Contributed by guest blogger: Jared Saunders ’13

Every winter, the general public frantically agonizes over influenza prevention and protection. But is the purchase of hand sanitizer in bulk and tissue boxes by the dozen really necessary? After all, many people don’t even get sick during the winter months, and some just feel a little down for a couple of days. Why do some people catch “the flu” and end up in the hospital, fighting lung infections and plowing through boxes of tissues, while others just end up with a cough or runny nose? The answer may be come down to three letters. DNA.

Recent research by Everitt et al. at the Wellcome Trust Sanger Institute (WTSI) has revealed that a single gene found in humans can determine your fate when infected with a variety of the most common strains of the influenza virus. The gene encodes the important protein referred to as IFITM3, a member of the interferon-inducible transmembrane protein family. These IFITM proteins have been shown to potently restrict the replication of a variety of pathogenic viruses, and IFITM3 has been shown to greatly alter the course of influenza infection in both mice and humans.

Brass et al. previously identified IFITM3 through a functional genetic screen that indicated it mediated resistance to influenza A, dengue virus, and West Nile virus infection in vitro. This supported the hypothesis  of the WTSI group (more than 30 authors!), that IFITM proteins are critical for intrinsic resistance to these viruses, and allowed them to proceed with determining the effects of IFITM3 in vivo using mice. IFITM3 knockout mice showed severe signs of clinical illness, including massive body weight loss, rapid breathing, and piloerection (also known as “goosebumps”) when infected with low-pathogenecity strains of influenza that do not usually cause such intense symptoms. Their presentation of infection was more consistent with high-virulence strains of influenza. Contrary to the knockout mice, the wild-type mice shed significantly less of their body weight before fully recovering.

With this significant data now being collected, the group moved on to testing their hypothesis that individuals who are homozygous dominant for the IFITM3 gene develop less virulent influenza infections. They sequenced the IFITM3 gene from 53 people who were hospitalized by the H1N1 or seasonal influenza infection during 2009 to 2010 to determine if they carried the wild-type gene or one with some polymorphism. Genetic analysis of a subset of these individuals showed no evidence of hidden population structure differences with respect to a 1000 genome control group from WTSI. In the hospitalized patients, the group found significant over-representation of a specific single nucleotide polymorphism (or SNP), referred to as SNP rs12252, that has a recessive C allele substituted for a normal dominant T allele. This leads to an ineffective IFITM3 variant lacking the first 21 amino acids of the protein. This recessive C variant leads to lower IFITM3 expression in the host and consequent increased susceptibility of the host to influenza infection, and is correlated with lower levels of IFITM3 protein expression.

The group’s work has shown conclusively that IFITM3 expression can act as a barrier to influenza A virus infection both in vitro and in vivo, and that in vivo it can lower the mortality and morbidity associated with infection by a variety of human influenza viruses. Discovery of this innate resistance factor in humans may explain why encounters with a novel strain that may cause severe infections in others that do not affect you or your family.

But can the IFITM3 gene be used to help develop treatments or vaccines for future influenza strain outbreaks? Is it possible to recover this gene, if an individual has an ineffective variant, through gene therapy so as to make someone more resistant to influenza? With more research being done on the genetic aspects of disease infection, many more questions will arise, and many more answers will as well!

Links:

http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10921.html

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824905/

Jared Saunders is a junior at Vassar College, majoring in biochemistry.