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Currently, there is a re-emergence of <jats:italic>Cryptosporidium<\/jats:italic> infection; however, no fully effective drug or vaccine is available to treat Cryptosporidiosis. In the present study, to better understand the detailed interaction between the host and <jats:italic>Cryptosporidium parvum<\/jats:italic>, a large-scale label-free proteomics study was conducted to characterize the changes to the proteome induced by <jats:italic>C<\/jats:italic>. <jats:italic>parvum<\/jats:italic> infection. Among 4406 proteins identified, 121 proteins were identified as differentially abundant (&gt; 1.5-fold cutoff, <jats:italic>P<\/jats:italic> &lt; 0.05) in <jats:italic>C<\/jats:italic>. <jats:italic>parvum<\/jats:italic> infected HCT-8 cells compared with uninfected cells. Among them, 67 proteins were upregulated, and 54 proteins were downregulated at 36 h post infection. Analysis of the differentially abundant proteins revealed an interferon-centered immune response of the host cells against <jats:italic>C<\/jats:italic>. <jats:italic>parvum<\/jats:italic> infection and extensive inhibition of metabolism-related enzymes in the host cells caused by infection. Several proteins were further verified using quantitative real-time reverse transcription polymerase chain reaction and western blotting. This systematic analysis of the proteomics of <jats:italic>C<\/jats:italic>. <jats:italic>parvum<\/jats:italic>-infected HCT-8 cells identified a wide range of functional proteins that participate in host anti-parasite immunity or act as potential targets during infection, providing new insights into the molecular mechanism of <jats:italic>C<\/jats:italic>. <jats:italic>parvum<\/jats:italic> infection.<\/jats:p>","DOI":"10.1371\/journal.pntd.0009949","type":"journal-article","created":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T18:25:48Z","timestamp":1637778348000},"page":"e0009949","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Comparative proteomics reveals Cryptosporidium parvum manipulation of the host cell molecular expression and immune 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