Basophils Protect against Reinfection with Hookworms Independently of Mast Cells and Memory Th2 Cells

Abstract

Hookworms infect several hundred million people worldwide, causing malnutrition, anemia, and growth retardation. Infections generally result in a strong type 2 immune response, but the effector mechanisms that mediate worm expulsion remain poorly characterized. In this study, we determined the role of mast cells and basophils in protective immunity against the murine hookworm, Nippostrongylus Brasiliensis, during primary and secondary infection. Mast cell–deficient c-KitW-sh mice had lower serum IgE levels compared with wild-type mice under steady-state conditions and after N. brasiliensis infection. Worm expulsion was delayed during primary but not during secondary infection of c-KitW-sh mice, even in the absence of CD4 T cells. However, protective immunity was lost when basophils were depleted before reinfection of c-KitW-sh mice. We conclude that basophils play a crucial role for worm expulsion during a memory type 2 immune response independently of mast cells and memory Th2 cells.

IL-33 drives biphasic IL-13 production for noncanonical Type 2 immunity against hookworms

“…The source of IL-4 within IL-33KO mice was CD4 + T cells but also could include mast cells and basophils. Indeed, basophils are a major source of IL-4 during secondary immune responses, and were shown to promote secondary immunity against N. brasiliensis (26,(45)(46)(47). Thus, while multiple redundant mechanisms are functioning during secondary challenge infection, our data support a hypothesis that eosinophils serve a predominant role in worm destruction during anamnestic immunity against GI nematodes (48,49).…”

“…Considerable debate has centered upon the site of worm killing and the types of granulocytes required for immunity against rechallenge (26,27,39). Our data showed no differences in worm burdens between WT and IL-33KO mice at d 3 postsecondary challenge.…”

“…Between 6-12 d postinfection, IL-4-and IL-13-dependent effects cause intestinal epithelial cells (IECs) to expel adult worms from the intestinal lumen through mechanisms that require resistin-like molecule beta (RELMβ), a goblet cell-specific protein that interferes with worm nutrition (23,24). If previously infected animals are rechallenged, STAT-6-dependent processes drive rapid expulsion of worms, potentially via IL-4 and CD4 + T cells, but there is lack of consensus on the exact mechanism (25)(26)(27)(28). Given that human hookworm infections are characterized by poor memory responses and high rates of reinfection (29), it is possible that better understanding of host protection in rodents will lead to novel approaches for reducing the burden of human disease.…”

Basophil-mediated protection against gastrointestinal helminths requires IgE-induced cytokine secretion

“…IL-4, IL-5, and IL-13 were measured by standard ELISA. Serum IgE concentrations were determined as described (42). Serum IgG1 was determined using the SBA clonotyping system (Southern Biotech).…”

“…By using depleting antibodies and constitutively basophildeficient Mcpt8Cre mice, we have shown previously that basophils contribute to protective immunity against Nb independently of mast cells and memory Th2 cells (13,42). Further, it was shown that basophils increase faster after secondary infection than after primary Nb infection, independently of IL-4 (43).…”