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SHP-2 Mediates Cryptosporidium parvum Infectivity in Human Intestinal Epithelial Cells
Eunice A Varughese1,2, Susan Kasper1, Emily M Anneken2
1Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
Abstract:
The parasite, Cryptosporidium parvum, induces human gastroenteritis through infection of host epithelial cells in the small intestine. During the initial stage of infection, C. parvum is reported to engage host mechanisms at the host cell-parasite interface to form a parasitophorous vacuole. We determined that upon infection, the larger molecular weight proteins in human small intestinal epithelial host cells (FHs 74 Int) appeared to globally undergo tyrosine dephosphorylation. In parallel, expression of the cytoplasmic protein tyrosine phosphatase Src homology-2 domain-containing phosphatase 2 (SHP-2) increased in a time-dependent manner. SHP-2 co-localized with the C. parvum sporozoite and this interaction increased the rate of C. parvum infectivity through SH2-mediated SHP-2 activity. Furthermore, we show that one potential target that SHP-2 acts upon is the focal adhesion protein, paxillin, which undergoes moderate dephosphorylation following infection, with inhibition of SHP-2 rescuing paxillin phosphorylation. Importantly, treatment with an inhibitor to SHP-2 and with an inhibitor to paxillin and Src family kinases, effectively decreased the multiplicity of C. parvum infection in a dose-dependent manner. Thus, our study reveals an important role for SHP-2 in the pathogenesis of C. parvum. Furthermore, while host proteins can be recruited to participate in the development of the electron dense band at the host cell-parasite interface, our study implies for the first time that SHP-2 appears to be recruited by the C. parvum sporozoite to regulate infectivity. Taken together, these findings suggest that SHP-2 and its down-stream target paxillin could serve as targets for intervention.
Insights
Cryptosporidium parvum infection hijacks host cells by manipulating tyrosine dephosphorylation, specifically involving the SHP-2 phosphatase. Inhibiting SHP-2 and paxillin reduces parasite infectivity, suggesting new therapeutic targets for cryptosporidiosis.
Area of Science:
- Parasitology
- Molecular Biology
- Cell Biology
Background:
- Cryptosporidium parvum causes human gastroenteritis by infecting small intestinal epithelial cells.
- Parasite infection involves host cell mechanisms to form a parasitophorous vacuole at the host cell-parasite interface.
- Tyrosine dephosphorylation of host proteins occurs during initial C. parvum infection stages.
Purpose of the Study:
- To investigate the role of protein tyrosine dephosphorylation and specific phosphatases in C. parvum infection.
- To identify host cell targets and mechanisms exploited by C. parvum for infectivity.
- To explore potential therapeutic interventions targeting host-parasite interactions.
Main Methods:
- Time-dependent analysis of protein tyrosine dephosphorylation in infected human intestinal epithelial cells (FHs 74 Int).
- Assessment of Src homology-2 domain-containing phosphatase 2 (SHP-2) expression, localization, and activity.
- Co-localization studies of SHP-2 with C. parvum sporozoites.
- Investigation of SHP-2's effect on the focal adhesion protein paxillin phosphorylation.
- Dose-dependent treatment with inhibitors of SHP-2, paxillin, and Src family kinases to assess C. parvum infection multiplicity.
Main Results:
- Global tyrosine dephosphorylation of host proteins was observed upon C. parvum infection.
- SHP-2 expression increased time-dependently and co-localized with C. parvum sporozoites.
- SHP-2 activity enhanced C. parvum infectivity, targeting paxillin for dephosphorylation.
- Inhibition of SHP-2 and paxillin significantly reduced C. parvum infection multiplicity.
Conclusions:
- SHP-2 plays a crucial role in the pathogenesis of C. parvum infection.
- C. parvum sporozoites appear to recruit SHP-2 to regulate infectivity, a novel finding.
- SHP-2 and its downstream target paxillin represent potential therapeutic targets for treating cryptosporidiosis.
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