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However, little is known about the host-parasite interactions and molecular mechanisms in play during the course of<jats:italic>P. knowlesi<\/jats:italic>malaria infections, which also may be relevant across<jats:italic>Plasmodium<\/jats:italic>species. Here we contrast<jats:italic>P. knowlesi<\/jats:italic>sporozoite-initiated infections in<jats:italic>Macaca mulatta<\/jats:italic>and<jats:italic>Macaca fascicularis<\/jats:italic>using whole blood RNA-sequencing and transcriptomic analysis. These macaque hosts are evolutionarily close, yet malaria-na\u00efve<jats:italic>M. mulatta<\/jats:italic>will succumb to blood-stage infection without treatment, whereas malaria-na\u00efve<jats:italic>M. fascicularis<\/jats:italic>controls parasitemia without treatment. This comparative analysis reveals transcriptomic differences as early as the liver phase of infection, in the form of signaling pathways that are activated in<jats:italic>M. fascicularis<\/jats:italic>, but not<jats:italic>M. mulatta<\/jats:italic>. Additionally, while most immune responses are initially similar during the acute stage of the blood infection, significant differences arise subsequently. The observed differences point to prolonged inflammation and anti-inflammatory effects of IL10 in<jats:italic>M. mulatta<\/jats:italic>, while<jats:italic>M. fascicularis<\/jats:italic>undergoes a transcriptional makeover towards cell proliferation, consistent with its recovery. Together, these findings suggest that timely detection of<jats:italic>P. knowlesi<\/jats:italic>in<jats:italic>M. fascicularis<\/jats:italic>, coupled with control of inflammation while initiating the replenishment of key cell populations, helps contain the infection. Overall, this study points to specific genes and pathways that could be investigated as a basis for new drug targets that support recovery from acute malaria.<\/jats:p>","DOI":"10.1038\/s41598-021-98024-6","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T10:30:41Z","timestamp":1632997841000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Dramatic transcriptomic differences in Macaca mulatta and Macaca fascicularis with Plasmodium knowlesi infections"],"prefix":"10.1038","volume":"11","author":[{"given":"Anuj","family":"Gupta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark P.","family":"Styczynski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary R.","family":"Galinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eberhard O.","family":"Voit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis L.","family":"Fonseca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,30]]},"reference":[{"key":"98024_CR1","unstructured":"World Health Organization. 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