Biomedicine

Decoding Pneumonia's Defenses

Researchers sequence more than 200 strains of the bug and find a catalog of ways they evade drugs and vaccines.

An in-depth genetic analysis of closely related strains of streptococcus pneumoniae, the bacterium that causes pneumonia, has revealed how the microbe has continually escaped attempts to defeat it. The findings show that the bug can easily swap chunks of DNA with other strains, allowing it to rapidly evolve defenses against both antibiotics and vaccines. Researchers say the findings will help them design more effective preventive measures and treatments.

Scheming bacteria: Researchers sequenced the genomes of 240 variants of a particular strain of streptococcus pneumonia, the bacterium (shown above) that causes pneumonia.

“It shows just how astonishingly quickly this bug can reinvent itself,” says William Hanage, associate professor of epidemiology at Harvard and one of the study’s authors. “I think the findings should renew our recognition of exactly how innovative we have to be in finding new ways to combat disease caused by this organism, which is readily capable of throwing off any intervention we direct against it.”

Despite antibiotics and a vaccine, the World Health Organization estimates that pneumonia-causing bacteria, known as pneumococcus, is responsible for about four million deaths per year, mostly among children from poor countries.

Researchers sequenced 240 strains of a drug-resistant form of the microbe, collected between 1984 and 2008 from 22 countries around the globe. The original variant, from which the others descended, is thought to have arisen about 40 years ago in response to the introduction of antibiotics. While researchers had previously compared a handful of genes in these microbes, this study was the first to analyze the entire genome, allowing researchers to re-create its evolutionary tree. The findings are published today in the journal Science.

“I think this is a landmark paper,” says Alexander Tomasz, professor of microbiology at the Rockefeller University. Tomasz contributed some of the DNA used in the study. “It uses the most sophisticated molecular techniques on [strains] collected at various sites over time to trace the evolution of one of the most important human pathogens.”

Microbes can evolve in two ways; via single letter changes to the gene-coding region of DNA, or by swapping large chunks of DNA. The latter mechanism occurs less frequently, but it is capable of producing much larger changes in the organism—including the ability to evade a vaccine.

The new research highlights just how common this swapping is in the pneumococcus bacteria. “We can see multiple occasions where the clone has acquired different elements of resistance, such as to macrolide antibiotics, at different times and in different parts of the world,” says Stephen Bentley, a scientist at the Wellcome Trust Sanger Institute, and the senior author of the study.

The researchers found, for example, two variants that had swapped out the portions of their genomes that made them vulnerable to the vaccine. “That kind of convergent evolution in parallel tells us something about how readily these things can pick up the opportunity to escape,” says Hanage. “We’ve known for years that it happens. What we hadn’t realized was just how many times it occurs in individual lineages.” The most recent version of the vaccine has already been updated to include antibodies against these strains.

Bentley says it’s not yet clear where the new chunks of DNA are coming from, though they likely originated in other types of pneumoniae bacteria inhabiting the same niche, namely, the nose.

The research also sheds light on how this population of microbes has evolved in response to the introduction, in 2000, of a vaccine against seven of the most common disease-causing subtypes in the United States. Scientists already knew that those subtypes were virtually eradicated once vaccination became popular, and that others arose to take their place. But it hadn’t been clear whether the new variants were present before 2000 and grew to fill a niche left by those that had been eradicated, or whether they had evolved in response to the vaccine, says Hervé Tettelin, associate professor of microbiology and immunology at the University of Maryland School of Medicine.  Scientists now know that the variants most likely existed before 2000.

“If we understand how those things are evolving, we can better decide on future vaccines and antibiotic treatment regimens so that we don’t make matters worse or displace the problem,” says Tettelin.

The newest version of the vaccine targets 13 of the most common subtypes. But given that there are more than 90 varieties of this strain of microbe, the researchers now predict that the microbial population will respond the same way it has responded to the previous vaccine.

Another option is to develop a vaccine that targets a protein shared by all strains, one that is vital to the microbes’ survival. Sequencing studies such as this one could help scientists identify such a protein. “If you sequence hundreds or thousands of genomes, this is when you can start defining the true core genome,” says Tettelin. “Then you can make a decision about what proteins to use in a vaccine.”

The strain under study in this project is just one of many disease-causing varieties of pneumococci. Bentley, Tettelin, and others are now analyzing other strains using a similar approach. Researchers are also using sequencing to look even more closely at the evolution of the bacteria. Bentley plans to analyze samples collected from a refugee camp in Thailand over 15 years. That should give a much higher resolution picture than the one the current project produced. That improved picture will, in turn, help trace how the bugs are transmitted from person to person.

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