Longitudinal Assessment of Cytokine Expression and Plasminogen Activation in Hantavirus Cardiopulmonary Syndrome Reveals Immune Regulatory Dysfunction in End-Stage Disease.

Autor: Simons P; Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA., Guo Y; Bioinformatics Shared Resource Center, Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA., Bondu V; Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA., Tigert SL; Clinical and Translational Science Center (CTSC), University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA., Harkins M; Division of Infectious Diseases, Department of Internal Medicine, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA., Goodfellow S; Division of Infectious Diseases, Department of Internal Medicine, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA., Tompkins C; Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA., Chabot-Richards D; Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA., Yang XO; Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA., Bosc LG; Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA., Bradfute S; Division of Infectious Diseases, Department of Internal Medicine, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA., Lawrence DA; Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA., Buranda T; Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
Jazyk: angličtina
Zdroj: Viruses [Viruses] 2021 Aug 12; Vol. 13 (8). Date of Electronic Publication: 2021 Aug 12.
DOI: 10.3390/v13081597
Abstrakt: Pathogenic New World orthohantaviruses cause hantavirus cardiopulmonary syndrome (HCPS), a severe immunopathogenic disease in humans manifested by pulmonary edema and respiratory distress, with case fatality rates approaching 40%. High levels of inflammatory mediators are present in the lungs and systemic circulation of HCPS patients. Previous studies have provided insights into the pathophysiology of HCPS. However, the longitudinal correlations of innate and adaptive immune responses and disease outcomes remain unresolved. This study analyzed serial immune responses in 13 HCPS cases due to Sin Nombre orthohantavirus (SNV), with 11 severe cases requiring extracorporeal membrane oxygenation (ECMO) treatment and two mild cases. We measured viral load, levels of various cytokines, urokinase plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1). We found significantly elevated levels of proinflammatory cytokines and PAI-1 in five end-stage cases. There was no difference between the expression of active uPA in survivors' and decedents' cases. However, total uPA in decedents' cases was significantly higher compared to survivors'. In some end-stage cases, uPA was refractory to PAI-1 inhibition as measured by zymography, where uPA and PAI-1 were strongly correlated to lymphocyte counts and IFN-γ. We also found bacterial co-infection influencing the etiology and outcome of immune response in two cases. Unsupervised Principal Component Analysis and hierarchical cluster analyses resolved separate waves of correlated immune mediators expressed in one case patient due to a sequential co-infection of bacteria and SNV. Overall, a robust proinflammatory immune response, characterized by an imbalance in T helper 17 (Th17) and regulatory T-cells (Treg) subsets, was correlated with dysregulated inflammation and mortality. Our sample size is small; however, the core differences correlated to survivors and end-stage HCPS are instructive.
Databáze: MEDLINE
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