B4 Macrophage and dendritic cell adaptation to sequential co-infection by Toxoplasma gondii and nematodes (Hartmann)
|Research Group:||Institute of Immunology|
|Address:||Freie Universität Berlin, Centre for Infection Medicine, Robert-von-Ostertag-Str. 7-13, 14163 Berlin|
|Supervisors:||Prof. Dr. Susanne Hartmann|
|Doctoral Researcher:||Benjamin Hamid, Luis Elizalde, Arkadi Kundik, Zaneta Kidiavai|
State of the art:
Co-infections with pathogens controlled by opposing immune responses impose a major
challenge to the immune system. Macrophages (MΦ) and dendritic cells (DC) as gatekeepers
sense antigens of invading pathogens and react e.g. by cytokine production. An adaptation of
innate myeloid cell responses depends on pathogen nature and dose. In this context we
aim to i) characterize how a Toxoplasma infection modulates DC and MΦ, resulting in their
inability to support Th2 responses to a subsequent nematode infection; ii) characterize the
signaling pathways imprinting the non-permissive state of DC; iii) analyze the primary parasite
dose effect on DC/MΦ activity; iv) decipher the marked distinction in DC pathways utilized for
recognition in mice versus pigs as host species. Thus, this project will identify the role of
parasite nature and dose in developing adaptive responses in co-infections in natural hosts.
Previous own work:
The 1st generation doctoral researcher determined the influence of the Th1-inducing infection
with Toxoplasma gondii (Tg) on the development of Th2 responses and protection against the
intestinal nematode Heligmosomoides polygyrus (Hp). We detected a defect in helminthspecific
Th2 differentiation and Th2-associated innate anti-helminth responses in intestinal
tissues. The immune response to Tg was unaffected by the co-infection. Strikingly, protozoan
co-infection led to aberrant anti-helminth adaptive responses, evident as nematode-specific
CD4+ T cells acquiring an IFNγ producing Th1- instead of GATA3+/Th2 cytokine expressing
state in the co-infected host. Thus, our data show that a previous Tg infection limits Th2
immunity and directs residual anti-helminth responses to inappropriate Th1 reactions.
Hypotheses and work plan:
1) The mucosal DC/MΦ compartment is restructured by a preceding Tg infection, disabling
subsequent Th2 instruction by DC to an Hp infection.
2) The primary pathogen dose defines the extent of reactivity to subsequent infections.
3) Parasites adjust the signaling events in innate immune gatekeepers.
4) Innate recognition of Tg in pigs is distinct from that utilized by rodents
Mice and pigs are natural hosts for the parasites in focus. In the murine system, we will
investigate how long anti-nematode Th2 responses are impeded after preceding Tg infection.
The functionality and phenotypic composition of mucosal and systemic DC populations and
bone marrow progenitors will be assessed 2, 4 and 6 weeks after Tg infection. The DC
competence for antigen presentation and their cytokine profile will be monitored ex vivo/in vitro.
In parallel, we will focus on local monocyte/MΦ and myeloid suppressor cells as regulators of
DC/T cell interactions and Th2 immunity in the co-infected host. The antagonistic AMPK –
mTOR signaling pathway will be assessed in DC and MΦ as a primary candidate possibly
involved in the defective Th2 response. The dependency of local DC/MΦ modulation on the
pathogen-dose will be investigated after low and high dose Tg infection. Further, we will
investigate Tg and Ascaris suum infections in pigs to define if regulatory circuits are similar in
a model closely reflecting the human immune system.