Recently, a growing number of genes with infectious disease promoting alleles have been discovered by forward genetics studies in the mouse, including Mx, Nramp1, Ly49h and Tlr4. Apart from providing vitally important insight into basic immune mechanisms, these new studies offer candidates for human infectious diseases in which orthologous genes of afflicted individuals contain disease predisposing mutations. Th2-bias, the genetic predisposition of certain inbred mouse strains toward developing immune responses of T helper type 2 (Th2) as opposed to type 1 (Th1), has long been associated with differential susceptibility across a wide range of diseases. What has remained poorly understood however is its molecular genetic basis and thus causal relationship to specific disease states. We initiated an investigation into the nature of this relationship by mapping a Th2-bias-regulatory quantitative trait locus (Dice) to distal chromosome 16. Subsequent interval- specific congenic fine-mapping and gene expression analysis led to the physical isolation of the Dice1.2 locus and identification of Mina, a Dice1.2-resident gene with Th2-bias regulatory activity. Th2-bias phenotype across a representative panel of inbred mouse strains correlated inversely with a Mina expression level trait whose two states (high or low) concorded perfectly with two distinct haplotypes defined by 21 SNPs spanning the Mina promoter, exon 1 and intron 1. Although these data suggested that a naturally occurring regulatory polymorphism controlling Mina expression level conferred dose-dependent negative regulation of Th2-bias, Mina's physiological roles remain unexplored. Our published and preliminary studies lead us to the central hypothesis of this proposal that genetic variation in JmjC immunoregulatory proteins is a major determinant of heritable variation in host defense against microbes. Based on this central hypothesis we propose to explore 2 Aims from the perspective of how natural variation at the Mina locus affects the host response to a globally important human pathogen class: helminthic parasites. For our studies we selected the gastrointestinal whipworm Trichuris muris (Tm, a close relative of the human pathogen Trichuris trichiura) because chronic and acute infection outcomes in this model correlate with Th2-bias, respectively requiring Th1 and Th2 host responses.
Aim 1. Determine Mina's role in the host response to Tm. Use germline and conditional Mina KO mice to test the hypothesis that Mina acts directly in IECs to activate Relm? secretion which in turn promotes development of an anti-protective Th1 response.
Aim 2. Determine the relationship between genetic variation at the Mina locus and the host response to Tm. Using SMAD3 KO and (BALB/c x C57BL/6)F1 mice, we will test the hypothesis that TGF? (induced by Tm infection) promotes Mina expression in IECs through a SMAD3-dependent pathway regulated by allelic variation at SNP17 in the intronic Mina enhancer. If validated, we will then explore whether BALB/c and C57BL/6 alleles of Mina SNP17 also differentially control levels of Relm?, Th1 response and Tm expulsion.
The lining of the intestines is the interface separating the inside of our bodies and the external environment. Remarkably, it is only 1 microscopic cell layer thick but covers a surface area the size of a tennis court. In coordination with multiple cel types of the immune system this tenuous cell layer must distinguish harmful from beneficial microbes, then transmit and process this information along inter- and intra-cellular channels so that appropriate physiological responses rather than disease states ensue. The research in this proposal aims to provide a molecular level understanding of this process, thereby providing new targets for the development of diagnostics and therapeutics for easing the burden of infectious diseases affecting the lives of millions of people.
| Pillai, Meenu R; Lian, Shangli; Bix, Mark (2014) Mina: a Th2 response regulator meets TGF?. Curr Opin Immunol 31:38-43 |
