Longitudinal Assessment of Cytokine Expression and Plasminogen Activation in Hantavirus Cardiopulmonary Syndrome Reveals Immune Regulatory Dysfunction in End-Stage Disease
Peter Simons,
Yan Guo,
Virginie Bondu,
Susan L. Tigert,
Michelle Harkins,
Samuel Goodfellow,
Cana Tompkins,
Devon Chabot-Richards,
Xuexian O. Yang,
Laura Gonzalez Bosc,
Steven Bradfute,
Daniel A. Lawrence,
Tione Buranda
Affiliations
Peter Simons
Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
Yan Guo
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
Virginie Bondu
Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
Susan L. Tigert
Clinical and Translational Science Center (CTSC), University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Michelle Harkins
Division of Infectious Diseases, Department of Internal Medicine, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA
Samuel Goodfellow
Division of Infectious Diseases, Department of Internal Medicine, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA
Cana Tompkins
Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
Devon Chabot-Richards
Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
Xuexian O. Yang
Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Laura Gonzalez Bosc
Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
Steven Bradfute
Division of Infectious Diseases, Department of Internal Medicine, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA
Daniel A. Lawrence
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Tione Buranda
Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
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.
