“How does a helminth parasite disrupt host innate immune signalling? A structural perspective”

Venue: Small Lecture Theatre, MSI

Hosts: Dr Mattie Pawlowic & Dr Henry McSorley

Bio 

I obtained my PhD in the lab of Dr. Amit Sharma at ICGEB, New Delhi, India, in structural biology and small molecule inhibitor discovery in human malaria. After PhD, I moved to Prof. Matt Higgins’ lab at the University of Oxford for my postdoc in structural parasitology. In the Higgins lab, I study host-parasite protein-protein interactions to understand the mechanisms underlying parasite resilience to the host. In particular, in collaboration with Dr Henry McSorley’s research team, I have studied how helminths modulate immunity. My long-term goal is to use mechanistic understanding of molecular host-parasite interactions to therapeutically impact parasitic diseases in humans and livestock.  

Abstract  

Helminths, such as H. polygyrus, aKect IL-33-dependent type 2 immunity by secreting two distinct, three-membered, CCP-domain protein families, HpARI and HpBARI. These proteins modulate IL-33 signalling by preventing IL-33 from binding to its receptor, ST2. Understanding how HpARI and HpBARI target IL-33:ST2 signalling is the central focus of this talk. I will reveal how HpARI and HpBARI function using structural biology (X-ray and cryo-EM) combined with biophysical and immunological methods. HpARI2 is monomeric and contains three CCP-domain-containing (CCP1-3), which contribute to IL-33 binding. Structure-guided in vivo studies confirm two key features of the HpARI2 function: i) a ‘large loop’ (CCP3) competitively blocks IL-33 access to ST2; ii) an electropositive CCP1 module that governs the half-life HpARI2 via heparan sulphate or DNA binding, prolonging immunosuppression. By contrast, the HpBARI are ST2-binding, trimeric molecules that directly blocks access of IL-33 and the signalling co-receptor to ST2. Ultimately, through these mechanisms HpARI and HpBARI proteins promote parasite survival and reduce host asthma.