The human gastric pathogen is a major causative agent of gastritis, peptic ulcer disease, and gastric cancer. As part of its adhesive lifestyle, the bacterium targets members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family by the conserved outer membrane adhesin HopQ. The HopQ-CEACAM1 interaction is associated with inflammatory responses and enables the intracellular delivery and phosphorylation of the CagA oncoprotein via a yet unknown mechanism. Here, we generated crystal structures of HopQ isotypes I and II bound to the N-terminal domain of human CEACAM1 (C1ND) and elucidated the structural basis of specificity toward human CEACAM receptors. Both HopQ alleles target the β-strands G, F, and C of C1ND, which form the dimerization interface in homo- and heterophilic CEACAM interactions. Using SAXS, we show that the HopQ ectodomain is sufficient to induce C1ND monomerization and thus providing a route to influence CEACAM-mediated cell adherence and signaling events.

Attachment to the host gastric mucosa is a key step in Helicobacter pylori infection. Recently, a novel adhesin, HopQ, was shown to bind distinct host CEACAM proteins—an interaction that was found to be essential for the translocation of CagA, a key virulence factor of H. pylori. The HopQ–CEACAM1 co-crystal structure revealed a binding mode dependent on loops in HopQ that are clasped by disulfide bonds. In this study, we investigated the importance of these cysteine residues for CEACAM1 engagement by H. pylori. We observed a loss of CEACAM1 binding and CagA translocation upon disruption of the disulfide bond in loop CL1 (connecting C103 to C132 in HopQ). Deletion of the Dsb-like oxidoreductase HP0231 did not affect cell surface expression of HopQ or alter the interaction of H. pylori with target cells. Although HP0231 deletion was previously described to impede CagA translocation, our results indicate that this occurs through a HopQ-independent mechanism. Together, our results open up new avenues to therapeutically target the HopQ–CEACAM1 interaction and reduce the burden of pathogenic H. pylori.

The gastric pathogen Helicobacter pylori infects half of the world’s population and is a major risk factor for gastric cancer development. In order to attach to human gastric epithelial cells and inject the oncoprotein CagA into host cells, H. pylori utilizes the outer membrane protein HopQ that binds to the cell surface protein CEACAM, which can be expressed on the gastric mucosa. Once bound, H. pylori activates a number of signaling pathways, including canonical and non-canonical NF-κB. We investigated whether HopQ–CEACAM interaction is involved in activating the non-canonical NF-κB signaling pathway. Different gastric cancer cells were infected with the H. pylori wild type, or HopQ mutant strains, and the activation of non-canonical NF-κB was related to CEACAM expression levels. The correlation between CEACAM levels and the activation of non-canonical NF-κB was confirmed in human gastric tissue samples. Taken together, our findings show that the HopQ–CEACAM interaction is important for activation of the non-canonical NF-κB pathway in gastric epithelial cells.

Alongside the wide distribution throughout sub Saharan Africa of schistosomiasis, the morbidity associated with this chronic parasitic disease in endemic regions is often coupled with infection-driven immunomodulatory processes which modify inflammatory responses. Early life parasite exposure is theorized to drive immune tolerance towards cognate infection as well as bystander immune responses, beginning with in utero exposure to maternal infection. Considering that 40 million women of childbearing-age are at risk of infection worldwide, treatment with Praziquantel during pregnancy as currently recommended by WHO could have significant impact on disease outcomes in these populations. Here, we describe the effects of anthelminthic treatment on parasite-induced changes to fetomaternal cross talk in a murine model of maternal schistosomiasis. Praziquantel administration immediately prior to mating lead to clear re-awakening of maternal anti-parasite immune responses, with persistent maternal immune activation that included enhanced anti-schistosome cytokine responses. Clearance of parasites also improved capacity of dams to endure the additional pressure of pregnancy during infection. Maternal treatment also drove lasting functional alterations to immune system development of exposed offspring. Prenatal anthelminthic treatment skewed offspring immune responses towards parasite clearance and reduced morbidity during cognate infection. Maternal treatment also restored offspring protective IgE antibody responses directed against schistosome antigens, which were otherwise suppressed following exposure to untreated maternal infection. This was further associated with enhanced anti-schistosome cytokine responses from treatment-exposed offspring during infection. In the absence of cognate infection, exposed offspring further demonstrated imprinting across cellular populations. We provide further evidence that maternal treatment can restore a more normalized immune profile to such offspring exposed in utero to parasite infection, particularly in B cell populations, which may underlie improved responsiveness to cognate infection, and support the WHO recommendation of anthelminthic treatment during pregnancy.