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While some<jats:italic>P. falciparum<\/jats:italic>clones make use of sialic acid (SA) residues on the surface of the human glycophorin receptors to invade the erythrocyte, others use alternative receptors independent of sialic acid residues. We hypothesized that over the years, intensified malaria control interventions and declining prevalence in The Gambia have resulted in a selection of parasites with a dominant invasion pathways and ligand expression profiles.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Blood samples were collected from 65 malaria-infected participants with uncomplicated malaria across 3\u00a0years (2015, 2016, and 2021). Genetic diversity was determined by genotyping the merozoite surface protein 2 (<jats:italic>msp2<\/jats:italic>) polymorphic gene of<jats:italic>P. falciparum.<\/jats:italic>Erythrocyte invasion phenotypes were determined using neuraminidase, trypsin, and chymotrypsin enzymes, known to cleave different receptors from the surface of the erythrocyte. Schizont-stage transcript levels were obtained for a panel of 6<jats:italic>P. falciparum<\/jats:italic>invasion ligand genes (<jats:italic>eba175, eba181, Rh2b, Rh4, Rh5<\/jats:italic>, and<jats:italic>clag2<\/jats:italic>) using 48\u00a0successfully cultured isolates.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Though the allelic heterozygosity of<jats:italic>msp2<\/jats:italic>repeat region decreased as expected with reduced transmission, there was an increase in infections with more than a single<jats:italic>msp2<\/jats:italic>allelotype from 2015 to 2021. The invasion phenotypes of these isolates were mostly SA independent with a continuous increase from 2015 to 2021. Isolates from 2021 were highly inhibited by chymotrypsin treatment compared to isolates from 2015 and 2016. Higher invasion inhibition for 2021 isolates was further obtained following erythrocyte treatment with a combination of chymotrypsin and trypsin. The transcript levels of invasion ligand genes varied across years. However, levels of<jats:italic>clag2<\/jats:italic>, a rhoptry-associated protein, were higher in 2015 and 2016 isolates than in 2021 isolates, while<jats:italic>Rh5<\/jats:italic>levels were higher in 2021 compared to other years.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Overall, these findings suggest increasing mixed infections with an increase in the use of sialic-acid independent invasion pathways by<jats:italic>P. falciparum<\/jats:italic>clinical isolates in the Western part of Gambia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Graphical Abstract<\/jats:title><\/jats:sec>","DOI":"10.1186\/s13071-023-05929-4","type":"journal-article","created":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T16:03:06Z","timestamp":1693497786000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Recent increase in low complexity polygenomic infections and sialic acid-independent invasion pathways in Plasmodium falciparum from Western Gambia"],"prefix":"10.1186","volume":"16","author":[{"given":"Nora Nghochuzie","family":"Nganyewo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatoumata","family":"Bojang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eniyou Cheryll","family":"Oriero","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ndey Fatou","family":"Drammeh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olumide","family":"Ajibola","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haddijatou","family":"Mbye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aminata Seedy","family":"Jawara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Corea","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gordon Akanzuwine","family":"Awandare","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Umberto","family":"D\u2019Alessandro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucas N.","family":"Amenga-Etego","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alfred","family":"Amambua-Ngwa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,8,31]]},"reference":[{"key":"5929_CR1","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/j.ijpara.2004.10.010","volume":"34","author":"D Gaur","year":"2004","unstructured":"Gaur D, Mayer DCG, Miller LH. 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