{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T12:46:24Z","timestamp":1768567584999,"version":"3.49.0"},"posted":{"date-parts":[[2024,9,13]]},"group-title":"Endocrinology (including Diabetes Mellitus and Metabolic Disease)","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,9,13]],"date-time":"2024-09-13T00:00:00Z","timestamp":1726185600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,9,13]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Aims\/hypothesis<\/jats:title>\n                  <jats:p>The nPOD-Virus group collaboratively applied innovative technologies to detect and sequence viral RNA in pancreas and other tissues from organ donors with type 1 diabetes. These analyses involved the largest number of pancreas samples collected to date.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We analysed pancreas, spleen, pancreatic lymph nodes, and duodenum samples from the following donor groups: a) donors with type 1 diabetes (n=71), with (n=35) or without (n=36) insulin-containing islets, (b) donors with single or double islet autoantibody positivity without diabetes (n=22) and c) autoantibody-negative donors without diabetes (control donors) (n=74). Five research laboratories participated in this collaborative effort using approaches for unbiased discovery of RNA viruses (two RNA-Seq platforms), targeted detection of\n                    <jats:italic>Enterovirus A-D<\/jats:italic>\n                    species using RT-PCR, and tests for virus growth in cell-culture.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Direct RNA-Seq did not detect virus signal in pancreas samples, whereas RT-PCR detected enterovirus RNA confirmed by sequencing in low amounts in pancreas samples in three of the five donor groups, namely donors with type 1 diabetes with insulin-containing islets, 16% (5\/32) donors being positive, donors with single islet autoantibody positivity with 53% (8\/15) donors being positive, and non-diabetic donors with 8% (4\/49) being enterovirus RNA positive. Detection of enterovirus RNA was significantly more frequent in single islet autoantibody-positive donors compared to donors with type 1 diabetes with insulin-deficient islets (p-value &lt;0.001) and control donors (p-value 0.004). In some donors, pancreatic lymph nodes were also positive. RT-PCR detected enterovirus RNA also in spleen of a small number of donors and virus enrichment in susceptible cell lines before RT-PCR resulted in much higher rate in spleen positivity, particularly in donors with type 1 diabetes. Interestingly, the enterovirus strains detected did not cause a typical lytic infection, possibly reflecting their persistence-prone nature.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions\/interpretation<\/jats:title>\n                  <jats:p>This was the largest coordinated effort to examine the presence of enterovirus RNA in pancreas of organ donors with type 1 diabetes, using a multitude of assays. These findings are consistent with the notion that both the subjects with type 1 diabetes and those with islet autoantibodies may carry a low-grade enterovirus infection in the pancreas and lymphoid tissues.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Research in context<\/jats:title>\n                  <jats:p>What is already known about this subject?<\/jats:p>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Enterovirus infections are among the prime candidates for environmental triggers of type 1 diabetes.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Pancreas (and other tissue) samples of subjects with type 1 diabetes have not been extensively studied for the presence of enterovirus RNA.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                  <jats:p>What is the key question?<\/jats:p>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Can enterovirus RNA be detected in the pancreas and lymphoid tissues of individuals with and without type 1 diabetes?<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                  <jats:p>What are the new findings?<\/jats:p>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Enterovirus RNA can be detected in low amounts in the pancreas and lymphoid tissues using selected enterovirus-specific methods.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Detection of enterovirus RNA in the pancreas was most frequent in prediabetic subjects.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Enterovirus RNA was found also in pancreatic lymph nodes and in spleen where it was more frequently detected in donors with type 1 diabetes compared to non-diabetic donors, with properties previously observed in persistent infections.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                  <jats:p>How might this impact on clinical practice in the foreseeable future?<\/jats:p>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>The findings support the enterovirus - type 1 diabetes association and may have an effect on the primary and secondary prevention strategies towards the disease.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2024.09.11.24313112","type":"posted-content","created":{"date-parts":[[2024,9,13]],"date-time":"2024-09-13T15:05:38Z","timestamp":1726239938000},"source":"Crossref","is-referenced-by-count":0,"title":["Detection of enterovirus RNA in pancreas and lymphoid tissues of organ donors with type 1 diabetes"],"prefix":"10.64898","author":[{"given":"Jutta E","family":"Laiho","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sami","family":"Oikarinen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofia","family":"Morfopoulou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maarit","family":"Oikarinen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashlie","family":"Renner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Depledge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew C","family":"Ross","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan C","family":"Gerling","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith","family":"Breuer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph F","family":"Petrosino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincent","family":"Plagnol","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Pugliese","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Toniolo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard E","family":"Lloyd","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heikki","family":"Hy\u00f6ty","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"JDRF nPOD-Virus Group","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024091604100696000_2024.09.11.24313112v1.1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-009-1276-0"},{"key":"2024091604100696000_2024.09.11.24313112v1.2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0700442104"},{"key":"2024091604100696000_2024.09.11.24313112v1.3","doi-asserted-by":"publisher","DOI":"10.2337\/db14-1370"},{"key":"2024091604100696000_2024.09.11.24313112v1.4","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-003-1297-z"},{"key":"2024091604100696000_2024.09.11.24313112v1.5","doi-asserted-by":"publisher","DOI":"10.1507\/endocrj.K09E-291"},{"key":"2024091604100696000_2024.09.11.24313112v1.6","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-021-05525-0"},{"issue":"8190","key":"2024091604100696000_2024.09.11.24313112v1.7","first-page":"354","article-title":"Pancreatic islet-cell damage in children with fatal viral infections","volume":"2","year":"1980","journal-title":"Lancet Lond Engl"},{"issue":"5","key":"2024091604100696000_2024.09.11.24313112v1.8","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1111\/neup.12121","article-title":"Coxsackievirus B4 myocarditis and meningoencephalitis in newborn twins","volume":"34","year":"2014","journal-title":"Neuropathol Off J Jpn Soc Neuropathol"},{"key":"2024091604100696000_2024.09.11.24313112v1.9","doi-asserted-by":"crossref","unstructured":"Krogvold L , Genoni A , Puggioni A , Campani D , Richardson SJ , Flaxman CS , et al. 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