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: