# Transthyretin is a novel innate immune effector against Gram negative bacteria

## TL;DR

Transthyretin, a protein known for carrying thyroid hormone, was found to fight Gram-negative bacteria like Pseudomonas aeruginosa by binding to their cell walls and reducing their viability.

## Contribution

This study reveals transthyretin as a novel innate immune effector and identifies its N-terminal region as a potent antimicrobial agent against Gram-negative bacteria.

## Key findings

- Transthyretin binds to the lipid A component of bacterial lipopolysaccharide, inducing bacterial agglutination and reduced viability.
- A synthetic peptide from the N-terminal region of transthyretin disrupts bacterial membranes and shows broad antimicrobial activity against Gram-negative isolates.
- The findings suggest that transthyretin has a new role in innate immunity beyond its traditional function as a carrier protein.

## Abstract

Pseudomonas aeruginosa is an opportunistic pathogen that frequently causes severe bloodstream and respiratory infections, yet the interactions between this bacterium and the innate immune system remain poorly investigated. In this study we identified transthyretin, the transporter protein of thyroid hormone and retinol, as a novel binding partner of the bacterium. We show that transthyretin binds to lipopolysaccharide via lipid A. Transthyretin binding induces the agglutination of transthyretin-bacteria complexes and a reduction in bacterial viability. Mapping studies reveal that the N-terminal region of transthyretin mediates bacterial interaction, and a synthetic peptide derived from this domain exhibits potent bactericidal activity against a broad collection of P. aeruginosa isolates as well as other Gram-negative bacteria by disrupting membrane integrity. These findings identify transthyretin as an endogenous antimicrobial factor and uncover cryptic antimicrobial activity within its N-terminal region. Beyond extending the functional repertoire of transthyretin, these results suggest a novel role for this protein in innate defense.

In this study, we identify human transthyretin (TTR)—best known as the carrier protein for thyroid hormone and retinol-binding protein—as a previously unrecognized binding partner of Pseudomonas aeruginosa. We show that TTR recognizes the lipid A portion of the bacterial lipopolysaccharide (LPS), a highly conserved feature of Gram-negative pathogens. Functionally, TTR binding promotes bacterial agglutination and reduces viability. We further map the bactericidal activity of TTR to its N-terminal region. A synthetic peptide derived from this region (TTR1′) directly disrupts bacterial membrane integrity and displays potent antimicrobial activity against a broad panel of Gram-negative clinical isolates, markedly reducing viability in most strains tested.

These findings expand the functional repertoire of TTR beyond its classical role as a carrier protein. The discovery that TTR—and particularly its N-terminal fragment—possesses direct antimicrobial properties reveals a new facet of innate immunity and suggests that host amyloidogenic proteins may act as natural antimicrobial agents.