New insights into the pathogenesis of invasive pulmonary aspergillosis: real time imaging of hypoxia and inflammation

Ref ID: 19433

Author:

O. G. Ibrahim-Granet,1 A. Rekiki,1 A. Savers,1 M. Parlato,1
M. Brock2 and J. M. Cavaillon1

Author address:

1Institut Pasteur, Paris, France and 2Hans-Kn€oll-Institute, Jena,
Germany

Full conference title:

6th Trends in Medical Mycology 2013

Date: 11 October 2014

Abstract:

Objectives Aspergillus fumigatus, is responsible for relevant diseases
especially in immunocompromised individuals. Among these, life-
threatening invasive pulmonary aspergillosis (IPA) results in mortal-
ity rates ranging from 30-90%. While investigating the role of
immune effector cells in host defense against A. fumigatus using a
bioluminescent A. fumigatus reporter strain, we recently showed that
one day post-infection lungs from cortisone acetate-treated mice dis-
played severe tissue necrosis and hypoxia (Brock et al 2008, Ibra-
him-Granet O et al 2010, Galiger et al 2013). Development of
hypoxia was confirmed by Grahl et al in 2011 using the hypoxia
marker pimonidazole hydrochloride on lungs sections from eutha-
nized mice with IPA.
In this study we focused on the in vivo real-time monitoring of
hypoxia and inflammation within the lungs of mice from three
immunologically distinct murine models of invasive pulmonary
aspergillosis, i. e. cortisone acetate versus cyclophospahmide treat-
ment versus CXCR2 knock- out mice (Ibrahim-Granet et al BMC
2010).
Methods To monitor disease progression, hypoxia and inflammation
we used bioluminescence imaging and fluorescence molecular tomog-
raphy systems (Perkin Elmer) on mice infected with the luminescent
A. fumigatus strain. Here, (i) fungal growth was quantified by biolu-
minescence, (ii) hypoxia was quantified by the cell surface expression
of carbonic anhydrase (CAIX) and (iii) inflammation was determined
through the pan cathepsin proteases known to be produced by
inflammatory cells. In addition, inflammation was investigated from
lung tissues homogenates by studying the inflammatory cytokine
patterns by ELISA.
Results Three days following infection hypoxia was detected under
all infectious conditions regardless the immune status of mice.
Even immunocompetent mice developed hypoxia levels five times
higher than mock-infected (control) animals although no invasive
aspergillosis developed. However, hypoxia was most pronounced in
susceptible CXCR2 KO mice (28 times higher than control) followed by corticosteroid and cyclophosphamide treated animals.
In the CXCR2 KO mice, the high level of hypoxia is associated
with an overwhelming inflammatory cytokines levels in the lungs
homogenate. Regarding the cathepsin level, in immunocompetent
animals, cathepsin was hardly detectable within the lungs of the
mice. However, in corticosteroid animals the presence of cathepsin
was more pronounced (11 times compared to control). Interest-
ingly, in CXCR2 KO, showing the highest level of hypoxia, the
presence of cathepsin was only moderate (3 times compared to
control). This indicates that the pan cathepsin proteases activity is
not necessarily linked to the severity of the infection and the role
of these proteases in the clearance of the infection needs further
investigations.
Conclusion This is the first study that correlates hypoxia with fun-
gal growth in real-time from in vivo models of murine IPA. Impor-
tantly our data brings new insights on the contribution of hypoxia to
lung inflammation during fungal infection. Impact of hypoxia on the
innate immune system during invasive pulmonary aspergillosis has
to be investigated.

Abstract Number: p282

Conference Year: 2013

Link to conference website: NULL

New link: NULL

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