G protein-coupled receptors: The choreographers of innate immunity in Caenorhabditis elegans

Caenorhabditis elegans is a free-living, bacterivorous nematode that frequently encounters
pathogens while foraging for food in decomposing vegetation. Like other invertebrates, C. elegans entirely relies on its innate immune system to combat invading pathogens. A basal flight
or fight response of animals is also observed in worms against infection. The former is an aversion response of C. elegans against select pathogens, and the latter is an inducible innate
response comprising of pathogen-specific effectors including lysozymes, lectins, antimicrobial
peptides (AMPs), and cytoprotective molecules. Although pathogen recognition in worms is
poorly understood, various signaling pathways and immune effectors facilitating defense
response are well studied, making this nematode an excellent model to study host–microbe
interactions. In higher vertebrates such as mice and humans, sensing of infection through
pathogen-associated molecular patterns (PAMPs) or host damage-associated molecular patterns (DAMPs) is primarily mediated by the toll-like receptors (TLRs), nod-like receptors
(NLRs), RIG-I like receptors (RLRs), C-type lectin domain (CTLD) proteins, and AIM-like
receptors (ALRs) [1]. Humans have 10 TLRs that sense PAMPs and DAMPs. However, TOL1, the only TLR homolog in C. elegans, does not seem to be essential during infections with
most pathogens, except during Salmonella enterica [2] and Serratia marcescens [3] infections.
The C. elegans RIG-I like receptor DRH-1 detects products of viral replication and activates an
intracellular pathogen response [4]. CLEC-39 and CLEC-49, two CTLD proteins in C. elegans,
are essential for immune responses against S. marcescens and are known to bind live bacteria
[5]. Despite all these findings, the molecular mechanisms involved in pattern recognition by C.
elegans during a majority of infections remain elusive. In this review, we examine the roles of
G protein-coupled receptors (GPCRs) as noncanonical pattern recognition receptors (PRRs)
and also discuss how GPCR signaling in C. elegans regulates various immune processes.
GPCRs form the largest superfamily of cell surface receptors in eukaryotes; C. elegans
encodes approximately 1,300 genes encoding putative GPCRs [6]. They are involved in a variety of physiological processes [7] and also for detecting various environmental cues, including
bacterial secondary metabolites [8]. In recent years, several studies on infection in C. elegans
have revealed the importance of GPCRs and their signaling in host defense. In this review, we
examine the role of GPCRs in innate immunity via the modulation of “flight” or “fight”
responses of C. elegans.