
Such a burgeoning amount of biological information that are available
and supposed to be published in upcoming days on Toll like receptors is
confronting and will confront researchers (as researchers often review
multiple publications and other databases to arrive at a comprehensive
understanding and generate or validate their hypotheses) with challenges in
dealing with this large volume of complicated data. Hence, to obtain a
complete picture of the Toll like receptors and associated proteins at the
molecular, cellular, and organism levels one must look both at all of these
attributes and the relationships among them. To do that currently requires
finding which databases contain the relevant information and then searching
through the databases one by one. Although public data repositories such as
the National Center for Biotechnology Information (NCBI) and the Protein
Data Bank (PDB) integrate several databases on one site and contain much
of the publicly held biological data, these sites still face difficult problems
caused by a flood of new and diverse data and variation in format. In
addition, they suffer from a lack of robustness in search techniques for
highly interconnected databases, such as being stranded during a series of
search processes. Some requests inherently require going through a
complicated serial search on highly inter-related databases. Under these
circumstances, researchers have a hard time locating useful information in
an efficient way and keeping informed of updates. Unlike general search
engines used on the Internet, biological information searching is a specific
application domain. Although search engines such as Google may return
many positive results, these pages are ranked by popularity, not scientific
merit. Although there is a database on TLR i.e. TollML database but
limitation is ,it holds only structural motifs ( F. Jamitzky, J .Gong, T. Wei,
W.M. Heckl, and Shaila C. R¨ossl.,2008).

So, looking at these problems it is necessary to construct a comprehensive

database for Toll like receptors to help researchers to find almost all in
formations on TLR and its related proteins under a single and user friendly
interface. The mission of this database is to provide a new and critical
research domain and use them to extract accurate and reliable information in
order to gain new biological insights.

FEATURE LIST:

How to generate and maintain the list of keywords i.e. feature list for
individual biological information is a crucial issue to the project, because the
keywords are the indicator of information content to which the digital library
is to have access, and if relevant keywords are missing, the system will not
be able to assist the user. We assume that all the information in the databases
is to be completely indexed.
So in our feature list Toll like receptors was initially divided into
two basic categories: invertebrate TLRs and vertebrate TLRs. Then
invertebrate TLRs were further sub-divided into different phyla. Each
phylum was supported with a representative organism or organisms which
were used as a model to characterize the different features of the TLRs of
that phylum .Vertebrate TLRs were then categorized into TLRs belonging to
different vertebrate classes. The features associated with each class were
then specified. The features mainly include no. of TLRs, TLR structure,
TLR ligands, adaptor molecules involved, Signal transduction pathways,
function, expression, regulation, inhibition, phylogeny, genetics,
polymorphism, disease co-relation and therapeutic approaches.
CONSTRUCTION OF THE DATA FLOW DIAGRAM
(DFD):
Data flow diagrams illustrate how data is processed by a system in terms of
inputs and outputs. After preparing feature list they are assembled and
subjected to DFD construction.

Fig:

DATA MINING:

For the purpose of a comprehensive database on Toll Like Receptors

(TLRs), various informations available in the existing databases like NCBI,
PDB, Uniprot, KEGG, also in public databases etc are extracted and
validated. The texts were extracted by performing searches using the search
keys: *TLR, where*means different suffixes. The main object of text mining
in relation to TLRs is identifying experimental evidence or methods in the
literature, finding papers relevant for curation, and addressing specific and
well motivated biomedical problems. Some of the most popular tasks for
dataminging are:

1. Classification - arranging the data into pre-defined groups

2. Clustering – arranging similar groups together
3. Association – searching for relationship among variables
4. Regression - attempting to find the function which models the data with
least error.

FUTUREPROSPECTS:

*Construction of Interface Agent:

The interface, i.e. what the user sees, will be developed. The goal is to allow
the user to interact easily with the system.

*Data conversion: Adding data to the database.

*Expanding feature list.

REFERENCES

Akira S., et al., Toll like receptors: critical proteins linking innate and
acquired immunity. Nature review immunol., 2001.

Akira S. and Takeda K., Toll-like receptor signaling. Nature review

immunol., 2004.

F. Jamitzky, J .Gong, T. Wei, W.M. Heckl, and Shaila C. R¨ossl., TollML:

A Database of Toll-Like Receptor Structural Motifs. John von Neumann
Institute for Computing., 2008.

HayashiF., et al., Toll-like receptors stimulate human neutrophil function.

BLOOD., 2003.

Janeway C. A., Jr. and Medzhitov R., Innate Immune Recognition. Annu.
Rev. Immunol., 2002.

Qureshi S.T. and Medzhitov R., Toll-like receptors and their role in
experimental models of microbial infection. Genes and Immunity, 2003.

Sabroe I., et al., Chemokines, innate and adaptive immunity, and

respiratory disease. L3kEur Respir J 2002.