BRIEF REPORT • JID 2007:195 (15 February) • 581
B R I E F R E P O R T
Hypersusceptibility to Invasive
in Experimental Sickle Cell
Disease Involves Platelet-Activating
Martha L. Miller,1Geli Gao,1Tamara Pestina,2Derek Persons,2
and Elaine Tuomanen1
1Department of Infectious Diseases and
Comprehensive Sickle Cell Center, St. Jude Children’s Research Hospital,
2Division of Experimental Hematology,
Children with sickle cell disease have a 600-fold increased
incidence of invasivepneumococcaldisease.Platelet-activating
factor receptor (PAFr) mediates pneumococcal invasion, and
up-regulation of PAFr on chronically activated endothelia
could contribute to increased bacterial invasion. Mice trans-
infection, and 57% died, compared with 16% of wild-type
mice. Histopathological analysis revealed that sickle cell mice
expressed significantly more PAFr on endotheliaandepithelia.
Pharmacological blockade or genetic deletion of PAFr pro-
tected sickle cell mice from mortality. We conclude that PAFr
plays an important role in hypersusceptibility to pneumococ-
cal infection in sickle cell disease.
Streptococcus pneumoniae is the leading cause of serious bacterial
infection in the pediatric population and is estimated to cause
17,000 cases of bacteremia each year . Children with sickle
cell disease have 400–600 times greater risk of invasive infection
with pneumococcus than their healthy peers, and the presen-
tation of disease in these patients is often a fulminant, lethal
sepsis . This invasive disease rate is well beyond the 2–3-fold
increased risk of sepsis from other encapsulated bacteria.
Received 5 July 2006; accepted 20 September 2006; electronically published 8 January 2007.
Potential conflicts of interest: none reported.
Financial support: National Institutes of Health (grants AI 27913 and AI 39482); NationalHeart,
Lung, and Blood Institute (grant U54HL070590); American Lebanese Syrian Associated Charities.
Research Hospital, 332 N. Lauderdale St., Memphis, TN 38105 (email@example.com).
The Journal of Infectious Diseases 2007;195:581–4
? 2007 by the Infectious Diseases Society of America. All rights reserved.
Insight into the mechanism underlying the increased vul-
nerability of children with sickle cell disease to invasive pneu-
mococcal infection could lead to more effective disease pre-
vention. Epidemiological studies have suggested that the rate
of carriage of pneumococci in sickle cell patients is equivalent
to healthy children (30%–40%) , indicating that the differ-
ence in incidence of invasive disease may relate to events after
colonization. No defects in amounts of complement compo-
nents, properdin, or neutrophil-killing capability have been
found . Splenic function decreases progressively in sickle cell
disease and may compromise bacterial clearance. Lowerconcen-
trations of opsonizing anticapsular antibody have also been sug-
gested to contributetosepsis[4,5].However,decreasedantibody
levels or decreased splenic function would be expected to cause
pathogens of childhood, not just the pneumococcus. Yet, the
heightened risk is not shared by other encapsulated pathogens
or by other anemias , suggesting that there is a potentially
the sickle cell phenotype.
As a consequence of chronic hypoxia and infection, patients
with sickle cell disease exhibit a state of perpetual endothe-
lial activation [6–8]. The increased expression of adhesionmol-
ecules and carbohydrate receptors exhibited on the sickle cell
endothelium supports this notion. Platelet-activating factor
receptor (PAFr), a G protein–coupled receptor that binds the
lipid chemokine PAF, is widely expressed throughout the body
and is up-regulated by inflammation . The critical role that
PAFr plays in pneumococcal invasion has been clearly estab-
lished in vitro and in vivo [10–13]. Phosphorylcholine on the
pneumococcal cell wall mimics thebioactivecomponentofPAF
and serves to insert the bacteria into the PAFr uptake pathway
to enter human cells. Bacterial translocation across the vascular
endothelium is severely impaired in pafr?/?mice and in wild-
type mice treated with PAFr antagonists . Using a murine
model of sickle cell disease, hypersusceptibility to pneumococ-
cal infection was recapitulated, and we tested the hypothesis
that PAFr is up-regulated in sickle cell disease and promotes
development of severe pneumococcal infection.
Materials and methods.
Lethally irradiated C57B/6J mice
were transplanted as described [14–16] with
bone marrow cells from either BERK sickle cell mice (n p 23),
cells from mice with b-thalassemia (
wild-type mice ( ). b-thalassemic mice were used as an p 31
control for anemia. Baytril (enrofloxacin; 2.27% solution, di-
luted 1:100 in drinking water; Bayer) was administered as an
) , or cells from
n p 24
by guest on November 4, 2015