Mechanisms and evolution of inborn genetic errors affecting enteric virus infections

The genetic make-up of an individual contributes to the susceptibility and response to viral infections.

Studies have indicated that as many as one in every 500 Caucasian has selective IgA deficiency, yet with modest clinical effects from mucosal rotavirus infections.

Our hypothesis is that rotavirus IgG antibodies present in circulation is transported through the mucosal epithelium with the neonatal Fc receptor and inactivate virus on the apical domain of the intestine or intracellularly and thus provide complementary protective mechanism for IgA.

To address these experiments, we will use human stem cell derived enteroids that mimic the small intestine and monitor human IgG transcytosis over the polarized epithelium to demonstrate virus neutralization.A remarkable example of inborn genetic errors is the Mendelian trait resistance to certain rotavirus and most common noroviruses among individuals with a nonsense mutation in FUT2 (G428A) on chromosome 19.

This homozygous nonsense mutation reaches 20% of Caucasians.

The extensive polymorphism and race specificity of the G428A nonsense mutation make it a most interesting target for studies of human evolution.

This novel project will be done by examining DNA from Neanderthals and homosapiens with the objective to illuminate the evolutionary history of the FUT2 mutation.

It is anticipated that those data will shed light on how human have coevolved with microbes such as norovirus and rotavirus.