{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T22:23:47Z","timestamp":1774045427047,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.14867.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2019,1,2]],"date-time":"2019-01-02T00:00:00Z","timestamp":1546387200000}}],"reference-count":81,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2019,1,2]],"date-time":"2019-01-02T00:00:00Z","timestamp":1546387200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/J008702\/1"],"award-info":[{"award-number":["MR\/J008702\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["G1000230"],"award-info":[{"award-number":["G1000230"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010757","name":"National Centre for the Replacement Refinement and Reduction of Animals in Research","doi-asserted-by":"publisher","award":["NC\/CO13295"],"award-info":[{"award-number":["NC\/CO13295"]}],"id":[{"id":"10.13039\/501100010757","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010757","name":"National Centre for the Replacement Refinement and Reduction of Animals in Research","doi-asserted-by":"publisher","award":["NC.CO13117"],"award-info":[{"award-number":["NC.CO13117"]}],"id":[{"id":"10.13039\/501100010757","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["104726"],"award-info":[{"award-number":["104726"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background<\/ns4:bold>\n                    : Human visceral leishmaniasis, caused by infection with\n                    <ns4:italic>Leishmania donovani<\/ns4:italic>\n                    or\n                    <ns4:italic>L. infantum,<\/ns4:italic>\n                    is a potentially fatal disease affecting 50,000-90,000 people yearly in 75 disease endemic countries, with more than 20,000 deaths reported. Experimental models of infection play a major role in understanding parasite biology, host-pathogen interaction, disease pathogenesis, and parasite transmission. In addition, they have an essential role in the identification and pre-clinical evaluation of new drugs and vaccines. However, our understanding of these models remains fragmentary. Although the immune response to\n                    <ns4:italic>Leishmania donovani<\/ns4:italic>\n                    infection in mice has been extensively characterized, transcriptomic analysis capturing the tissue-specific evolution of disease has yet to be reported.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Methods<\/ns4:bold>\n                    : We provide an analysis of the transcriptome of spleen, liver and peripheral blood of BALB\/c mice infected with\n                    <ns4:italic>L. donovani<\/ns4:italic>\n                    . Where possible, we compare our data in murine experimental visceral leishmaniasis with transcriptomic data in the public domain obtained from the study of\n                    <ns4:italic>L. donovani<\/ns4:italic>\n                    -infected hamsters and patients with human visceral leishmaniasis. Digitised whole slide images showing the histopathology in spleen and liver are made available via a dedicated website,\n                    <ns4:ext-link xmlns:ns3=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" ns3:href=\"http:\/\/www.leishpathnet.org\">www.leishpathnet.org<\/ns4:ext-link>\n                    .\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Results:<\/ns4:bold>\n                    Our analysis confirms marked tissue-specific alterations in the transcriptome of infected mice over time and identifies previously unrecognized parallels and differences between murine, hamster and human responses to infection. We show commonality of interferon-regulated genes whilst confirming a greater activation of type 2 immune pathways in infected hamsters compared to mice. Cytokine genes and genes encoding immune checkpoints were markedly tissue specific and dynamic in their expression, and pathways focused on non-immune cells reflected tissue specific immunopathology. Our data also addresses the value of measuring peripheral blood transcriptomics as a potential window into underlying systemic disease.\u00a0\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Conclusions:<\/ns4:bold>\n                    Our transcriptomic data, coupled with histopathologic analysis of the tissue response, provide an additional resource to underpin future mechanistic studies and to guide clinical research.\n                  <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.14867.2","type":"journal-article","created":{"date-parts":[[2019,1,2]],"date-time":"2019-01-02T06:35:06Z","timestamp":1546410906000},"page":"135","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis"],"prefix":"10.12688","volume":"3","author":[{"given":"Helen","family":"Ashwin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin","family":"Seifert","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8332-7196","authenticated-orcid":false,"given":"Sarah","family":"Forrester","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Najmeeyah","family":"Brown","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandy","family":"MacDonald","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sally","family":"James","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0637-281X","authenticated-orcid":false,"given":"Dimitris","family":"Lagos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jon","family":"Timmis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5574-3766","authenticated-orcid":false,"given":"Jeremy C","family":"Mottram","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon L.","family":"Croft","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8796-4755","authenticated-orcid":false,"given":"Paul M.","family":"Kaye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2019,1,2]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"805-17","DOI":"10.1084\/jem.20061141","article-title":"Splenic accumulation of IL-10 mRNA in T cells distinct from CD4+CD25+ (Foxp3) regulatory T cells in human visceral leishmaniasis.","volume":"204","author":"S Nyl\u00e9n","year":"2007","journal-title":"J Exp Med."},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"1134-7","DOI":"10.1093\/infdis\/jir461","article-title":"IL-10 neutralization 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Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-135\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-135\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-135\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,1,10]],"date-time":"2019-01-10T10:00:09Z","timestamp":1547114409000},"score":1,"resource":{"primary":{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-135\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,2]]},"references-count":81,"URL":"https:\/\/doi.org\/10.12688\/wellcomeopenres.14867.2","relation":{"has-review":[{"id-type":"doi","id":"10.21956\/wellcomeopenres.16356.r34507","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.16356.r34507","asserted-by":"object"}]},"ISSN":["2398-502X"],"issn-type":[{"value":"2398-502X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1,2]]},"assertion":[{"value":"Indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-135\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.16203.r34133, Yasuyuki Goto, \u00a0Laboratory of Molecular Immunology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan, 14 Nov 2018, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-135\/v1#referee-response-34133","order":0,"name":"referee-response-34133","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Paul Kaye<\/b>; \n<i>Posted: 17 Dec 2018<\/i>; Major\n<i>1.&nbsp;&nbsp;comment on strain choice and specific differences in response to infection<\/i>The reviewer is correct that we and others also use B6 mice extensively in studies of murine VL.&nbsp;&nbsp;We have expanded in the Discussion on the rationale for our choice of BALB\/c mice in this study.&nbsp;&nbsp;However, we are currently preparing another manuscript from the CRACKIT program, which will include transcriptomic data from infected B6 as well as B6.\n<i>Rag<\/i>-\/- mice.&nbsp;\n<i>2. why look at a common 26 gene signature? Differences across species should be pursued.<\/i>I think in this manuscript we have done both.&nbsp;&nbsp;The value for a common gene signature might be in the identification of common underlying mechanisms or the identification of biomarkers that might be useful for clinical monitoring of disease progression.&nbsp;&nbsp;We have expanded the discussion to address this.&nbsp;&nbsp;\n<i>3. clarify use of different time points in different species and relation to disease pattern<\/i>Unfortunately, we are limited by the availability of data.&nbsp;&nbsp;Researchers working with hamsters have only studied spleen (and as their study was not published at the time we began our own investigations, we could not \u201ctime match\u201d even if that was desirable). Researchers investigating human disease have to date only published transcriptomic data from peripheral blood. We hope our current manuscript will highlight the need for better comparative studies, but it will always be difficult to match to disease profile as these differ widely between models and indeed humans.&nbsp;&nbsp;\n<i>4. clarify discussion on upstream negative regulators<\/i>We have amended the text to explain how IPA determines upstream regulators&nbsp;\n<i>5. improve clarity and description of Figure 3E<\/i>We have included new text to clarify this figure.&nbsp;Minor\n<i>1. check abbreviation call outs<\/i>These have been corrected&nbsp;\n<i>2. error in Figure 1A\/B RAW data table<\/i>This has been corrected&nbsp;\n<i>3. page 9: add reference to Kong et al&nbsp;&nbsp;<\/i>This has been corrected","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-135\/v2#referee-comment-3764","order":1,"name":"referee-comment-3764","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.16356.r34507, Washington Luis Conrado dos-Santos, Caroline Vilas Boas de Melo, Funda\u00e7\u00e3o Oswaldo Cruz, Instituto Gon\u00e7alo Moniz, Salvador, Brazil, 09 Jan 2019, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-135\/v2#referee-response-34507","order":2,"name":"referee-response-34507","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.16203.r34135, Syamal Roy, Cooch Behar Panchanan Barma University, Cooch Behar, West Bengal, India, 20 Nov 2018, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-135\/v1#referee-response-34135","order":3,"name":"referee-response-34135","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Paul Kaye<\/b>; \n<i>Posted: 17 Dec 2018<\/i>; \n<i>1. elaborate on why mouse d36 and hamster d28 was considered \u201cbest match\u201d for analysis<\/i> We have amended the text in the Results to indicate \u201cat the peak of splenic infection\u201d rather than \u201cbest matched\u201d and made a further comment to this effect in the Discussion.&nbsp; &nbsp; \n<i>2. software to generate weighted Venn diagram in Figure 5A<\/i> We have added this information to the M&amp;M &nbsp; \n<i>3. software to generate correlation plot in Figure 5B<\/i> We have added this information to the M&amp;M","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-135\/v2#referee-comment-3762","order":4,"name":"referee-comment-3762","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.16203.r34134, Philip Scott, Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA, 22 Nov 2018, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-135\/v1#referee-response-34134","order":5,"name":"referee-response-34134","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Paul Kaye<\/b>; \n<i>Posted: 17 Dec 2018<\/i>; \n<i>1. batch effects resulting from conducting two independent experiments<\/i> We are aware of the possibility of batch effects and have tried to control for these as best as possible.&nbsp;The size and scale of the experiments performed for this study (and also to support additional analysis to be described elsewhere) made it logistically impossible to use a single cohort processed on the same day.&nbsp;&nbsp;We confirmed health status across cohorts according to FELASA guidelines and had matched \u201cna&iuml;ve\u201d control mice for each cohort (and for each time point in CRACKIT_2).&nbsp;Differential gene expression was conducted relative to these matched controls rather than to a common \u201cna&iuml;ve\u201d group to further reduce batch effects. These details are described in the M&amp;M and Results.&nbsp;&nbsp; &nbsp; \n<i>2. issues resulting from comparison of RNA-Seq to microarray<\/i> We have expanded our discussion on this point as suggested by the referee &nbsp; \n<i>3 tissue specific differences in parasite control in spleen and liver<\/i> We have included some additional comments on this issue throughout the manuscript.&nbsp;&nbsp;However, as this data represented the platform on which to base further mechanistic studies, we have refrained from making too many conclusions purely on expression data. &nbsp; \n<i>4. font size of figures<\/i> We have reviewed all the figures for legibility and where necessary either increased the font size, of re-designed the figure to improve readability. For the STRING diagrams in Figs 11 and 12, the main aim is to show the extent to which different groups of DE genes are clustered. We tried increasing font size, but this actually makes the figure less clear due to proximity of each name. We think it valuable for readers to be able to view the gene names (even if requiring zoom on a pdf version of the manuscript and so have retained a small font on Figs 11 and 12). &nbsp; \n<i>5. was no difference in granulomas between d21 and d42 expected?<\/i> There are some subtle differences in the size distribution over time, and at d42 there is already some killing of parasites within granulomas (as evident from Fig 1A).&nbsp;This is not fully reflected in change in granuloma size, however.&nbsp;","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-135\/v2#referee-comment-3761","order":6,"name":"referee-comment-3761","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was funded by a National Centre for Replacement, Refinement and Reduction of Animal in Research (NC3Rs) \/ Innovate UK CRACKIT Challenge Award (NC.CO13117 and NC\/CO13295 to PMK, SLC, JT and JM), by a UK MRC Programme Grant (G1000230 to PMK) and by a Wellcome Trust Senior Investigator Award (WT104726 to PMK). KS and SLC were also supported by UK MRC (MR\/J008702\/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":7,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}