Host-Pathogen Interactions in Innate Immune Pathways
Host-pathogen interactions describe complex and dynamic processes that
include all stages of pathogenic infection, from invasion to
dissemination. Both host cells and pathogens have evolved to adopt a
wide array of strategies to interact and survive, adding to the
traditional views of host-pathogen interactions. These new insights shed
light on the intracellular signaling pathways that lead to the innate
immune response. Central to the new studies was the discovery of pattern
recognition receptors (PRRs) on the innate immune cells (dendritic cells
and macrophages) that can recognize pathogen-associated molecular
patterns (PAMPs) derived from various microbes. Among several classes of
these PRRs including RIG-I-like receptors (RLRs) and Nod-like receptors
(NLRs), the toll-like receptors (TLRs) are best characterized and are
specific in their response.1 Human TLRs can be
classified as either cell-surface TLRs (i.e., TLR1, TLR2, TLR4, TLR5,
TLR6, and TLR10) or intracellular TLRs that are localized in the
endosome (i.e., TLR3, TLR7, TLR8, TLR9, TLR11, TLR12, and TLR13). Each
TLR is composed of leucine-rich repeats (LRRs) that recognize PAMPs, a
transmembrane domain, and a cytoplasmic Toll/IL-1 receptor (TIR) domain
that triggers downstream signaling, resulting in the production of
effector molecules, including cytokines, chemokines, and antimicrobial
proteins, to combat the invading pathogens.2 Signaling
pathways associated with different TLRs can also vary, since they
respond to different stimuli and recruit different adaptor proteins in
different temporal patterns. For example, TLR4 recognizes
lipopolysaccharide (LPS), an integral component of the outer membranes
of Gram-negative bacteria that causes endotoxic shock and activates the
MyD88/IRAK signaling pathways.3 TLR3 is localized in
the endosome and recognizes double-stranded RNA (dsRNA), a viral
replication intermediate, initiating the downstream signaling for
interferon production.4 TLR signaling occurs via two
major pathways, MyD88 dependent and TRIF dependent, named after the
adaptor proteins initiating signal transduction pathways. MyD88 and TRIF
activate NF-κB, IRFs (interferon regulatory factors) and MAPK
(mitogen-activated protein kinase) to regulate the expression of
inflammatory cytokines and type I IFNs.5
Aberrations in the PAMP recognition or mutations in molecules involved
in TLR signaling pathway can cause autoimmune, inflammatory and allergic
diseases. Post translational modifications (PTMs) on the signaling
molecules such as ubiquitination and phosphorylation play critical roles
in the activation of TLR signaling, and hence their characterization is
highly informative in decoding the mechanism of signaling. Efforts have
been made to identify molecules (proteins, transcripts, metabolites and
lipids), through integrated approaches, at both cell and tissue
level.6
Here, we provide a comprehensive overview of the current and emerging
tools for systems level analysis of innate immunity. The next sections
highlight the prominent contribution of “omics” methodologies in
understanding the innate immune signaling pathways at systems level.
Along with the description of techniques, case studies are also
presented to elaborate on the suitability and applicability of each
technique, depth and breadth of information it provides, and the data
analysis needed to process the information. Figure 1. presents a brief
timeline of the various “omics” technologies in terms of their first
appearance and the application in context.
MULTIOMICS IN INNATE IMMUNITY: