title: Vascular Permeability Drives Susceptibility to Influenza Infection in a Murine Model of Sickle Cell Disease.
abstract: Sickle cell disease (SCD) is a major global health concern. Patients with SCD experience disproportionately greater morbidity and mortality in response to influenza infection than do others. Viral infection is one contributing factor for the development of Acute Chest Syndrome (ACS), a major cause of morbidity and mortality in SCD patients. We determined whether the heightened sensitivity to influenza infection could be reproduced in the two different SCD murine models to ascertain the underlying mechanisms of increased disease severity. In agreement with clinical observations, we found that both genetic and bone marrow-transplanted SCD mice had greater mortality in response to influenza infection than did wild-type animals. Despite similar initial viral titers and inflammatory responses between wild-type and SCD animals during infection, SCD mice continued to deteriorate and failed to resolve the infection, resulting in increased mortality. Histopathology of the lung tissues revealed extensive pulmonary edema and vascular damage following infection, a finding confirmed by heightened vascular permeability following virus challenge. These findings implicate the development of exacerbated pulmonary permeability following influenza challenge as the primary factor underlying heightened mortality. These studies highlight the need to focus on prevention and control strategies against influenza infection in the SCD population.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN USA.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Karlsson
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Oguin
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Meliopoulos
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Iverson
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN USA.
authors.forename: Alexandria
authors.initials: A
authors.lastname: Broadnax
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN USA.
authors.forename: Sun-Woo
authors.initials: SW
authors.lastname: Yoon
authors.affiliation: Department of Experimental Hematology, St. Jude Children's Research Hospital, Memphis, TN USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Pestina
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Thomas
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Webby
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Schultz-Cherry
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Rosch
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications*; D000818:Animals; D002199:Capillary Permeability; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D006651:Histocytochemistry; D006801:Humans; D007251:Influenza, Human / Q000276:immunology*; D008168:Lung / Q000473:pathology; D051379:Mice; D016019:Survival Analysis