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Mammal Immune Proteins Are “Blind” to Deep-Sea Microbes

Phoenix Islands Protected Area
The microbes used in the study came from the waters surrounding the Phoenix Islands Protected Area (PIPA) in Kirabati. | Schmidt Ocean Institute

Fishing out microbes from a relatively unexplored zone in the central
Pacific, scientists have identified several new species of bacteria that
seem to violate one of the fundamental tenets of immunology. Their
findings, appearing in the March 12 issue of Science Immunology, suggest
that humans and other mammals cannot recognize any foreign bacteria they
encounter, as was previously thought.

"No one had ever really tested the universality of the rules of immunity;
we just assume that the way that humans and mice interact with microbes we
encounter every day would apply to all host-microbe interactions," said
Jonathan Kagan, professor of pediatrics at Harvard Medical School and
Boston Children's Hospital and co-author of this study.

By revealing potential limits to this microbe-detecting capability, these
findings shake the grounds of a concept called pattern recognition that was
thought to be near universal, applying to bacteria encountered both within
and outside the immediate environment.

"This was surprising because global recognition is a widespread assumption,
but now, local pattern recognition makes sense," said co-author Randi
Rotjan, a research assistant professor at Boston University and co-chief
scientist of the Phoenix Islands Protected Area (PIPA), where this study
was conducted. "There is no selective pressure for mammals to detect
bacteria that inhabit an ecosystem different from their own — such as the
deep sea."

Their work also demonstrates the value of ocean conservation areas as
unique havens providing new windows into basic biology that can inform the
development of biological tools and therapeutics, while also contributing
important justification for increasing ocean protection, noted Rotjan.

"PIPA's existence and prominence is what has driven cutting-edge research
to this particular patch of ocean," added Kagan.

Deep Sea Differences

Their study began with a 2017 expedition onboard the Schmidt Ocean
Institute research vessel Falkor to the PIPA site located in the
central Pacific island nation of Kiribati. The sheltered nature of the
area, replete with microbes never before encountered by mammals, opened an
opportunity to test the limits of the pattern recognition concept.

Pattern recognition of microbes is carried out by sensory proteins called
pattern recognition receptors (PRRs), which are expressed by a variety of
innate immune cells in mammals. The proteins detect molecules typically
released when a pathogen invades the body, such as those associated with
cell damage. Because PRRs are essential for protection against pathogens,
it's critical that these proteins can recognize a variety of microbes in
the environment.

research crew near Kiribati
Scientists onboard the Falkor. | Schmidt Ocean Institute

Armed with an interdisciplinary team and unprecedented access to an
underexplored location, scientists could tackle the question of whether
PRRs could indeed recognize a wide variety of microbes, even those residing
in a marine environment devoid of mammalian contact.

"To deep sea bacteria, humans are Martians. What would happen when
organisms from these distinct ecosystems interact?" asked Kagan.

The researchers targeted four PIPA sites, ranging in depth from 200 to
3,000 meters, and sampled seawater, sediment, coral tissue, sponge tissue,
and the gut contents of sea stars for microbes. They then cultured their
samples in the lab.

Most of the microbe species they examined were of a type called
gram-negative bacteria, which contain a molecule called cell wall
lipopolysaccharide (LPS) that is known to stimulate pattern recognition

But unlike nearly all known gram-negative bacteria, 80% of these deep-sea
microbes were immune-silent, with LPS structures undetectable by mouse and
human cells in culture. The remaining 20% could be detected by mammalian
LPS receptors.

"If we only detected one out of five microbes we encountered on land, there
would be a high possibility of infection," Rotjan said. "The further away from
our terrestrial habitat we explore, the less effective the LPS detections
systems seem to be at providing comprehensive immune surveillance."

Revising the Rules of Engagement

Based on their findings, the authors suggest that the pattern recognition
rule of immune engagement is not global, but rather defined by the local
environment. Future work will help determine whether this holds true in
other uncharted habitats and for different families of PRR.

"Now that we have these new LPS tools, we can use them to understand more
about mammalian immune systems: probe the origins of immune response,
identify nuances in signaling pathways of microbial recognition, and
increase the potential for immunotherapeutics," said Anna Gauthier, a Ph.D.
candidate in virology at the Harvard Division of Medical Sciences and first
author of this study.

Gautier further noted that their work could not have existed without a
collaborative effort with the government of Kiribati, "showcasing the
importance and beauty of international partnerships."

In June 2021, the scientists will head back to PIPA, this time working in
both Kiribati and U.S. waters.

[Credit for associated image: Schmidt Ocean Institute]