Abstract
Over 25% of the world's population are infected with helminth parasites, the majority of which colonise the gastrointestinal tract. However, no vaccine is yet available for human use, and mechanisms of protective immunity remain unclear. In the mouse model of Heligmosomoides polygyrus infection, vaccination with excretory-secretory (HES) antigens from adult parasites elicits sterilising immunity. Notably, three purified HES antigens (VAL-1, -2 and -3) are sufficient for effective vaccination. Protection is fully dependent upon specific IgG1 antibodies, but passive transfer confers only partial immunity to infection, indicating that cellular components are also required. Moreover, immune mice show greater cellular infiltration associated with trapping of larvae in the gut wall prior to their maturation. Intra-vital imaging of infected intestinal tissue revealed a four-fold increase in extravasation by LysM+GFP+ myeloid cells in vaccinated mice, and the massing of these cells around immature larvae. Mice deficient in FcRγ chain or C3 complement component remain fully immune, suggesting that in the presence of antibodies that directly neutralise parasite molecules, the myeloid compartment may attack larvae more quickly and effectively. Immunity to challenge infection was compromised in IL-4Rα- and IL-25-deficient mice, despite levels of specific antibody comparable to immune wild-type controls, while deficiencies in basophils, eosinophils or mast cells or CCR2-dependent inflammatory monocytes did not diminish immunity. Finally, we identify a suite of previously uncharacterised heat-labile vaccine antigens with homologs in human and veterinary parasites that together promote full immunity. Taken together, these data indicate that vaccine-induced immunity to intestinal helminths involves IgG1 antibodies directed against secreted proteins acting in concert with IL-25-dependent Type 2 myeloid effector populations.
Highlights
The immune system has evolved suites of defense mechanisms to protect against infectious pathogens of all types ranging from viral and bacterial micro-organisms to more complex eukaryotic fungi, protozoa and helminths
We show here that immunity requires specific IgG1 antibodies directed to the secreted products, acting together with innate myeloid cells that require activation through the canonical Type 2 cytokine receptor, IL-4Rα, as well as through a pathway not previously known to be involved in effector mechanisms, IL-25
These myeloid cells act to trap and envelop helminth larvae while in the submucosal tissues of the small intestine, massing in large numbers and preventing their maturation and exit into the gut lumen
Summary
The immune system has evolved suites of defense mechanisms to protect against infectious pathogens of all types ranging from viral and bacterial micro-organisms to more complex eukaryotic fungi, protozoa and helminths. In contrast to our detailed knowledge of anti-microbial immune mechanisms, we have yet to develop a clear picture of how immunity acts to eliminate parasites such as gastrointestinal helminths which even today infect over 1 billion people across the world [1]. Under natural conditions, near-ubiquitous and the mammalian immune system will have evolved specific mechanisms of activation and regulation to optimally respond to their challenge. It is likely that studying pathways of immunity to helminths will uncover new facets and properties of the immune system not apparent under conditions of infection with micro-organisms, and not necessarily predictable from our current knowledge of Type 2 activation in anti-helminth immunity [5,6]
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