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biorxiv; 2023.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2023.12.01.569608


RationaleThe role of the innate immune system in Idiopathic Pulmonary Fibrosis (IPF) remains poorly understood. However, a functional myeloid compartment is required to remove dying cells and cellular debris, and to mediate innate immune responses against pathogens. Aberrant macrophage activity has been described in patients with Post-acute sequelae of COVID fibrosis (PASC-F). Therefore, we examined the functional and synthetic properties of myeloid cells isolated from normal donor lung and lung explant tissue from both IPF and PASC-F patients and explored the effect of LTI-2355, a Caveolin Scaffolding Domain (CSD) peptide, on these cells. Methods & ResultsCD45+ myeloid cells isolated from lung explant tissue from IPF and PASC-F patients exhibited an impaired capacity to clear autologous dead cells and cellular debris. Uptake of pathogen-coated bioparticles was impaired in myeloid cells from both fibrotic patient groups independent of type of pathogen highlighting a cell intrinsic functional impairment. LTI-2355 improved the phagocytic activity of both IPF and PASC-F myeloid cells, and this improvement was paired with decreased pro-inflammatory and pro-fibrotic synthetic activity. LTI-2355 was also shown to primarily target CD206-expressing IPF and PASC-F myeloid cells. ConclusionsPrimary myeloid cells from IPF and PASC-F patients exhibit dysfunctional phagocytic and synthetic properties that are reversed by LTI-2355. Thus, these studies highlight an additional mechanism of action of a CSD peptide in the treatment of IPF and progressive fibrotic lung disease.

biorxiv; 2023.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2023.09.13.557622


The long-term health effects of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are quickly evolving into a major public health concern, but the underlying cellular and molecular etiology remain poorly defined. There is growing evidence that PASC is linked to abnormal immune responses and/or poor organ recovery post-infection. However, the exact processes linking non-resolving inflammation, impaired tissue repair, and PASC are still unclear. In this report, we utilized a cohort of respiratory PASC patients with viral infection-mediated pulmonary fibrosis and a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. Using a combination of imaging and spatial transcriptomics, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, and the development of fibrotic sequelae after acute viral pneumonia. Mechanistically, CD8+ T cell derived IFN-{gamma} and TNF stimulated lung macrophages to chronically release IL-1{beta}, resulting in the abnormal accumulation of dysplastic epithelial progenitors in fibrotic areas. Notably, therapeutic neutralization of IFN-{gamma} and TNF, or IL-1{beta} after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC and identify potential therapeutic targets to dampen chronic pulmonary sequelae post respiratory viral infections including SARS-CoV-2.

Leora I. Horwitz; Tanayott Thaweethai; Shari B. Brosnahan; Mine S. Cicek; Megan L. Fitzgerald; Jason D. Goldman; Rachel Hess; S. L. Hodder; Vanessa L. Jacoby; Michael R. Jordan; Jerry A. Krishnan; Adeyinka O. Laiyemo; Torri D. Metz; Lauren Nichols; Rachel E. Patzer; Anisha Sekar; Nora G. Singer; Lauren E. Stiles; Barbara S. Taylor; Shifa Ahmed; Heather A. Algren; Khamal Anglin; Lisa Aponte-Soto; Hassan Ashktorab; Ingrid V. Bassett; Brahmchetna Bedi; Nahid Bhadelia; Christian Bime; Marie-Abele C. Bind; Lora J. Black; Andra L. Blomkalns; Hassan Brim; Mario Castro; James Chan; Alexander W. Charney; Benjamin K. Chen; Li Qing Chen; Peter Chen; David Chestek; Lori B. Chibnik; Dominic C. Chow; Helen Y. Chu; Rebecca G. Clifton; Shelby Collins; Maged M. Costantine; Sushma K. Cribbs; Steven G. Deeks; John D. Dickinson; Sarah E. Donohue; Matthew S. Durstenfeld; Ivette F. Emery; Kristine M. Erlandson; Julio C. Facelli; Rachael Farah-Abraham; Aloke V. Finn; Melinda S. Fischer; Valerie J. Flaherman; Judes Fleurimont; Vivian Fonseca; Emily J. Gallagher; Jennifer C. Gander; Maria Laura Gennaro; Kelly S. Gibson; Minjoung Go; Steven N. Goodman; Joey P. Granger; Frank L. Greenway; John W. Hafner; Jenny E. Han; Michelle S. Harkins; Kristine S.P. Hauser; James R. Heath; Carla R. Hernandez; On Ho; Matthew K. Hoffman; Susan E. Hoover; Carol R. Horowitz; Harvey Hsu; Priscilla Y. Hsue; Brenna L. Hughes; Prasanna Jagannathan; Judith A. James; Janice John; Sarah Jolley; S. E. Judd; Joy J. Juskowich; Diane G. Kanjilal; Elizabeth W. Karlson; Stuart D. Katz; J. Daniel Kelly; Sara W. Kelly; Arthur Y. Kim; John P. Kirwan; Kenneth S. Knox; Andre Kumar; Michelle F. Lamendola-Essel; Margaret Lanca; Joyce K. Lee-lannotti; R. Craig Lefebvre; Bruce D. Levy; Janet Y. Lin; Brian P. Logarbo Jr.; Jennifer K. Logue; Michele T. Longo; Carlos A. Luciano; Karen Lutrick; Shahdi K. Malakooti; Gail Mallett; Gabrielle Maranga; Jai G. Marathe; Vincent C. Marconi; Gailen D. Marshall; Christopher F. Martin; Jeffrey N. Martin; Heidi T. May; Grace A. McComsey; Dylan McDonald; Hector Mendez-Figueroa; Lucio Miele; Murray A. Mittleman; Sindhu Mohandas; Christian Mouchati; Janet M. Mullington; Girish N Nadkarni; Erica R. Nahin; Robert B. Neuman; Lisa T. Newman; Amber Nguyen; Janko Z. Nikolich; Igho Ofotokun; Princess U. Ogbogu; Anna Palatnik; Kristy T.S. Palomares; Tanyalak Parimon; Samuel Parry; Sairam Parthasarathy; Thomas F. Patterson; Ann Pearman; Michael J. Peluso; Priscilla Pemu; Christian M. Pettker; Beth A. Plunkett; Kristen Pogreba-Brown; Athena Poppas; J. Zachary Porterfield; John G. Quigley; Davin K. Quinn; Hengameh Raissy; Candida J. Rebello; Uma M. Reddy; Rebecca Reece; Harrison T. Reeder; Franz P. Rischard; Johana M. Rosas; Clifford J. Rosen; Nadine G. Rouphae; Dwight J. Rouse; Adam M. Ruff; Christina Saint Jean; Grecio J. Sandoval; Jorge L. Santana; Shannon M. Schlater; Frank C. Sciurba; Caitlin Selvaggi; Sudha Seshadri; Howard D. Sesso; Dimpy P. Shah; Eyal Shemesh; Zaki A. Sherif; Daniel J. Shinnick; Hyagriv N. Simhan; Upinder Singh; Amber Sowles; Vignesh Subbian; Jun Sun; Mehul S. Suthar; Larissa J. Teunis; John M. Thorp Jr.; Amberly Ticotsky; Alan T. N. Tita; Robin Tragus; Katherine R. Tuttle; Alfredo E. Urdaneta; P. J. Utz; Timothy M. VanWagoner; Andrew Vasey; Suzanne D. Vernon; Crystal Vidal; Tiffany Walker; Honorine D. Ward; David E. Warren; Ryan M. Weeks; Steven J. Weiner; Jordan C. Weyer; Jennifer L. Wheeler; Sidney W. Whiteheart; Zanthia Wiley; Natasha J. Williams; Juan P. Wisnivesky; John C. Wood; Lynn M. Yee; Natalie M. Young; Sokratis N. Zisis; Andrea S. Foulkes; - Recover Initiative.
medrxiv; 2023.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2023.05.26.23290475


Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. Methods: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged [≥]18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. Discussion: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.

medrxiv; 2020.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2020.07.23.20161182


Coronavirus disease 2019 (COVID-19) has quickly become the most serious pandemic since the 1918 flu pandemic. In extreme situations, patients develop a dysregulated inflammatory lung injury called acute respiratory distress syndrome (ARDS) that causes progressive respiratory failure requiring mechanical ventilatory support. Recent studies have demonstrated immunologic dysfunction in severely ill COVID-19 patients. To further delineate the dysregulated immune response driving more severe clinical course from SARS-CoV-2 infection, we used single-cell RNA sequencing (scRNAseq) to analyze the transcriptome of peripheral blood mononuclear cells (PBMC) from hospitalized COVID-19 patients having mild disease (n = 5), developing ARDS (n = 6), and recovering from ARDS (n = 6). Our data demonstrated an overwhelming inflammatory response with select immunodeficiencies within various immune populations in ARDS patients. Specifically, their monocytes had defects in antigen presentation and deficiencies in interferon responsiveness that contrasted the higher interferon signals in lymphocytes. Furthermore, cytotoxic activity was suppressed in both NK and CD8 lymphocytes whereas B cell activation was deficient, which is consistent with the delayed viral clearance in severely ill COVID-19 patients. Finally, we identified altered signaling pathways in the severe group that suggests immunosenescence and immunometabolic changes could be contributing to the dysfunctional immune response. Our study demonstrates that COVID-19 patients with ARDS have an immunologically distinct response when compared to those with a more innocuous disease course and show a state of immune imbalance in which deficiencies in both the innate and adaptive immune response may be contributing to a more severe disease course in COVID-19.