ABOVE: Artist’s rendition of Neisseria gonorrhoeae, the bacteria that causes gonorrhea © ISTOCK.COM, DESIGN CELLS

In recent years, scientists have identified various naturally occurring mutations in the human genome that ward off Alzheimer’s disease. Now, in a study published July 9 in Molecular Biology and Evolution, researchers explain how one such gene variant initially emerged to protect against a different type of threat: gonorrhea.

According to the paper, a mutant form of an immune receptor, found in roughly one fifth of people, helps the immune system detect Neisseria gonorrhoeae, the bacteria responsible for the sexually transmitted disease. Typically, white blood cells particularly monocytes and macrophages, use a receptor called CD33, to distinguish between host cells and unwelcome pathogens invading the body. When CD33 binds to sialic acids—sugars that tend to adorn the membranes of host cells, acting as a molecular ID— immune cells recognize those cells and prevent the immune system from launching an attack. 

But “bacteria are expressing sialic acid as a way to fool the human immune system,” Ajit Varki, a molecular biologist at the University of California, San Diego, who coauthored the study, tells The Scientist. To roam the body undetected, N. gonorrhoeae cover themselves in sialic acid molecules. When immune cells bind to the sugar coating, they misidentify the pathogen as a host cell, allowing it to go scot-free. 

Our cells synthesize two forms of CD33: a full-length version and a mutated, inactive form that lacks the sugar-binding site. Those with a particular point mutation—different by a single changed nucleotide—produce a higher proportion of the mutant CD33, reducing the immune system’s ability to recognize sialic acids. As a result, mutated immune cells are able to see through gonorrhea’s disguise and initiate an attack. That same mutation, the researchers found, leads to a similar mechanism in the brain that protects neural tissue against Alzheimer’s.

Just as the altered receptor helps the immune system target N. gonorrhoeae elsewhere in the body, it also helps the brain clear away damaged cells and amyloid plaques associated with Alzheimer’s disease. Microglia—immune cells that patrol the brain—ignore the toxic amyloid build-ups when they interact with sialic acids. But this interaction is lost in individuals with the CD33 variant, allowing microglia to clear away amyloid aggregates.

See “Meningitis Vaccine May Protect Against Gonorrhea

CD33 levels determine “whether microglial cells are going to be Dr. Jekyll or Mr. Hyde,” says Rudolph E. Tanzi, a neurologist at Harvard University who wasn’t involved in the research. “Are they going to be clearing amyloid while you sleep or are they going to stop doing so and worse, induce inflammation which will result in cell death and Alzheimer’s disease?”

To determine how effectively gonorrhea bacteria bind to CD33 variants, Varki’s team mixed fluorescently labeled N. gonorrhoeae with 15 versions of the receptor, which harbored various mutations acquired since humans diverged from chimpanzees. The mutant receptors were fixed to a multi-well plate and the strength of the pathogen-receptor interaction was determined by measuring the fluorescent signal emitted by each well. While the bacteria happily interacted with normal CD33, and many of the other mutants, they were incapable of binding to the neuroprotective receptor. Another group of pathogens, Group B Streptococcus, which cause meningitis and pneumonia, bound only weakly to the mutated receptor, suggesting that other pathogens rely on similar sialic acid-based strategies of immune evasion. Considering how CD33 influences the brain’s immune cells, “it’s not surprising that CD33 evolved in the way the paper shows,” Tanzi says. 

CD33 levels determine “whether microglial cells are going to be Dr. Jekyll or Mr. Hyde.”

—Ajit Varki, Harvard University

Although scientists already knew about the role of CD33 in Alzheimer’s and the concept of pathogenic immune evasion, the paper is the first to link the two concepts. It reveals how the immune system’s adaptations to fight infection provided the potential to safeguard cognition, says Ronald Schnaar, a pharmacologist and neuroscientist at Johns Hopkins University School of Medicine who was not involved in the work. “It’s a feasible model,” he adds.

The researchers then attempted to trace the evolution of the protective allele and pinpoint when the mutant form emerged by comparing the CD33 protein sequence from Homo sapiens, with that of the ancient hominins Neanderthals and Denisovans. They compared eight ancient genomes from publicly available DNA databases derived from fossilized bone fragments with 1,000 modern human genomes. Unlike humans living today, all of the Neanderthal and Denisovan genomes possessed the gene encoding CD33 with its binding site intact, suggesting that the mutation arose after we diverged from our ancestral cousins.

The study authors speculate that evolution may have acted on the mutated receptor twice: first to reduce infection, and then again to protect against Alzheimer’s disease. “Selection after you finish reproduction goes against the standard dogma of evolutionary biology,” Varki says. And yet, scientists have over the years discovered numerous genetic variants associated with healthy aging that don’t seem to confer reproductive benefits more closely associated with natural selection. Variations in the AGT gene, for example, reduce the risk of high blood pressure, while the protective version of PON1 protects against atherosclerosis.

Genes that are advantageous in the elderly are often used as evidence for the grandmother hypothesis, which is the evolutionary theory that women live longer to assist in child rearing, improving the odds that their grandkids survive early childhood. It is often used to explain why, unlike most species, the lifespan of human females extends well beyond their reproductive years.  CD33 and other protective variants that stave off neurodegeneration or other health conditions linked to aging may have enabled grandmothers to have a bigger impact on group survival, Varki says. And for that, it appears we have gonorrhea to thank.