Less toxic staph cause more severe disease

A scanning electron micrograph of methicillin-resistant Staphylococcus aureus and dead human immune cells. (Credit: National Institute of Allergy and Infectious Diseases. CC BY 2.0)
A scanning electron micrograph of methicillin-resistant Staphylococcus aureus and dead human immune cells. (Credit: National Institute of Allergy and Infectious Diseases. CC BY 2.0)

We hear a lot about toxins in the news these days. Specifically, the hidden toxins lurking in the food we eat, the household products we use, the air we breathe and why we need to go on a juice cleanse to detox our bodies, lose weight and feel great!

But right now, let’s ignore those exaggerations and pseudoscience (because that’s a lengthy post in and of itself) and talk about real toxins. Real bacterial toxins. These toxins are proteins made and secreted by bacteria that help them establish an infection and cause disease. Staphylococcus aureus, commonly known as staph, is one species of bacteria that deploys a large and diverse arsenal of toxins. Most people carry staph bacteria asymptomatically on their skin and in their noses. In certain individuals, such as those with a weakened immune system, the bacteria can cause a wide spectrum of diseases from minor skin and soft tissue infections to life-threatening pneumonia and bloodstream infections. A key component of the bacteria’s survival strategy are the toxins that damage tissues and attack immune cells to interfere with the host’s defense system. Toxins are also responsible for disease symptoms such as the skin lesions commonly seen in patients with a staph infection.

Given the important role that toxins play in establishing and maintaining an infection, it would be logical to assume that the more toxins a bacteria produces, the more severe the infection. Until recently, that was the prevailing belief in the research community.

Now that idea has been turned on its head with new research published in PLoS Biology showing that the least toxic staph strains actually cause the most severe disease. In their study, researchers at the University of Bath in the UK analysed two large collections of staph bacteria isolated from patients. The first collection came from a single patient who progressed from being an asymptomatic carrier to having a bloodstream staph infection over a 15-month period. The second collection consisted of 134 isolates of the USA300 strain of methicillin-resistant staph (MRSA) isolated from healthy volunteers who were asymptomatic carriers or patients suffering from either a skin and soft tissue infection or a bloodstream infection.

To measure how much toxins were produced by a staph isolate, the researchers grew the bacteria in a nutrient broth and added the spent broth, which contained the secreted toxins, to a petri fish of growing human cells. Since toxins act by killing host cells, the percent of dead cells in the petri dish was directly linked to the amount of toxins produced and secreted by the bacteria.

When the researchers first analyzed the collection of staph isolates from the single patient, they found that that isolates from the patient’s nose taken at the 12-month mark were significantly less toxic than those taken in the first 11 months. This reduction in toxin production coincided with the patient developing a bloodstream infection three months later at the 15-month mark. Staph isolated from the patient’s blood at 15 months also produced lower levels of toxins than staph. By comparing the DNA sequences of the staph isolates, the researchers identified a single genetic mutation in a gene called rsp that seemed to be responsible for the change in toxicity and enabled the bacteria to move from the nose to the bloodstream.

The researchers next extended these findings with the second collection of staph isolates from healthy volunteers and patients with varying degrees of infection. Consistent with their earlier results, they found that staph isolated from patients with a bloodstream infection were significantly less toxic than staph from healthy asymptomatic carriers and patients with a minor skin and soft tissue infection.

To make sense of this unexpected result, the researchers tested a number of different hypotheses for why low toxin producers cause more severe disease. Perhaps the low toxin-producing staph were better at invading host cells? Or maybe they were more resistant to the antimicrobial compounds made by the host to kill foreign invaders? As is often the case in science, none of their initial hypotheses proved to be correct—there was no significant difference between the high and low toxin-producing staph strains in any of those traits.

Their final hypothesis was that the two types of staph differed in how well they grew in human serum, a component of blood. Serum is not a very hospital place for bacteria to grow—it contains few nutrients and is overrun with immune factors seeking to destroy microbial pathogens. Furthermore, growth in serum causes staph to ramp up their production of toxins. Given that producing and pumping out toxins requires a lot of energy and resources, the researchers hypothesized that the high toxin-producing staph strains could be at a growth disadvantage in the serum. When they tested the growth of high and low toxicity staph in broth supplemented with serum, they found that the high toxicity staph strains increased their toxin production even more and were significantly less fit than their low toxicity counterparts. When the strains were grown in broth without serum, this difference was less dramatic. Because they are not able to grow as well in serum, the high toxicity strains are less likely to establish a bloodstream infection and cause severe disease.

If the high toxicity strains are at a growth disadvantage compared to the low toxicity strains, why are they still around? Why aren’t all staph bacteria low toxin producers? To answer this question, the researchers used mathematical modelling to predict what would happen to two competing strains of staph that differed in their toxin production. As it turns out, when their model accounted for the inverse relationship between toxicity and likelihood of bloodstream infection, the high toxin-producing strains gained a competitive advantage at the population level. This is because primarily because bloodstream infections are a transmission dead end for staph. Low toxin strains are less likely to be transmitted from one person to another when their hosts die or if their hosts are too sick to interact with other people. In this case, the milder disease caused by the high toxicity strains actually helps those bacteria transmit from person to person and persist in the population.

In the end, it’s a complex balancing act between transmission and disease, fitness in one environment versus another, pathogen against host. And that’s why microbiology is so darn cool.

Reference: Laabei M, Uhlemann AC, Lowy FD, Austin ED, Yokoyama M, Ouadi K, Feil E, Thorpe HA, Williams B, Perkins M, Peacock SJ, Clarke SR, Dordel J, Holden M, Votintseva AA, Bowden R, Crook DW, Young BC, Wilson DJ, Recker M, & Massey RC (2015). Evolutionary Trade-Offs Underlie the Multi-faceted Virulence of Staphylococcus aureus. PLoS biology, 13 (9) PMID: 26331877

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