In a tiny squid, bacterial toxin governs organ development

In a tiny Pacific Ocean squid, a toxic molecule that causes whooping cough and gonorrhea in humans has been found to be a critical catalyst for organ development.

The toxin, produced by different types of bacteria in different hosts, is known as tracheal cytotoxin. And the astonishing discovery that it can be either good or bad – depending on its biological context – promises to rattle long-held perceptions of microbes and their role as pathogens.

The new work, funded by the National Institutes of Health, was reported this week (Nov. 12) in the journal Science.

That the same toxic molecule produced by different bacteria in different host animals plays such disparate roles – disease and massive tissue damage on the one hand, and critical organ development on the other – may force biologists to rethink the relationship between the world’s many microorganisms and their host plants and animals, according to Margaret McFall-Ngai, a UW–Madison professor of medical microbiology and the corresponding author of the Science paper.

“It is all context dependent,” says McFall-Ngai. “It has to be that we have mechanisms to use these molecules in different ways. Until now, molecules of a virulent nature have not been recognized as having essential roles in development.”

In the diminutive Hawaiian bobtail squid, the toxin was found to spur the development of a structure, a light-producing organ that acts as a sort of “Klingon cloaking device,” mimicking starlight to confuse hungry predators lurking in the depths. In humans, the same toxic molecule, produced by different species of bacteria, causes massive tissue damage in the lungs in the case of whooping cough, and in the fallopian tubes in the case of gonorrhea.

When the squid are born, they are about half the size of a grain of rice, and they must acquire the toxin-producing bacteria from their ocean environment. Specialized features on the surface of the squid’s nascent light organ facilitate colonization by the bacteria, which, in turn, promote the development of the functioning light organ.

“If you deprive the animal of those microbes, the system doesn’t develop,” McFall-Ngai says.

This critical symbiotic relationship, the Wisconsin scientist points out, almost certainly arose within the grand scheme of evolution where “all animals arose in the microbial soup of the ocean. In that context,” she notes, “animals could develop a set of body plans that repel bacteria or associate with them.”

In people, it is estimated that there are no fewer than 2,300 different kinds of bacteria that live in either beneficial or benign harmony with their human hosts. Many of those live in the gut and help with critical processes, such as digestion and the provision of certain vitamins. Also, the bacterial partners that normally occur with the healthy human are critical for the development of the immune system. There is evidence, for example, that their influence is responsible for suppressing autoimmune disease and allergies.

In contrast, there are probably no more than 100 species of bacteria that cause serious illness in humans.

The implications that humans are awash in benign and beneficial microbes raises new concerns about the overuse of antibiotics, and suggests that medical science – with its emphasis on studies of pathogenic bacteria – is overlooking a vast biological domain that may have an important influence on human health and well-being.

“We’re walking ecosystems. We’ve known that,” says McFall-Ngai. “What’s new is how many there are and how much we rely on them.”

According to McFall-Ngai, it may be that the molecular crosstalk between bacteria and their host organisms determines whether or not the relationship is beneficial, neutral or harmful. Communication between the host and the bacteria that depend on the host, apparently, can be either “civil conversation or a shouting match,” depending on the biological context that has developed as the two organisms evolved together.

“We don’t understand if beneficial associations or pathogenic associations result from the same language,” McFall-Ngai notes. “The surprise of this study is that the molecules used to signal development of the organ in the squid are the same that signal for pathogenesis in the case of whooping cough or gonorrhea.”

McFall-Ngai argues that the new finding should be cause for yet more caution in the administration of antibiotics. The ability of pathogenic microbes to acquire resistance to commonly used antibiotics has been the primary concern. But because the agents kill microbes indiscriminately, microorganisms that play important roles within their human hosts also are at risk.

From a scientific perspective, the new findings may encourage researchers to begin to pay more attention to the many microbes that live in association with humans. The advent of new genetic sequencing technology is permitting biologists to begin to identify the many varieties of bacteria that live in association with humans and other animals.

In addition to McFall-Ngai, authors of the Science paper include Tanya A. Koropatnick of the University of Hawaii, Jacquelyn T. Engle and William E. Goldman of the Washington University School of Medicine, Michael A. Apicella of the University of Iowa and Eric V. Stabb of the University of Georgia.