Immunological Insights from an Unlikely Source: What we learned from emptying the guts of carnivorous starfish

What does it take to test the limits of the mammalian immune system? Twenty days in the deep Pacific Ocean and the contents of starfish guts make for a good starting point. In order to protect against infection, an organism’s body needs to be able to detect the presence of foreign microorganisms and attack them before irreparable damage is caused. Researchers have found that while mammalian immune systems are programmed to quickly recognize invaders from their local habitat, they’re actually pretty bad at detecting bacteria from places on the globe that aren’t a part of their natural ecosystem. 

Mammals, like all multicellular organisms, have a set of receptor proteins on the surface of most of their cells called pattern recognition receptors (PRRs). These receptors allow cells to become aware of potentially harmful bacteria within their environment and initiate an immune response when they come into contact with molecules known as PAMPs, or pathogen-associated molecular patterns. Common PAMPs, such as sugar chains or lipoproteins, are expressed on the cell wall of most bacteria, and many of these molecules are conserved and share structural similarities, allowing PRRs to respond to and generate an immune response against a myriad of bacteria. 

Near-universal pattern recognition is a foundational concept of modern immunology. Basically, cells should be able to use PRRs to recognize when they’re interacting with a harmful microorganism, whether or not they’ve encountered it before. But what about bacteria that occupy different ecological niches? Can they be as easily identified? This question led a team of scientists to ask: does pattern recognition have limits

Voyage to the Deep

Scientists wanted to test whether mammalian cells could identify bacteria that reside far outside their natural ecosystem. To collect samples for their experiment, they spent 20 days aboard a research vessel, scouring the waters of Kiribati’s Phoenix Islands Protected Area, UNESCO’s largest and deepest World Heritage Site. Located in the remote Pacific Ocean, the protected waters surrounding the Kiribati Phoenix Islands are home to a distinct ecosystem that’s inhospitable to land-dwelling life. This region of the deep sea is devoid of any light, and underwater pressure there can reach up to 20 times the atmospheric pressure at sea level. 

It was from this extreme environment that the researchers collected samples of 117 different bacterial colonies, extracting them from the seawater itself, sediment, coral tissue, and from the guts of coral-eating sea stars (corals are commonly mischaracterized as plants, but are actually animals, hence the carnivorous starfish). They made sure to sample from water that was between 200 to 3,000 meters deep – far enough that no land-dwelling or marine mammal would ever normally go there. 

Among these samples, Moritella, a bacteria that expresses cell wall structures expected to stimulate the immune system in mammals, stood out as an ideal candidate for their experiment. It was exclusively found in deeper waters, making it unlikely that mammals would have had natural opportunities to interact with it, and had several different strains (types) that the scientists could include in their “experimental toolbox.” 

Deep sea Moritella vs the Immune Machine

The researchers tested several of their Moritella colonies against mouse and human monocytes (a type of white blood cell) to see whether these cells would recognize the bacteria as foreign. They also exposed the cells to E. coli, a common pathogenic bacteria that generates a robust immune response, as a useful control to determine whether the monocytes were successfully recognizing any of the Moritella strains as invaders. After exposing the monocytes to live bacteria for 20 minutes, the scientists measured the loss of PRRs from the cells’ surface, which served as an indication that the monocytes had successfully interacted with the bacteria. The researchers also tested a model of Moritella infection in mice and looked for the initiation of immune responses there as well. 

Interestingly, mouse and human monocytes were unable to detect 80% of the deep-sea bacteria that were tested. Similarly, mice that were exposed to Moritella only mounted an immune response to some, but not all, strains used. Mice that were injected with Moritella strains #5 and #24 exhibited a strong inflammatory response, evidenced by a rapid accumulation of cytokines (small, secreted proteins that contribute to inflammation) in the blood, while no cytokines were detected in the blood of mice that were injected with Moritella strains #28 and #36 (Figure 1).

Figure 1: Toll-like receptors (TLRs), a type of pattern recognition receptor expressed on the surface of most mammalian cells, can interact with PAMPs within their environment to initiate an immune response. PAMPs from Moritella strains #5 and #24 were recognized by TLRs and therefore induced an inflammatory response in mice in vivo, whereas PAMPs from Moritella strains #28 and #36 were “immuno-silent” and failed to elicit an inflammatory response.

These results suggest that pattern recognition strategies aren’t global, but instead have evolved to primarily identify pathogens that are normally found in the ecosystem in which an organism lives. Basically, our immune systems are GPS-locked – mostly. The 20% that were detected offer support for the theory of innate pattern recognition immunity, which says that cells can detect harmful bacteria even if they haven’t previously encountered them. 

But why is this important? In an age of increasing globalization and the exploitation of deep-sea resources, humans are venturing into ecosystems that we have never had cause to explore before. It’s possible that in our quest to know the planet more and take what it has to offer, we may end up encountering bacteria that are accidentally “immune-evasive,” which can have consequences well worth considering. 

This discovery represents an important step toward understanding the limits of mammalian immune systems. Not only that, it’s likely that deep-sea invertebrates have evolved pattern recognition receptors that can specifically detect bacteria that inhabit that region, but because most immune research to date has focused on mammals, this finding opens up a whole new realm for scientists to explore. Following this line of research could help us to understand and appreciate the diversity of ecosystems on our planet – and perhaps teach us new ways to preserve and protect them.

Journal Article: Gauthier AE, Chandler CE, Poli V, et al. Deep-sea microbes as tools to refine the rules of innate immune pattern recognition. Sci Immunol. 2021;6(57):eabe0531. doi:10.1126/sciimmunol.abe0531

Cover image courtesy of 1643606 from Pixabay

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