Specific Pathogen Recognition by Multiple Innate Immune Sensors in an Invertebrate

Abstract

Detection of pathogens by all living organisms is the primary step needed to implement a coherent and efficient immune response. This implies a mediation by different soluble and/or membrane-anchored proteins related to innate immune receptors called PRRs (pattern-recognition receptors) to trigger immune signaling pathways. In most invertebrates, their roles have been inferred by analogy to those already characterized in vertebrate homologs. Despite the induction of their gene expression upon challenge and the presence of structural domains associated with the detection of pathogen-associated molecular patterns in their sequence, their exact role in the induction of immune response and their binding capacity still remain to be demonstrated. To this purpose, we developed a fast interactome approach, usable on any host–pathogen couple, to identify soluble proteins capable of directly or indirectly detecting the presence of pathogens. To investigate the molecular basis of immune recognition specificity, different pathogens (Gram-positive bacterium, Micrococcus luteus; Gram-negative, Escherichia coli; yeast, Saccharomyces cerevisiae; and metazoan parasites, Echinostoma caproni or Schistosoma mansoni) were exposed to hemocyte-free hemolymph from the gastropod Biomphalaria glabrata. Twenty-three different proteins bound to pathogens were identified and grouped into three different categories based on their primary function. Each pathogen was recognized by a specific but overlapping set of circulating proteins in mollusk’s hemolymph. While known PRRs such as C-type lectins were identified, other proteins not known to be primarily involved in pathogen recognition were found, including actin, tubulin, collagen, and hemoglobin. Confocal microscopy and specific fluorescent labeling revealed that extracellular actin present in snail hemolymph was able to bind to yeasts and induce their clotting, a preliminary step for their elimination by the snail immune system. Aerolysin-like proteins (named biomphalysins) were the only ones involved in the recognition of all the five pathogens tested, suggesting a sentinel role of these horizontally acquired toxins. These findings highlight the diversity and complexity of a highly specific innate immune sensing system. It paves the way for the use of such approach on a wide range of host–pathogen systems to provide new insights into the specificity and diversity of immune recognition by innate immune systems.

Glabralysins, Potential New β-Pore-Forming Toxin Family Members from the Schistosomiasis Vector Snail Biomphalaria glabrata

“…Biomphalysin forms a complex with humoral immune molecules (FREP, TEP) [45]. Altogether, this suggests that Biomphalysin is involved in pathogen clearance [27].…”

“…Therefore, it can be expected that snails have to co-evolve with these pathogen communities and should possess sophisticated immune processes to cope with them. In the past decade, the molecular basis of the B. glabrata innate immune response has been investigated at the genomic [14][15][16][17], transcriptomic [18][19][20], proteomic/biochemical [21][22][23][24][25][26][27] and epigenomic levels [28][29][30][31][32]. These studies have revealed that various molecules and pathways involved in immune recognition, immune regulation/activation and immune effector systems participate in a complex interplay between host and pathogen to maintain the homeostasis of the organism.…”

“…Immune recognition molecules have been investigated in B. glabrata snails. Among them, different families of pattern recognition receptors (PRRs) have been described, such as (i) the peptidoglycan recognition proteins (PGRPs), (ii) the toll like receptors (TLR) [33,34], (iii) calcium-dependent (C-type) lectins or C-type lectin-related proteins (CREPs) [27,35,36], and finally (iv) the fibrinogen-related proteins (FREPs) [37]. All these PRRs are essential for pathogen recognition due to their high levels of polymorphism/diversification and potential multimerization [33].…”

“…Biomphalysin has been shown to directly bind to S. mansoni sporocysts and to have a lytic activity Genes 2020, 11, 65 3 of 17 enhanced by unidentified snail plasmatic factor(s) [25]. In addition to anti-schistosome activity, different Biomphalysin isoforms have been demonstrated to bind to gram-negative and -positive bacteria, yeast and echinostome parasites [27]. Biomphalysin forms a complex with humoral immune molecules (FREP, TEP) [45].…”

Aspartic acid at residue 185 modulates the capacity of HP-PRRSV nsp4 to antagonize IFN-I expression

“…Type I interferons (IFNs), the crucial antiviral cytokines, activate intracellular antimicrobial programs and influence the development of innate and adaptive immune responses (Ivashkiv and Donlin, 2014). During virus infection, the pattern-recognition receptors (PRRs) recognize specific pathogen-associated molecular patterns (PAMPs) to regulate the expression of IFNs through intracellular signaling cascades (Takeuchi and Akira, 2007;Tetreau et al, 2017). In these signaling pathways, NF-κB essential modulator (NEMO) and virus-induced signaling adapter (VISA, also called MAVS or IPS-1) play essential roles in regulating the expression of IFN-I and inflammatory cytokines (Kawai et al, 2005;Satoshi and Shizuo, 2006;Akira et al, 2006).…”