Preprint Unraveling SARS-CoV-2 Host-Response Heterogeneity through Longitudinal Molecular Subtyping, 2024, Wang, Iwasaki+

Unraveling SARS-CoV-2 Host-Response Heterogeneity through Longitudinal Molecular Subtyping

Spoiler: Wang et al.

Kexin Wang; Yutong Nie; Cole Maguire; Caitlin Syphurs; Heejune Sheen; Meagan Karoly; Linda Lapp; Jeremy P. Gygi; Naresh Doni Jayavelu; Ravi K. Patel; Annmarie Hoch; IMPACC Network; David Corry; Farrah Kheradmand; Grace A. McComsey; Ana Fernandez-Sesma; Viviana Simon; Jordan P. Metcalf; Nelson I. Agudelo Higuita; William B. Messer; Mark M. David; Kari C. Nadeau; Monica Kraft; Chris Bime; Joanna Schaenman; David Erle; Carolyn S. Calfee; Mark A. Atkinson; Scott C. Brackenridge; David A. Hafler; Albert C. Shaw; Adeeb Rahman; Catherine L. Hough; Linda N. Geng; Al Ozonoff; Elias K. Haddad; Elaine F. Reed; Harm van Bakel; Seunghee H. Kim-Schulze; Florian Krammer; Michael Wilson; Walter Eckalbar; Steve Bosinger; Charles R. Langelier; Rafick Selaky; Ruth R. Montgomery; Holden Maecker; Harlan Krumholz; Esther Melamed; Hanno Steen; Bali Pulendran; Alison D. Augustine; Charles B. Cairns; Nadine Rouphael; Patrice M. Becker; Slim Fourati; Casey P. Shannon; Kinga K. Smolen; Bjoern Peters; Steven H. Kleinstein; Ofer Levy; Matthew C. Altman; Akiko Iwasaki; Joann Diray-Arce; Lauren I. R. Ehrlich; Leying Guan

Hospitalized COVID-19 patients exhibit diverse immune responses during acute infection, which are associated with a wide range of clinical outcomes. However, understanding these immune heterogeneities and their links to various clinical complications, especially long COVID, remains a challenge.

In this study, we performed unsupervised subtyping of longitudinal multi-omics immunophenotyping in over 1,000 hospitalized patients, identifying two critical subtypes linked to mortality or mechanical ventilation with prolonged hospital stay and three severe subtypes associated with timely acute recovery. We confirmed that unresolved systemic inflammation and T-cell dysfunctions were hallmarks of increased severity and further distinguished patients with similar acute respiratory severity by their distinct immune profiles, which correlated with differences in demographic and clinical complications.

Notably, one critical subtype (SubF) was uniquely characterized by early excessive inflammation, insufficient anticoagulation, and fatty acid dysregulation, alongside higher incidences of hematologic, cardiac, and renal complications, and an elevated risk of long COVID. Among the severe subtypes, significant differences in viral clearance and early antiviral responses were observed, with one subtype (SubC) showing strong early T-cell cytotoxicity but a poor humoral response, slower viral clearance, and greater risks of chronic organ dysfunction and long COVID.

These findings provide crucial insights into the complex and context-dependent nature of COVID-19 immune responses, highlighting the importance of personalized therapeutic strategies to improve both acute and long-term outcomes.


Link | PDF (Preprint: BioRxiv) [Open Access]