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.
Highlights
Sickle cell disease (SCD) is one of the most common inherited autosomal recessive disorders worldwide
While numerous other murine models of Acute Chest Syndrome (ACS) have been created that have no infectious etiology[17,18,19], these data implicate that development of ACS-like symptomology could be contributing to the enhanced mortality to influenza infection in SCD and provide the first animal model for influenza virus-induced ACS in SCD
We first sought to determine whether the heightened mortality of influenza virus in patients with SCD could be recapitulated in the SCD transplant murine model
Summary
Sickle cell disease (SCD) is one of the most common inherited autosomal recessive disorders worldwide. Acute chest syndrome (ACS), is a common complication of the sickling disorders and is a major cause of morbidity and mortality associated with SCD1,2. While numerous clinical reports have confirmed the increased morbidity and mortality associated with influenza infection in SCD patients, to date, no laboratory models have investigated influenza infection in a murine model of SCD. While numerous other murine models of ACS have been created that have no infectious etiology[17,18,19], these data implicate that development of ACS-like symptomology could be contributing to the enhanced mortality to influenza infection in SCD and provide the first animal model for influenza virus-induced ACS in SCD
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