Zinga M.Ibrahim A.Mohring F.Chainarin S.Jonsdottir T.K.Ngernna S.Amabilino-Perez B.Pholcharee T.Turkiewicz A.Campino S.Clark T.G.Miao J.Cui L.Roobsoong W.Sattabongkot J.Moon R.W.Nguitragool W.Mahidol University2026-04-102026-04-102026-01-01Blood (2026)00064971https://repository.li.mahidol.ac.th/handle/123456789/116044Plasmodium knowlesi, a zoonotic malaria species, has become a significant public health concern in Southeast Asia. In regions such as Malaysia and southern Thailand, P knowlesi incidence has risen, even as other human malaria parasites are nearing elimination. Similar to its close relative Plasmodium vivax, P knowlesi relies on the Duffy antigen receptor for chemokine (DARC) as a key receptor for erythrocyte invasion. Only Duffy-positive individuals are thought to be susceptible to clinical infection. Here, we demonstrate that P knowlesi possesses greater invasion plasticity than previously recognized. This parasite can bypass the need for DARC, as shown by its in vitro adaptation to invade and replicate within Duffy-negative (Fy−) erythrocytes. This adaptation is stable and independent of DARC binding, enabling the adapted parasite line to be maintained in Fy− erythrocytes and to resist inhibition by α-DARC antibodies. Genomic analysis identified a genomic recombination event between the parasite's dbp<inf>α</inf> and dbp<inf>γ</inf> genes, resulting in a new chimeric gene dbp<inf>αγ</inf>. Using CRISPR-Cas9 targeted reversion, we could demonstrate that dbp<inf>αγ</inf> is essential for invasion of Fy− erythrocytes. These findings shed new light on the invasion plasticity of P knowlesi, with implications for the parasite’s potential spread beyond Southeast Asia and for understanding the complex host-cell specificity and atypical invasion pathways seen in P vivax.Biochemistry, Genetics and Molecular BiologyMedicineImmunology and MicrobiologyArticleSCOPUS10.1182/blood.20250295572-s2.0-1050345106171528002041701978