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Disruption of Active Trans-Sialidase Genes Impairs Egress from Mammalian Host Cells and Generates Highly Attenuated Trypanosoma cruzi Parasites. | LitMetric

AI Article Synopsis

  • Trans-sialidases (TS) are enzymes on the Trypanosoma cruzi parasite, important for its virulence in Chagas disease, and only a few have catalytic activity.
  • Researchers used CRISPR-Cas9 to create knockout cell lines lacking active trans-sialidases, finding that these mutants had no TS activity and exhibited impaired development and egress from host cells.
  • In experiments with mice, aTS mutants did not cause infection and could even provide immunity against virulent strains, suggesting they could be developed into a vaccine for Chagas disease, which currently has no effective treatment.

Article Abstract

Trans-sialidases (TS) are unusual enzymes present on the surface of Trypanosoma cruzi, the causative agent of Chagas disease. Encoded by the largest gene family in the T. cruzi genome, only few members of the TS family have catalytic activity. Active trans-sialidases (aTS) are responsible for transferring sialic acid from host glycoconjugates to mucins, also present on the parasite surface. The existence of several copies of TS genes has impaired the use of reverse genetics to study this highly polymorphic gene family. Using CRISPR-Cas9, we generated aTS knockout cell lines displaying undetectable levels of TS activity, as shown by sialylation assays and labeling with antibodies that recognize sialic acid-containing mucins. infection assays showed that disruption of aTS genes does not affect the parasite's capacity to invade cells or to escape from the parasitophorous vacuole but resulted in impaired differentiation of amastigotes into trypomastigotes and parasite egress from the cell. When inoculated into mice, aTS mutants were unable to establish infection even in the highly susceptible gamma interferon (IFN-γ) knockout mice. Mice immunized with aTS mutants were fully protected against a challenge infection with the virulent T. cruzi Y strain. Altogether, our results confirmed the role of aTS as a T. cruzi virulence factor and indicated that aTS play a major role during the late stages of intracellular development and parasite egress. Notably, mutants lacking TS activity are completely avirulent in animal models of infection and may be used as a live attenuated vaccine against Chagas disease. Trypanosoma cruzi is the causative agent of Chagas disease, a neglected tropical disease that affects approximately 6 to 8 million people and for which there is no effective treatment or vaccine. The parasite expresses a family of surface proteins, named trans-sialidases, responsible for transferring sialic acid from host glycoconjugates to parasite mucins. Although recognized as a main virulence factor, the multiple roles of these proteins during infection have not yet been fully characterized, mainly because the presence of several copies of aTS genes has impaired their study using reverse genetics. By applying CRISPR-Cas9, we generated aTS knockout parasites and showed that, although aTS parasite mutants were able to infect cells , they have an impaired capacity to egress from the infected cell. Importantly, aTS mutants lost the ability to cause infection but provided full protection against a challenge infection with a virulent strain.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8787462PMC
http://dx.doi.org/10.1128/mbio.03478-21DOI Listing

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