Differential regulation of the host response to Aspergillus fumigatus by NOD receptors

Ref ID: 19516

Author:

MS Gresnigt1,2*, M Oosting1,2, R Lubbers1,2, DJ de Jong3, LAB Joosten1,2, T Kanneganti4,
MG Netea1,2, FL van de Veerdonk1,2

Author address:

1Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
2Nijmegen Institute for Infection Inflammation and Immunity (N4i), Nijmegen, The Netherlands
3Department of Gastroenterology and Hepatology, Radboud Univ

Full conference title:

6th Advances Against Aspergillosis 2014

Abstract:

Purpose:
Invasive aspergillosis is remains one of the most severe complications in immunocompromised
patients. Screening for polymorphisms, that can make these patients potentially more susceptible to
develop aspergillosis, can prove to be beneficial in preventing invasive infections. Several studies
demonstrate that the intracellular pattern recognition receptor nucleotide-binding oligomerization
domain (NOD)2 plays an important role in the host defense against Aspergillus. The purpose of our
study was to investigate how polymorphisms in NOD2 influence the host response to A. fumigatus.
Additionally, we investigated whether the other NOD receptor, NOD1 and the RICK kinase (shared
by both receptors) are also involved in the host response to Aspergillus.
Methods:
Human peripheral blood mononuclear cells (PBMCs) with polymorphisms in NOD2 (rs2066847
and rs2066842), NOD1 (ND1+32656 T/GG) and RICK (rs42490) were stimulated with Aspergillus
to investigate how these variations modulated the innate cytokine response. To compare the
effect of polymorphisms with complete deficiency of these receptors, splenocytes of wildtype,
NOD1-/-, NOD2-/- and RICK-/- mice were stimulated with Aspergillus. Immunofluorescence staining
for NOD1 was performed with anti-NOD1 antibody on monocytes that were exposed to FITClabeled
conidia.
Results:
We found that PBMCs with polymorphisms in NOD2 and cells of NOD2-/- patients responded
with both decreased innate and IL-17, IL-22 and IFNγ responses to Aspergillus stimulation. This
decreased production of T-cell cytokines correlated with a decreased proliferation of IL-17+, IL-22+,
and IFNγ + T-cells upon stimulation with Aspergillus. By immunofluorescence staining we were
able to demonstrate that NOD1 localizes to phagocytosed conidia in monocytes, suggesting a role
for NOD1 in Aspergillus recognition. In contrast to NOD2, PBMCs with a polymorphism in NOD1
responded with increased innate cytokine responses compared to wildtype PBMCs. Complementary,
we found that NOD1-/-murine splenocytes also responded with increased innate and T-cell responses
to Aspergillus stimulation. RICK kinase is responsible for the downstream signaling of both the
NOD receptors. We found that a polymorphism in RICK results in an increased cytokine response
to Aspergillus. Furthermore, RICK-/- murine splenocytes demonstrated a similar increased cytokine
response to Aspergillus similar to NOD1-/-splenocytes.
Conclusions:
Our data demonstrates that polymorphisms in the NOD receptors are differentially regulating cytokine
signaling in response to Aspergillus. On the one hand NOD2 is required for induction of responses
while on the other hand NOD1 localizes to phagocytosed conidia and together with RICK
reduces Aspergillus-induced cytokine responses. To discern whether these polymorphisms are
either advantageous or detrimental our future experiments are aimed to investigate the role of these
polymorphisms in susceptibility to invasive aspergillosis.
NOTE: THIS ABSTRACT HAS BEEN SELECTED FOR ORAL PRESENTATION.

Abstract Number: 44

Conference Year: 2014

Link to conference website: http://www.AAA2014.org

New link: NULL

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