Apolipoprotein E Plays a Key Role against Cryptosporidial Infection in Transgenic Undernourished Mice

Abstract

Apolipoliprotein E (apoE), a critical targeting protein in lipid homeostasis, has been found to have immunoinflammatory effects on murine models of infection and malnutrition. The effects of apoE in undernourished and Cryptosporidium parvum-infected mice have not been investigated. In order to study the role of apoE in a model of C. parvum infection, we used the following C57BL6J mouse genetic strains: APOE-deficient, wild-type controls, and APOE targeted replacement (TR) mice expressing human APOE genes (E3/3; E4/4). Experimental mice were orally infected with 107-unexcysted-C. parvum oocysts between post-natal days 34–35 followed by malnutrition induced with a low-protein diet. Mice were euthanized seven days after C. parvum-challenge to investigate ileal morphology, cytokines, and cationic arginine transporter (CAT-1), arginase 1, Toll-like receptor 9 (TLR9), and inducible nitric oxide synthase (iNOS) expression. In addition, we analyzed stool oocyst shedding by qRT-PCR and serum lipids. APOE4/4-TR mice had better weight gains after infection plus malnutrition compared with APOE3/3-TR and wild-type mice. APOE4/4-TR and APOE knockout mice had lower oocyst shedding, however the latter exhibited with villus blunting and higher ileal pro-inflammatory cytokines and iNOS transcripts. APOE4/4-TR mice had increased ileal CAT-1, arginase-1, and TLR9 transcripts relative to APOE knockout. Although with anti-parasitic effects, APOE deficiency exacerbates intestinal inflammatory responses and mucosal damage in undernourished and C. parvum-infected mice. In addition, the human APOE4 gene was found to be protective against the compounded insult of Cryptosporidium infection plus malnutrition, thus extending our previous findings of the protection against diarrhea in APOE4 children. Altogether our findings suggest that apoE plays a key role in the intestinal restitution and immunoinflammatory responses with Cryptosporidium infection and malnutrition.

Apolipoprotein E and Sex Bias in Cerebrovascular Aging of Men and Mice

“…For example ε 4 carrying children in a Brazilian slum had fewer episodes of diarrhea and better cognitive development[108]. Similarly, in ApoE transgenic mice, ε 4 increased resistance to intestinal cryptosporidial infections[109]. The role of infections in AD pathogenesis is increasingly discussed[107].…”

Neurodevelopment, Nutrition, and Inflammation: The Evolving Global Child Health Landscape

“…77 Table 2 provides some highlights of this seminal research. Taken together, these findings of a potential benefit of the ApoE4 allele in protecting the cognitive development of children (or enteropathy in mice) 78 with repeated diarrhea or enteropathy in early childhood (or specific infections in mice) could help explain a potential selective advantage for this ApoE4 allele despite its clear association with an increased risk for Alzheimer's disease in later life (an effect that has been termed "antagonistic pleiotropy, " or when a single gene controls more than a single trait, ≥1 of which has beneficial and ≥1 of which has detrimental effects on the fitness of the host). Thus, the evolutionary benefit of ApoE4 (perhaps like other genes, such as the sickle cell trait gene) may only persist in the presence of such health threats as diarrhea or enteropathy (or malaria).…”

“…Findings include: protected intestinal villus morphometry, improved growth trajectories, and reduced shedding of Cryptosporidium parasites in experimental infections with malnutrition. 78 The bridge with basic studies may lie in Colton and Czapiga's work 79,80 showing that: these mice exhibit increased expression of cationic amino acid transporter-1 that is responsible for arginine uptake…”

The Global Burden of Pediatric Cryptosporidium Infections

“…These models, which need further validation in human studies, demonstrate that specific nutrient deprivation has a profound impact on the character and intensity of inflammation [19,20], such as an apparent bias away from Th1-type primary immune responses (Bartelt, unpublished) similar to what has been shown in malnourished children in Haiti with cryptosporidiosis [21]. Also, the field observation that the APOE4/4 allelotype was protective against early childhood diarrhea and the cognitive impacts in malnourished children [22] was also shown to protect malnourished transgenic mice from weight loss and parasite burden following Cryptosporidium parvum challenge [23].…”