# Cell targeting by the bicomponent leukocidin subunit HlgB drives Staphylococcus aureus pathophysiology

## TL;DR

This study reveals how a bacterial toxin subunit, HlgB, helps Staphylococcus aureus break down red blood cells to access iron, a key step in causing infection.

## Contribution

The study identifies specific structural elements in HlgB that enable erythrocyte binding and lysis, independent of HlgA and DARC.

## Key findings

- HlgB binds to erythrocytes independently of HlgA and the DARC receptor.
- Certain loops in the rim domain of HlgB are essential for erythrocyte binding and lysis.
- HlgB's role in erythrocyte lysis was confirmed in tissue culture and mouse models.

## Abstract

Staphylococcus aureus is a global health concern, resulting in significant disease burden in both hospital and community settings. To establish infection, the bacteria must contend with a multitude of host defense mechanisms, including “nutritional immunity,” in which nutrients are sequestered away from invading pathogens. Importantly, S. aureus requires iron for growth during infection, which it acquires through the lysis of erythrocytes (hemolysis). HlgAB, a secreted bi-component pore-forming toxin, contributes to the ability of S. aureus to lyse erythrocytes to release heme iron. HlgAB consists of two subunits, the S-subunit HlgA and the F-subunit HlgB. Prior work has shown that the hemolytic activity of HlgAB is dependent on the binding of HlgA to the host receptor Duffy Antigen Receptor for Chemokines (DARC). Here we show that HlgB binds the surface of erythrocytes independent of DARC or HlgA. Our comparative genomic analysis reveals high conservation of hlgA and hlgB genes across S. aureus lineages. By performing structure–function studies, we identified a series of loops within the rim domain of HlgB that are required for the binding of HlgB to erythrocytes and erythrocyte lysis by HlgAB. The importance of HlgB-mediated host targeting was validated in a tissue culture model of S. aureus-mediated lysis of primary human erythrocytes, in an in vivo murine model of intoxication, and during in vivo systemic infection. Altogether, these findings expand our mechanistic insights into how S. aureus overcomes nutritional immunity and the role of HlgB in S. aureus pathophysiology.