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B5 The inflammasome, alarmins and microbiota modulate T effector responses in parasite mono- and co-infections (Rausch)

Research Group: Institute of Immunology
Address: Centre for Infection Medicine
Freie Universität Berlin
Robert-von-Ostertagstr. 7-13, 14163 Berlin
Supervisors: Dr. Sebastian Rausch
Doctoral Researcher: Bhavya Kapse, Hongwei Zhang

Project Description      

State of the art:
Appropriate Th2 and Th17 effector cell responses are central to the control of nematode and
Giardia infections, respectively. We investigated T helper cell heterogeneity in helminth
infections and demonstrated that Th2/1 hybrid cell responses limit the control of the natural
murine nematode Heligmosomoides polygyrus. Inflammasome-mediated IL-1β/IL-18
activation was recently shown to restrict Th2 immunity in nematode infection (3) and to support
protective inflammatory Th17 responses in enteric infections. Furthermore, alarmins
released during nematode infections have been associated with Th17-supportive and
regulatory functions. We hence aim to i) determine the role of the inflammasome in Th2/1,
Th2/17 and Th17/1 instruction in nematode and Giardia muris infection and to ii) characterize
the inflammasome/alarmin-dependent impact of nematode infection on Giardia co-infections,
a setting frequently affecting men and livestock.

Previous own work:
The 1st generation doctoral student showed that Th2/1 cells induced by the murine nematode
Heligmosomoides polygyrus (Hp) limit parasite control. Th2/1 cells developed
independently of the host microbiota, and were identified as the main parasite-specific
IFNγ source and accumulated in the spleen and gut, leading to increased IFNγ activity.
Supporting Th2/1 responses increased worm burdens and the extent of Th2/1 generation was
linked to the differential host susceptibility for nematode infection. An associated project
demonstrated differential mucosal Th17 and Treg responses as determinants of susceptibility
for Giardia muris (Gm) infections. Microbiota exchange between inbred mice equilibrated Treg
responses and permitted more efficient Gm control in mice previously highly susceptible to Gm
infection.

Hypotheses and work plan:
1) Th2/1 responses driven by inflammasome activation imprint susceptibility to worm
infections.
2) Acute vs. chronic nematode co-infections differentially affect anti-Giardia immunity.
3) Microbiota shifts perturb pathogen control in nematode/Giardia co-infections.
The 2nd generation project will first characterize the role of inflammasome activation in Th2/1
instruction, identify early IFNγ sources supporting Th2/1 differentiation and determine the role
of the spleen as Th2/1 instructor and modulator of Th2 immunity in Hp-infected mice.
Inflammasome activation and T helper cell heterogeneity (Th17, Th17/1) will then be
characterized in Gm infected mice. Finally, inflammasome activation, alarmin release and Treg
activity during nematode infection will be surveyed for their effects on T cell mediated immunity
in Hp/Gm co-infections. As the microbiome structure affects parasite control in Hp and Gm
infections (7,8), the microbiota-immunity interplay in Hp/Gm co-infections will be the focus of
the 3rd generation project.

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