Sexual reproduction may have never become possible if organisms hadn’t evolved a way to restrain the immune system during fertilization, according to a new study from the lab of Sagi Shapira, PhD, assistant professor of systems biology.

The study, published today in Immunity, took an in-depth look at how vertebrate eggs are fertilized.

To fight invading pathogens, all organisms (including vertebrate cells) are programmed to detect and attack any DNA and foreign RNA found outside of the nucleus in the cell’s cytoplasm. It’s usually a safe bet that any DNA found in the cytoplasm is from a foreign microbe, because the cell’s own DNA is safely sequestered in the nucleus. But during fertilization, DNA and RNA from sperm may be briefly exposed to the cytoplasm of an egg—and to the danger of being recognized and attacked.

For fertilization to succeed, Dr. Shapira reasoned that something must prevent the immune system from attacking DNA during fertilization and searched for candidates in the genome.

The search revealed a gene called NLRP14, which encodes a protein that Dr. Shapira’s laboratory demonstrated to play a role in the innate immune system. Without NLRP14, the immune system induces a strong inflammatory response to DNA and RNA found in the cytoplasm, and the fertilization process comes to a halt.

The finding could lead to new ways to treat infertility or develop novel contraceptives.
NLRP14 and related genes are found in many other organisms, Dr. Shapira says, “and safeguarding the genetic material is hardwired into every organism. So, evolving machinery to inhibit that process in gametes may have been a prerequisite for the evolution of sexual reproduction.”

The finding could lead to new ways to treat infertility (about 2 percent of people carry a NLRP14 mutation) or, conversely, to develop novel contraceptives.

In addition, since NLRP14 suppresses a critical arm of the immune system, it may serve as a viable therapeutic target for tuning immune responses in various disease states (i.e., to dampen in the case of autoimmune diseases like IBD, asthma, and lupus, and enhance in the case of cancer).