{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:57:48Z","timestamp":1768507068212,"version":"3.49.0"},"posted":{"date-parts":[[2023,6,1]]},"group-title":"Microbiology","reference-count":78,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  <jats:italic>Toxoplasma gondii<\/jats:italic>\n                  \u2019s propensity to infect its host and cause disease is highly dependent on its ability to modulate host cell functions. One of the strategies the parasite uses to accomplish this is via the export of effector proteins from the secretory dense granules. Dense granule (GRA) proteins are known to play roles in nutrient acquisition, host cell cycle manipulation, and immune regulation. Here, we characterize a novel dense granule protein named GRA83, which localizes to the parasitophorous vacuole in tachyzoites and bradyzoites. Disruption of\n                  <jats:italic>GRA83<\/jats:italic>\n                  results in increased virulence, weight loss, and parasitemia during the acute infection, as well as a marked increase in the cyst burden during the chronic infection. This increased parasitemia was associated with an accumulation of inflammatory infiltrates in tissues in both the acute and chronic infection. Murine macrophages infected with \u0394\n                  <jats:italic>gra83<\/jats:italic>\n                  tachyzoites produced less interleukin-12 (IL-12)\n                  <jats:italic>in vitro<\/jats:italic>\n                  , which was confirmed with reduced IL-12 and interferon gamma (IFN-\u03b3)\n                  <jats:italic>in vivo<\/jats:italic>\n                  . This dysregulation of cytokines correlates with reduced nuclear translocation of the p65 subunit of the NF-\u03baB complex. While GRA15 similarly regulates NF-\u03baB, infection with \u0394\n                  <jats:italic>gra83\/<\/jats:italic>\n                  \u0394\n                  <jats:italic>gra15<\/jats:italic>\n                  parasites did not further reduce p65 translocation to the host cell nucleus, suggesting these GRAs function in converging pathways. We also used proximity labelling experiments to reveal candidate GRA83 interacting\n                  <jats:italic>T. gondii<\/jats:italic>\n                  derived partners. Taken together, this work reveals a novel effector that stimulates the innate immune response, enabling the host to limit parasite burden.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Toxoplasma gondii<\/jats:italic>\n                    poses a significant public health concern as it is recognized as one of the leading foodborne pathogens in the United States. Infection with the parasite can cause congenital defects in neonates, life-threatening complications in immunosuppressed patients, and ocular disease. Specialized secretory organelles, including the dense granules, play an important role in the parasite\u2019s ability to efficiently invade and regulate components of the host\u2019s infection response machinery to limit parasite clearance and establish an acute infection.\n                    <jats:italic>Toxoplasma\u2019<\/jats:italic>\n                    s ability to avoid early clearance, while also successfully infecting the host long enough to establish a persistent chronic infection, is crucial in allowing for its transmission to a new host. While multiple GRAs directly modulate host signaling pathways, they do so in various ways highlighting the parasite\u2019s diverse arsenal of effectors that govern infection. Understanding how parasite-derived effectors harness host functions to evade defenses yet ensure a robust infection are important for understanding the complexity of the pathogen\u2019s tightly regulated infection. In this study, we characterize a novel secreted protein named GRA83 that stimulates the host cell\u2019s response to limit infection.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.05.31.543158","type":"posted-content","created":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T07:55:13Z","timestamp":1685606113000},"source":"Crossref","is-referenced-by-count":2,"title":["The\n                  <i>Toxoplasma gondii<\/i>\n                  effector GRA83 modulates the host\u2019s innate immune response to regulate parasite infection"],"prefix":"10.64898","author":[{"given":"Amara C.","family":"Thind","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline M.","family":"Mota","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana Paula N.","family":"Gon\u00e7alves","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jihui","family":"Sha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James A.","family":"Wohlschlegel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiago W.P.","family":"Mineo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8481-0638","authenticated-orcid":false,"given":"Peter J.","family":"Bradley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023060308400401000_2023.05.31.543158v1.1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1469-0691.2002.00485.x"},{"key":"2023060308400401000_2023.05.31.543158v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpara.2009.04.003"},{"key":"2023060308400401000_2023.05.31.543158v1.3","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.ijpara.2020.11.001","article-title":"Control of human toxoplasmosis","volume":"51","year":"2021","journal-title":"International Journal for Parasitology"},{"key":"2023060308400401000_2023.05.31.543158v1.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199212033272306"},{"key":"2023060308400401000_2023.05.31.543158v1.5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2008.03692.x"},{"key":"2023060308400401000_2023.05.31.543158v1.6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2011.00305.x"},{"key":"2023060308400401000_2023.05.31.543158v1.7","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciu793"},{"key":"2023060308400401000_2023.05.31.543158v1.8","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.11.2.267"},{"key":"2023060308400401000_2023.05.31.543158v1.9","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-012-0339-3"},{"key":"2023060308400401000_2023.05.31.543158v1.10","doi-asserted-by":"publisher","DOI":"10.1126\/science.161.3843.804"},{"key":"2023060308400401000_2023.05.31.543158v1.11","doi-asserted-by":"publisher","DOI":"10.1126\/science.3128869"},{"key":"2023060308400401000_2023.05.31.543158v1.12","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.4049\/jimmunol.143.6.2045","article-title":"Importance of endogenous IFN-gamma for prevention of toxoplasmic encephalitis in mice","volume":"143","year":"1989","journal-title":"The Journal of Immunology"},{"key":"2023060308400401000_2023.05.31.543158v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2011.03.009"},{"key":"2023060308400401000_2023.05.31.543158v1.14","doi-asserted-by":"publisher","DOI":"10.1126\/science.1109893"},{"key":"2023060308400401000_2023.05.31.543158v1.15","unstructured":"Recognition of Profilin by Toll-like Receptor 12 Is Critical for Host Resistance to Toxoplasma gondii | Elsevier Enhanced Reader. https:\/\/reader.elsevier.com\/reader\/sd\/pii\/S1074761312005158?token=8B83A7354419BB8FCE59C61AE8AB3A2F455AACF3C66AFF7909480EABE62DC3E57FC8E4AE6598CE6F302AE3A72D443FF3&originRegion=us-east-1&originCreation=20230417185049. 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