The sophisticated (and surprising) immune system of mussels

2024-10-03 17:07:05

Mussels and other bivalves possess the largest and most diverse number of pathogen-detecting sensors in the entire animal kingdom. They act as real natural “alarms” against possible infections.

It’s about Toll receptors (TLR, acronym in English for toll-like receptors), essential components of the innate immune system of almost all animals.

The French-Luxembourg biologist Jules Hoffmann at the press conference for the awarding of the 2011 Nobel Prizes.
Holger Motzkau/Wikimedia Commons, CC BY

The name comes from German tollmeaning incredible or fantastic. It was coined by the biologist Christiane Nüsslein-Volhard in the 1980s when he discovered a key gene in the embryonic development of the fly Drosophila melanogaster. After, Jules Hoffmann they found that this gene was also crucial for the fly’s immune defense. When similar proteins responsible for pathogen recognition were identified in mammals, they were named Toll-like receptors due to its similarity to the Toll gene.

Invertebrates defend themselves from infections

Hoffmann’s discovery was a milestone in biology. He broke with the traditional idea that invertebrates lacked advanced immune mechanisms. In recognition of this pioneering work, Hoffmann was awarded the Nobel Prize in Physiology or Medicine in 2011, shared with Bruce Beutlerwho discovered the role of TLRs in mammalian innate immunity.

Their findings opened a new era in the study of immunology, revealing that basic defense mechanisms against pathogens are profoundly conserved across the animal kingdom.

Defensive arsenal of bivalves

In vertebrates, including humans, the immune system could be grouped into two: the innate and the adaptive, which are constantly in communication. The innate response – which includes TLRs – is a rapid but non-specific response, while the adaptive response is more specialized and produces antibodies specific to each pathogen.

TLR receptors are present in most metazoans (multicellular animals) and play a crucial role in immunity. Its role is to identify pathogens – such as bacteria or viruses – and trigger the body’s immune response to fight the infection. However, not all animals have the same arsenal.

Bivalves, such as mussels – which rely solely on their innate immune system and do not generate antibodies – have around 260 TLR genes. More than any other animal species. This allows them to recognize a large number of pathogens. By comparison, humans have 10 TLRs – but, in exchange, we have antibodies and other specific immune tools.

The sea urchin has fewer innate immune system receptors than mussels, with which it shares an ecosystem and pathogens.
Wikimedia Commons, CC BY

This difference is very surprising. Especially when we compare them to other invertebrates that share the same ecosystem and the same exposure to potential infections. Sea urchins have many of these genes, but in much fewer numbers.

The above are some of the conclusions obtained by our Immunology and Genomics Group, of the Marine Research Institute-CSIC, and published in 2023 in a study In Molecular Biology and Evolution on the evolution of TLR genes in 85 species of the animal kingdom.

Surprising genetic diversity

In other animals, including many invertebrates such as insects, TLR genes are concentrated in a single evolutionary group or clade. However, in mussels, their 260 TLR genes are distributed across three major clades. This demonstrates an unprecedented level of diversity in the animal kingdom.

Furthermore, comparing mussels to other metazoan species, such as cnidarians (a group that includes jellyfish and corals), these animals were found to have far fewer TLRs. This places bivalves in a unique evolutionary position.

Mussels vs. vertebrates

In vertebrates, the adaptive immune system allows them to create specific antibodies to fight specific pathogens. This provides them with specific long-term resistance. But bivalves, which lack this ability, have developed an incredibly diverse innate immune response. This allows them to react quickly and efficiently to a wide range of threats, displaying an impressive evolutionary strategy.

This fact is crucial, as mussels and other bivalves live in marine environments where they continually filter water laden with microorganisms, including pathogens. It is estimated that around 10 million viruses and 1 million bacteria can be found in just one milliliter of seawater. Not all of these microorganisms are harmful, but many are.

According to our findings, this diversity of TLR sensors is not only in number, but also in functionality: they are specially designed to recognize different types of viruses, bacteria and protozoa.

Pangenome, ideal for group protection

AND complementary discovery conducted by our team of researchers in 2020 revealed something equally fascinating: the mussel genome is an open pangenome. This means that new genes continue to be discovered as more individuals of the species are sequenced.

Therefore, genetic diversity is not yet fully known, and each new sample may add more unique genes to the species’ genome. In a closed pangenome (like the human one), all the possible genes of a species are already known and no new ones are expected.

Unlike vertebrates, where the variability between individual genomes is relatively low, in mussels it has been observed that a high percentage of genes, especially those related to immunity, vary from individual to individual.

This means that different individuals in a colony may have different immune defenses, allowing the colony as a whole to be more resistant to environmental changes and pathogens.

In animals with adaptive immune systems, such as humans, variability between individuals is not as crucial, as the production of specific antibodies adapts to the pathogens they encounter. However, in bivalves, this genetic diversity is critical for the species to thrive in such diverse and challenging marine environments.

This genetic uniqueness not only makes them more resistant to marine pathogens, but also opens new questions about the evolution of immunity in different animal species. Bivalves, with their highly sophisticated innate immune systems, demonstrate that there are multiple ways to survive in a world full of microbial threats.