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In this study, we analyzed the virulence of four serotype A\n                      <jats:italic toggle=\"yes\">C. neoformans<\/jats:italic>\n                      strains with different polysaccharide structures: two multi-motif (H99 and KN99\u03b1) and two single-motif (Mu-1 and ATCC-24064 (24064)). Mice were infected by the intranasal (IN) or intravenous (IV) route. Survival, fungal load (colony-forming unit), cell lung population, cytokines, and histology were analyzed. No differences in cell size or capsule size were found between the four strains. However, polysaccharide sizes were highly variable, and no significant differences were observed for all other virulence factors. Nitrite production in cell culture dendritic cells was reduced for the H99 or KN99\u03b1 strains of EPS. The reactive oxygen species in cell culture M1 macrophages and dendritic cells were increased for the H99 or KN99\u03b1 strain\u2019s EPS. Cytokines differed from the IN and IV infections. Lung histology showed increased inflammatory cell presence after infection with Mu-1 or 24064 strains, with no cryptococcal cells observed in the lung parenchyma or alveoli, whereas the opposite pattern was seen after challenges with H99 or KN99\u03b1. There were differences in lung neutrophil infiltration between the analyzed strains, and a higher presence of activated macrophages and CD4+ lymphocytes for the Mu-1 or 24064 strains. Polysaccharides from single and multi-motif strains elicited different effects on macrophage-like cells\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      . These results suggest that variation in polysaccharide composition and structure can translate into differences in virulence and pathogenicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Cryptococcosis is a systemic fungal infection that causes approximately 1 million cases globally, leading to approximately 625,000 annual deaths. Two species are responsible for the majority of cases,\n                      <jats:italic toggle=\"yes\">Cryptococcus neoformans<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">Cryptococcus gattii<\/jats:italic>\n                      .\n                      <jats:italic toggle=\"yes\">C. neoformans<\/jats:italic>\n                      usually causes disease in immunosuppressed hosts, whereas\n                      <jats:italic toggle=\"yes\">C. gattii<\/jats:italic>\n                      can infect and cause disease in immunocompetent hosts. The capsule of\n                      <jats:italic toggle=\"yes\">Cryptococcus<\/jats:italic>\n                      spp. is one of its major virulence factors, due to its immunomodulation abilities. The capsule is composed of three major different molecules: glucuronoxylomannan (GXM), galactoxylomannan (GalXM), and mannoproteins. GXM is composed of six different structures called motifs. The exact mechanism and structures associated with its immunomodulation are still not well elucidated. Here, we looked at different immune responses based on the capsule composition. Our results strongly suggest that the capsule motif composition can affect the virulence, pathogenicity, and immunomodulatory capabilities of the\n                      <jats:italic toggle=\"yes\">Cryptococcus<\/jats:italic>\n                      capsule.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.02646-25","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T13:00:23Z","timestamp":1759150823000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":11,"title":["<i>Cryptococcus neoformans<\/i>\n                    serotype A virulence and pathogenicity are capsular glucuronoxylomannan (GXM) motif composition dependent"],"prefix":"10.1128","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5564-3538","authenticated-orcid":true,"given":"Samuel","family":"Rodrigues Dos Santos Junior","sequence":"first","affiliation":[{"name":"W. 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Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gracen R.","family":"Gerbig","sequence":"additional","affiliation":[{"name":"W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health","place":["Baltimore, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Livia C.","family":"Liporagi Lopes","sequence":"additional","affiliation":[{"name":"W. 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