{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:01:12Z","timestamp":1790186472667,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,19]]},"group-title":"Microbiology","reference-count":102,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:00:00Z","timestamp":1789776000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,19]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Human gammaherpesviruses (yHVs) including Epstein-Barr Virus and Kaposi\u2019s sarcoma associated herpesvirus are linked to cancer and inflammatory disease development. The outcome of yHV infection is highly regulated by cell type, with macrophages identified as an important early infection target that can also serve as a latency reservoir. Here, we used the mouse yHV model, murine gammaherpesvirus (MHV68), to identify a dose-dependent outcome of MHV68 infection of macrophages, with high dose infection resulting in extensive morphological changes, viral gene expression, and a pronounced inflammatory cell death not observed under conditions of lytic replication occurring at lower infectious dose. Virion envelope and tegument components were not sufficient for this dose-dependent cell death, which required intact viral DNA and virus transcription, yet occurred independently of viral DNA replication and late gene transcription. Necrostatin-1 (Nec-1) treatment, an anti-inflammatory therapeutic, limited cell death and reduced cell morphology alterations, with no impact on virus replication, uncoupling cell death from lytic replication. Activation of autophagy profoundly limited high dose infection outcomes, with increased cell survival and reduced viral gene expression. Despite the improved cell survival observed in cells treated with Nec-1, biochemical analysis of infected cultures identified robust apoptosis induction with subsequent activation of gasdermin E, suggesting a multi-modal cell death mechanism culminating in pyroptosis. Our findings suggest that high dose macrophage infection byMHV68 is a major driver of inflammatory cell death to potentially shape downstream inflammation and immune responses.<\/jats:p>\n                <jats:sec>\n                  <jats:title>IMPORTANCE<\/jats:title>\n                  <jats:p>The human gammaherpesviruses (yHVs) are globally prevalent viruses which can cause many cancers and chronic inflammatory diseases. Despite their pervasiveness, little is known about the nature of yHV infection in macrophages, a relevant host cell type, that is highly responsive to the environment and plays major roles in immune modulation. During infection, macrophages are likely to be exposed to different amounts of virus, based on their proximity to sites of ongoing virus replication or reactivation. By studying how macrophages respond to different amounts of virus, we find that the amount of virus macrophages are exposed to determines the likelihood of survival versus an inflammatory death mediated by integrated programmed cell death mechanisms. This inflammatory death can be inhibited by Necrostatin-1, a promising treatment for multiple inflammatory diseases. Overall, our work highlights the impact of virus dose on promoting oncogenic conditions and introduces a potential treatment option to limit this inflammation.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.16.752237","type":"posted-content","created":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T03:55:11Z","timestamp":1789876511000},"source":"Crossref","is-referenced-by-count":0,"title":["High Dose Gammaherpesvirus Infection in Macrophages Results in Inflammatory Multimodal Cell Death"],"prefix":"10.64898","author":[{"given":"Gabrielle","family":"Vragel","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado Denver | Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gracyn","family":"Nelson-Reid","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado Denver | Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael E.","family":"Kostelecky","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado Denver | Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Spear","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado Denver | Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moses","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Georgia State University, Atlanta, Georgia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek W.","family":"Abbott","sequence":"additional","affiliation":[{"name":"Department of Immunology and Genomic Medicine, National Jewish Health, Denver, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2662-5554","authenticated-orcid":false,"given":"Linda F.","family":"van Dyk","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado Denver | Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric T.","family":"Clambey","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado Denver | Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026092310050911000_2026.09.16.752237v1.1","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-021-03824-y"},{"key":"2026092310050911000_2026.09.16.752237v1.2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abj8222"},{"key":"2026092310050911000_2026.09.16.752237v1.3","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.71.8.5894-5904.1997"},{"issue":"1","key":"2026092310050911000_2026.09.16.752237v1.4","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1146\/annurev-virology-011921-082615","article-title":"Conquering the Host: Determinants of Pathogenesis Learned from Murine Gammaherpesvirus 68","volume":"8","year":"2021","journal-title":"Annu Rev Virol"},{"key":"2026092310050911000_2026.09.16.752237v1.5","doi-asserted-by":"crossref","unstructured":"Longnecker, R. and F. 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