Immunomodulatory and biological properties of helminth-derived small molecules: Potential applications in diagnostics and therapeutics

Abstract

Parasitic helminths secrete and excrete a vast array of molecules known to help skew or suppress the host’s immune response, thereby establishing a niche for sustained parasite maintenance. Indeed, the immunomodulatory potency of helminths is attributed mainly to excretory/secretory products (ESPs). The ESPs of helminths and the identified small molecules (SM) are reported to have diverse biological and pharmacological properties. The available literature reports only limited metabolites, and the identity of many metabolites remains unknown due to limitations in the identification protocols and helminth-specific compound libraries. Many metabolites are known to be involved in host-parasite interactions and pathogenicity. For example, fatty acids (e.g., stearic acid) detected in the infective stages of helminths are known to have a role in host interaction through facilitating successful penetration and migration inside the host. Moreover, excreted/secreted SM detected in helminth species are found to possess various biological properties, including anti-inflammatory activities, suggesting their potential in developing immunomodulatory drugs. For example, helminths-derived somatic tissue extracts and whole crude ESPs showed anti-inflammatory properties by inhibiting the secretion of proinflammatory cytokines from human peripheral blood mononuclear cells and suppressing the pathology in chemically-induced experimental mice model of colitis. Unlike bigger molecules like proteins, SM are ideal candidates for drug development since they are small structures, malleable, and lack immunogenicity. Future studies should strive toward identifying unknown SM and isolating the under-explored niche of helminth metabolites using the latest metabolomics technologies and associated software, which hold potential keys for finding new diagnostics and novel therapeutics.

Gastrointestinal worms and bacteria: From association to intervention

“…58,77 The gut of parasitized hosts harbours a vast array of helminth-derived small molecules (i.e., chemical compounds whose molecular weight is <1 kDa) that, potentially, could represent targets of bacterial biosensors for in situ detection of GI helminths. 78 Nevertheless, in order for this technology to be fully exploited, two key technical barriers must be overcome; first, specific molecules acting as unequivocal indicators of infection must be identified; second, these indicators must be detectable through bacterial biosensors. Once these live biosensors are developed, their use could be extended to diagnostic purposes, 78,79 coupling the detection system with a response mechanism that outputs a detectable (and measurable) signal.…”

“…78 Nevertheless, in order for this technology to be fully exploited, two key technical barriers must be overcome; first, specific molecules acting as unequivocal indicators of infection must be identified; second, these indicators must be detectable through bacterial biosensors. Once these live biosensors are developed, their use could be extended to diagnostic purposes, 78,79 coupling the detection system with a response mechanism that outputs a detectable (and measurable) signal. 80 Lastly, microbial bioengineering approaches might also be applied to fine-tuning of host-parasite interactions to achieve a beneficial effect for the host.…”

“…Indeed, several bacterial species have been engineered to deliver a range of biomolecules with therapeutic activity, either continuously or upon sensing a particular stimulus, and some of these are already being evaluated in pre‐clinical and clinical trials 58,77 . The gut of parasitized hosts harbours a vast array of helminth‐derived small molecules (i.e., chemical compounds whose molecular weight is <1 kDa) that, potentially, could represent targets of bacterial biosensors for in situ detection of GI helminths 78 . Nevertheless, in order for this technology to be fully exploited, two key technical barriers must be overcome; first, specific molecules acting as unequivocal indicators of infection must be identified; second, these indicators must be detectable through bacterial biosensors.…”

Immunomodulators secreted from parasitic helminths act on pattern recognition receptors

“…However, it is difficult to distinguish between ES products released from different sites (Drurey et al, 2020). ES products are composed of proteins, glycans, lipids, nucleic acids, small metabolites, and extracellular vehicles (EVs) (Claycomb et al, 2017;Hokke and van Diepen, 2017;Maizels et al, 2018;Wangchuk et al, 2019;Drurey and Maizels, 2021;Yeshi et al, 2022). Innate and adaptive immune cells are manipulated by ES immunomodulators, which affect the balance between type 1 and type 2 immune responses (Maizels and McSorley, 2016;Maizels et al, 2018).…”

Immunoblotting Identification of Diagnostic Antigens of Paragonimus westermani Type 1 for the Detection of Human Pulmonary Paragonimiasis in North East India

“…Excretory–secretory (ES) products are mixture of molecules (proteins, glycans, and lipids) released by lung flukesinto the host’s biological fluids. These secreted and excreted molecules are presented at the host–parasite interface and elicit an immune response in the host; they are therefore considered a good source for antigens with serodiagnostic potential [ 21 ]. Apart from excreted–secreted proteins, adult worms contain many proteins that are important in performing various functions, including nutrition invasion, host immune response, and immune evasion [ 22 ].…”