HEALTH NEWS

Study Title:

Toxin Responsible for MRSA Severity

Study Abstract

Staphylococcus aureus is a prominent human pathogen and leading cause of bacterial infection in hospitals and the community. Community-associated methicillin-resistant S. aureus (CA-MRSA) strains such as USA300 are highly virulent and, unlike hospital strains, often cause disease in otherwise healthy individuals. The enhanced virulence of CA-MRSA is based in part on increased ability to produce high levels of secreted molecules that facilitate evasion of the innate immune response. Although progress has been made, the factors that contribute to CA-MRSA virulence are incompletely defined. We analyzed the cell surface proteome (surfome) of USA300 strain LAC to better understand extracellular factors that contribute to the enhanced virulence phenotype. A total of 113 identified proteins were associated with the surface of USA300 during the late-exponential phase of growth in vitro. Protein A was the most abundant surface molecule of USA300, as indicated by combined Mascot score following analysis of peptides by tandem mass spectrometry. Unexpectedly, we identified a previously uncharacterized two-component leukotoxin–herein named LukS-H and LukF-G (LukGH)-as two of the most abundant surface-associated proteins of USA300. Rabbit antibody specific for LukG indicated it was also freely secreted by USA300 into culture media. We used wild-type and isogenic lukGH deletion strains of USA300 in combination with human PMN pore formation and lysis assays to identify this molecule as a leukotoxin. Moreover, LukGH synergized with PVL to enhance lysis of human PMNs in vitro, and contributed to lysis of PMNs after phagocytosis. We conclude LukGH is a novel two-component leukotoxin with cytolytic activity toward neutrophils, and thus potentially contributes to S. aureus virulence.

From press release:

A research project to identify all the surface proteins of USA300—the most common community-associated strain of the methicillin-resistant form of the bacterium Staphylococcus aureus (MRSA)—has resulted in the identification and isolation of a plentiful new toxin that laboratory studies indicate is a potent killer of human immune cells. Scientists at the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, say the toxin could be a key factor in the severity of MRSA infections in otherwise healthy people.

The toxin, named LukGH, consists of two small proteins found on the surface of the bacteria and is secreted freely into the surrounding environment.

The scientists identified 113 proteins associated with the surface of USA300 and began to examine the role of the previously uncharacterized proteins. S. aureus surface proteins are key indicators of how the pathogen will respond to contact with immune system cells, such as neutrophils, which the body produces in large numbers to kill invading microbes. Some proteins can aggressively attack these immune cells, and the demise of the neutrophils ultimately enables the bacteria to replicate and thrive. When the LukGH toxin was removed from USA300, studies showed that the strain caused little to no damage to human neutrophils. With the toxin present, the bacteria began forming pores in neutrophils which eventually led to their destruction.

The scientists, including Frank DeLeo, Ph.D., Chief of the Laboratory of Human Bacterial Pathogenesis, say they do not know the full contribution of LukGH to the severity of MRSA infection. However, LukGH is the only MRSA toxin currently known to promote destruction of human neutrophils after the bacteria have been ingested by the immune cells designed to destroy them.

Using animal models of MRSA infection, the NIH team is continuing to study the role of LukGH in disease.

Study Information

1.Ventura et al.
Identification of a novel Staphylococcus aureus two-component leukotoxin using cell surface proteomics.
PLoS ONE
2010 July
Laboratory of Human Bacterial Pathogenesis, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, United States of America