Comprehensive characterization of Cysteine-rich protein-coding genes of Giardia lamblia and their role during antigenic variation

Rodríguez-Walker, Macarena; Molina, Cecilia R.; Lujan, Lucas; Saura, Alicia; Jerlström-Hultqvist, Jon; Svärd, Staffan G.; Fernández, Elmer; Luján, Hugo D.

doi:10.1016/j.ygeno.2022.110462

Cited by 7 publications

(12 citation statements)

References 77 publications

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“…Giardia isolates are arranged into genetic groups or assemblages, each having a particular VSP repertoire 7 – 9 . When Giardia trophozoites are exposed to anti-VSP monoclonal antibodies (mAbs) or serum collected from infected animals, parasites agglutinate into large aggregates that have been considered clusters of dead cells 6 – 8 , 17 – 19 .…”

Section: Resultsmentioning

confidence: 99%

“…AV in Giardia involves VSPs, which cover the entire trophozoite surface and are the major antigens recognised by their hosts 4 , 7 . VSPs are integral membrane proteins with antigenically variable ectodomains containing multiple CXXC motifs and a highly conserved C-terminal region comprising a transmembrane domain (TMD) and a short cytoplasmic tail (CT) 8 , 9 . The parasite genome encodes a repertoire of 136 VSPs 9 , but only one is expressed on the surface of individual trophozoites at any time 8 , 9 .…”

Section: Introductionmentioning

confidence: 99%

“…VSPs are integral membrane proteins with antigenically variable ectodomains containing multiple CXXC motifs and a highly conserved C-terminal region comprising a transmembrane domain (TMD) and a short cytoplasmic tail (CT) 8 , 9 . The parasite genome encodes a repertoire of 136 VSPs 9 , but only one is expressed on the surface of individual trophozoites at any time 8 , 9 . Expression of a unique VSP is regulated post-transcriptionally by an RNAi-like mechanism and maintained epigenetically 10 .…”

Section: Introductionmentioning

confidence: 99%

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Antibodies to variable surface antigens induce antigenic variation in the intestinal parasite Giardia lamblia

et al. 2023

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The genomes of most protozoa encode families of variant surface antigens. In some parasitic microorganisms, it has been demonstrated that mutually exclusive changes in the expression of these antigens allow parasites to evade the host’s immune response. It is widely assumed that antigenic variation in protozoan parasites is accomplished by the spontaneous appearance within the population of cells expressing antigenic variants that escape antibody-mediated cytotoxicity. Here we show, both in vitro and in animal infections, that antibodies to Variant-specific Surface Proteins (VSPs) of the intestinal parasite Giardia lamblia are not cytotoxic, inducing instead VSP clustering into liquid-ordered phase membrane microdomains that trigger a massive release of microvesicles carrying the original VSP and switch in expression to different VSPs by a calcium-dependent mechanism. This novel mechanism of surface antigen clearance throughout its release into microvesicles coupled to the stochastic induction of new phenotypic variants not only changes current paradigms of antigenic switching but also provides a new framework for understanding the course of protozoan infections as a host/parasite adaptive process.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antibodies to variable surface antigens induce antigenic variation in the intestinal parasite Giardia lamblia

et al. 2023

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“…In addition to VSPs, there are other proteins classified in cysteine-rich proteins, such as Cys-rich membrane proteins (CRMPs) and secretory Cys-rich proteins (SCRPs). However, CRMPs and SCRPs are also encoded in the Giardia’s genome, but their functions are controversial [ 37 ]. Over 136 VSP genes have been identified in the Giardia genome [ 37 ], of which only one VSP is expressed on the cell surface at any given time; however, a switch in expression to an antigenically distinct VSP has been reported to occur spontaneously [ 31 ].…”

Section: Antigenic Protein Candidates In Giardiamentioning

confidence: 99%

“…However, CRMPs and SCRPs are also encoded in the Giardia’s genome, but their functions are controversial [ 37 ]. Over 136 VSP genes have been identified in the Giardia genome [ 37 ], of which only one VSP is expressed on the cell surface at any given time; however, a switch in expression to an antigenically distinct VSP has been reported to occur spontaneously [ 31 ]. One of the two surface-resident VSPs is lost during switching after 12–36 h, and if the process is considered linear, the half-life is 17.3 h. The dynamics of VSP flipping resembles those of other parasites that undergo antigenic changes both topically and mechanically.…”

Section: Antigenic Protein Candidates In Giardiamentioning

confidence: 99%

Conserved Candidate Antigens and Nanoparticles to Develop Vaccine against Giardia intestinalis

et al. 2022

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Giardia intestinalis (Giardia lambia, Giardia duodenalis) infections in humans may be asymptomatic or symptomatic and associated with diarrhea (without blood), abdominal cramps, bloating, flatulence, and weight loss. The protozoan Giardia is the third most common cause of diarrhea and death in children under five, preceded only by rotavirus and by Cryptosporidium parvum and C. hominis infections. Antimicrobial drugs, particularly 5-nitroimidazole (5-NIs), are used to treat giardiasis in humans. Immunologically naive or immunocompromised host are more vulnerable to Giardia infection, whereas a degree of resistance to this protozoan is present in humans living in endemic areas. This suggests that vaccination may be a potential and appropriate means to control this parasitic disease outbreak and protect the human population. This review discusses Giardia antigens related to vaccine development. Additionally, based on the latest development of nanoparticle technology, a combination of methods for future research and development is proposed for the design of the next generation of powerful immunogens and an effective vaccine against Giardia.

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Expanded gene and taxon sampling of diplomonads shows multiple switches to parasitic and free-living lifestyle

Wiśniewska,

Salomaki,

Silberman

et al. 2024

BMC Biol

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Background Diplomonads are anaerobic flagellates classified within Metamonada. They contain both host-associated commensals and parasites that reside in the intestinal tracts of animals, including humans (e.g., Giardia intestinalis), as well as free-living representatives that inhabit freshwater and marine anoxic sediments (e.g., Hexamita inflata). The evolutionary trajectories within this group are particularly unusual as the free-living taxa appear to be nested within a clade of host-associated species, suggesting a reversal from host-dependence to a secondarily free-living lifestyle. This is thought to be an exceedingly rare event as parasites often lose genes for metabolic pathways that are essential to a free-living life strategy, as they become increasingly reliant on their host for nutrients and metabolites. To revert to a free-living lifestyle would require the reconstruction of numerous metabolic pathways. All previous studies of diplomonad evolution suffered from either low taxon sampling, low gene sampling, or both, especially among free-living diplomonads, which has weakened the phylogenetic resolution and hindered evolutionary insights into this fascinating transition. Results We sequenced transcriptomes from 1 host-associated and 13 free-living diplomonad isolates; expanding the genome scale data sampling for diplomonads by roughly threefold. Phylogenomic analyses clearly show that free-living diplomonads form several branches nested within endobiotic species. Moreover, the phylogenetic distribution of genes related to an endobiotic lifestyle suggest their acquisition at the root of diplomonads, while traces of these genes have been identified in free-living diplomonads as well. Based on these results, we propose an evolutionary scenario of ancestral and derived lifestyle transitions across diplomonads. Conclusions Free-living taxa form several clades nested within endobiotic taxa in our phylogenomic analyses, implying multiple transitions between free-living and endobiotic lifestyles. The evolutionary history of numerous virulence factors corroborates the inference of an endobiotic ancestry of diplomonads, suggesting that there have been several reversals to a free-living lifestyle. Regaining host independence may have been facilitated by a subset of laterally transferred genes. We conclude that the extant diversity of diplomonads has evolved from a non-specialized endobiont, with some taxa becoming highly specialized parasites, others becoming free-living, and some becoming capable of both free-living and endobiotic lifestyles.

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Comprehensive characterization of Cysteine-rich protein-coding genes of Giardia lamblia and their role during antigenic variation

Cited by 7 publications

References 77 publications

Antibodies to variable surface antigens induce antigenic variation in the intestinal parasite Giardia lamblia

Antibodies to variable surface antigens induce antigenic variation in the intestinal parasite Giardia lamblia

Conserved Candidate Antigens and Nanoparticles to Develop Vaccine against Giardia intestinalis

Expanded gene and taxon sampling of diplomonads shows multiple switches to parasitic and free-living lifestyle

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