A surprising link between a staph toxin and CCR5
A research project that began by asking how the bacterium Staphylococcus aureus wreaks havoc in the human body found one of its answers in an unexpected place—a cell-surface receptor that a handful of pathogens, among them HIV, exploit to enter target cells. The study, led by New York University (NYU) researchers, showed that a soluble, bivalent pore-forming toxin called leukotoxin ED, or LukED, which S. aureus secretes to kill immune cells, appears to rely on the presence of the CCR5 protein to carry out the lethal act (Nature 2012, doi:10.1038/nature11724). HIV, Toxoplasma gondii and poxviruses are known to exploit CCR5 to target immune cells. But this appears to be the first time that S. aureus has been linked to the cell-surface protein.
This is of particular importance because antibiotic-resistant strains of S. aureus are a leading source of sometimes lethal infections contracted in hospitals. “In fact, in the US, S. aureus has been found to kill more people than HIV,” says Victor Torres, assistant professor in the microbiology department at NYU School of Medicine and a co-author of the paper. “S. aureus is in every single hospital in the country. It’s a major problem.” The link between CCR5 and LukED could prove to be of some medical significance: an antiretroviral drug that disrupts HIV docking with this co-receptor is in widespread use today, raising the possibility that one means of dealing with drug resistant infections by S. aureus may already exist in the pharmacopeia.
The HIV co-receptor came into focus as a possible target of the bacterium when in vitro experiments conducted by Torres and his colleagues showed human T-cell lines expressing CCR5 died when exposed to a recombinant form of LukED, while Jurkat T-cell lines with undectable CCR5 were insensitive to the bacterial toxin. The cell lines came from the laboratory of Derya Unutmaz, associate professor of microbiology, pathology and medicine at NYU School of Medicine and a co-author of the paper. The picture became even clearer when a human osteosarcoma cell line engineered to express CCR5 was found to be sensitive to LukED, but not to other leukotoxins secreted byS. aureus.
Torres and his colleagues further found that the CCR5 antagonist maraviroc also blocked LukED’s ability to kill CCR5+ T cells in vitro at concentrations similar to those required to block HIV infection. This suggests that the antiviral drug might have some value in treating S. aureus strains that produce LukED toxin.
Mouse studies conducted by the team revealed that while mice lacking the CCR5 gene are largely resistant to infection with LukED+ S. aureus, wild-type mice are highly susceptible to the infection. Additionally, primary murine macrophages treated with high concentrations of maraviroc were partly protected from toxin-mediated killing, further evidence that LukED directly targets mouse CCR5. Indeed, the researchers nailed down CCR5+ effector memory T cells, macrophages, and dendritic cells as the preferred targets of the bivalent toxin, a clue as to why the S. aureus bug is so brutal. “CCR5+ memory T cells secrete the cytokines (IL-17 or IFNg) that orchestrate the combat of the immune system against staph,” says Unutmaz. “Targeting these cells is a quite ingenious way to knock down the command center of the adaptive immunity.”
Torres says maraviroc could potentially be used as an adjunct treatment for staph. LukED-producing strains have been isolated from patients at a rate of 78%-95% depending on the study and site of infection. “Maraviroc has the potential of boosting immune cell survival, which will aid the host in controlling the bacterial infection.” Mary Carrington, a senior investigator at the National Cancer Institute and SAIC in Frederick, who was not involved in the study, described the paper as “richly exciting” and agreed that it presents some “excellent possibilities for treating S. aureus infection.”
The LukED findings also raise some intriguing questions relevant to HIV, notably whether S. aureus leukotoxins may have influenced the selection of the CCR5Δ32 allele associated with HIV resistance in rare individuals. NYU’s Unutmaz thinks it might be worth studying whether individuals who carry the mutation are also relatively resistant to S. aureus. A proportion of individuals of Northern European heritage harbor the mutation, but when it surfaced, or why, is unclear. One theory was that it evolved in response to the Black Plague.
“We have no data to show that S. aureus [influenced selection],” says Torres. “What is intriguing is that S. aureushas been around humans for thousands of years, and at least in animal models, the pathogenesis of LukED+ strains is primarily elicited in a CCR5-dependent manner.”
But Carrington, who has studied cohorts of individuals who carry CCR5Δ32, says it isn’t entirely clear what accounts for the persistence of the allele. “If the mutation was indeed selected by resistance to some deadly pathogen, then we would expect that pathogen to have been particularly devastating a few thousand years ago, when the mutation arose in Northern Europe, where the frequency of the delta32 allele is highest,” she says. “That is why the plague was such a popular candidate for the driving force. But I don’t know of any data that this was the case for S. aureus, but who knows. Even Icelandic health records were not so complete at that time.” —Regina McEnery