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Microbiome Project Kicks Off with Aim of Understanding Ecology Behind Hospital-Acquired Infections

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As other groups marshal next-generation sequencing resources to retrace and rein in pathogen outbreaks in healthcare settings (CSN 12/19/2012), one team is embarking on a study aimed at understanding the ecology of pathogens and other microbes in hospital environments.

Researchers involved in the Hospital Microbiome Project plan to collect and profile some 15,000 microbial samples from people and places within a newly built Chicago hospital over the coming year. Along with targeted sequencing to identify members of microbial communities, they will likely use metagenomic sequencing to look at the full sequence for a subset of samples.

By following the structure of these hospital microbe communities over time — before and after the center opens its door to patients — organizers believe they'll get a much clearer understanding of how pathogens take hold in healthcare settings. They also hope to learn more about ways in which pathogens are influenced by their physical surroundings and other organisms that share these spaces.

"The project aims to see how nosocomial infections and hospital-acquired infections develop with the rest of the microbiome in hospitals, as patients and doctors actually move into it," project leader Jack Gilbert, an environmental microbiology researcher at Argonne National Laboratory and assistant professor of ecology and evolution at the University of Chicago, told Clinical Sequencing News.

"This kind of study can lead to a significant improvement in our understanding of the development and pathogenicity of hospital-acquired infections or health care-associated infections," he added.

Researchers at the University of Chicago, Argonne National Laboratory, and the Walter Reed Army Institute of Research are spearheading the collaborative two-year initiative and samples will be processed at UChicago and ANL.

"The idea is to develop a consortium of folks who are interested in using 'omics — metagenomics, amplicon sequencing technologies — to examine the development and characterization of microbial communities in these hospital environments," Gilbert said.

Sampling for the study is primarily centered at the University of Chicago, where researchers have access to a newly built hospital. Some samples were collected while the facility was being built. And researchers kicked off regularly scheduled sampling of surfaces at specific sites in the hospital this week, in anticipation of the first patients' arrival early next month.

"The idea will be that we then have a month of intense screening in each of the rooms and each of the surfaces and in any people who are in those rooms at the time of sampling, including the samplers themselves," Gilbert said.

This will include daily or weekly sampling at specific sites, combined with air and water testing, and sampling of certain patients and staff members in the wards.

"That kind of longitudinal, temporal sampling — both high and low resolution — over a long period of time with even larger cross-sectional studies of surfaces, rooms, people, et cetera, will provide a dataset of unparalleled capability for understanding the development of pathobiomes and the microbiomes in this system," Gilbert said.

The group is also collecting samples at a US Army military hospital in Germany for an associated hospital study set up in collaboration with Captain Ben Kirkup from the Walter Reed Army Institute in DC, who will be overseeing sample collection at that site.

That branch of the project is "predicated on the need to understand the propensity for microbial infection in wounded warriors," Gilbert said, adding that it "has a very different experimental design" and is "not exactly comparable to what we're doing in Chicago."

At the German military hospital, researchers aim to collect roughly 1,600 samples in all, spread over 16 sampling cycles. There, samples will be taken in a clean intensive care room prior to each patient's arrival and then again daily over the course of his or her stay.

The Hospital Microbiome Project secured close to $1 million in funding from the Sloan Foundation this past fall. That funding will be sufficient to support the two-year study proposal in its current iteration, though Gilbert said the group is looking for additional funding to extend and broaden the scope of the project.

Studies in the US have put the burden of hospital-acquired infections on par with those acquired in the environment or community, organizers of the study explained on the Hospital Microbiome Project website. Moreover, microbial infections contracted in healthcare settings are often more deadly, perhaps owing to the immune-compromised nature of the population involved.

There are clues, too, that some of the techniques used to sterilize hospital environments may, in some cases, remove microbial community members that would otherwise help ward off more pathogenic bugs.

"We know that when you sterilize an environment and you put a Staphylococcus aureus or an Enterobacteriaceae organism in that environment, it will blossom," Gilbert noted. "And if somebody touches that surface, they have a higher chance of becoming a carrier for that disease."

"If, however, there's a healthy microbial flora on that surface, the pathogen cannot develop, cannot bloom, cannot reach an abundance that makes it infective," he added. "So we're very interested in trying to characterize the development of these pathogen microbiomes in these hospital areas and on the surfaces."

Beyond the potential clinical importance of understanding microbial ecology in healthcare settings, the study organizers explained that the hospital environment has features that make it appealing as a setting for microbiome research.

"Variables such as building materials, temperature, humidity, air source, HVAC, square footage, and cleaning procedures/schedules are relatively consistent across individual patient rooms," they wrote online, "thereby enhancing our ability to measure the effect of individual occupants on microbial diversity."

The team is focusing in particular on two wards in the new Chicago hospital, each found on a different floor of the building: an oncology ward, where patients are sometimes admitted for weeks or months; and a general surgery ward, where patient stays are generally much shorter.

"That differential temporal transition — people in different rooms for different periods of time — will really help us understand what impact the length of time you spend in the room has on the development of the pathobiome in that room," Gilbert explained, "and the potential for you to become infected."

The specific sites being sampled within these wards, meanwhile, were selected with an eye toward high-traffic areas. For instance, samples will be collected at nursing stations in each of the wards. Specific staff members, patient rooms, and patients moving into and out of those rooms will also be sampled.

The team plans to do 16S ribosomal RNA gene sequencing on samples to characterize bacterial components of communities, while fungal internal transcribed spacer sequencing, or ITS, and 18S rRNA sequencing will be used to track the identity of fungal and other eukaryotic community members.

The 18S and fungal ITS techniques will be used in parallel, since there is no universal primer set for identifying fungi across the board.

"The idea will be that we'll pick up some fungi with the 18S," Gilbert explained.

"The fungi ITS is designed to particularly target known fungal organisms that are prevalent in indoor environments," he added, "and also to try to diversify that — so to pick up things that we don't know as well."

For some of the samples, researchers also intend to do shotgun metagenomics to get a snapshot of the bacterial and viral genes present in the microbiomes.

"The key study will be 16S, 18S, and fungal ITS," Gilbert said. "And [it] also involves some shotgun metagenomics, both of viruses and bacteria."

The group is aiming for around 50,000 reads per sample for the amplicon sequencing analyses, to be done using Illumina's HiSeq and MiSeq instruments. Gilbert explained that these platforms were selected both for their reliability as well as the depth of sequence they offer and length of sequence fragments they generate.

In addition to sequencing-based analyses of the samples, the researchers anticipate using quantitative PCR, microarray, and culturing assays to look at features such as microbial abundance and antibiotic resistance marker levels within some samples.

They are also toying with the possibility of sequencing selected new reference genomes as the project progresses.

"Should specific organisms come up in the cultivation surveys of the hospital or in our cultivation surveys that are of interest, then we will genome sequence them," Gilbert said.

"The idea will be that we will look to genome sequence maybe 1,000 or so genomes over the course of the year," he noted. "And in doing that, we will use that information to determine if there has been an evolution of certain species or taxa within the system or selection for certain taxa, with certain SNPs, functional attributes, or plasmids."

If so, having access to amplicon, metagenomic, and genome sequence information may also help the researchers see how such evolution or selection presents itself in each data set.

Such strategies are all part of the researchers' scheme to "answer hard-core ecological questions about the succession, development, stability, and adaptability of microbial communities into this new environment," Gilbert said.

"When all of these sick people arrive, we want to know what effect they have on the development of the microbial community and the system and its stability," he added.

The group plans to make information about the Hospital Microbiome Project available to the public via the project website, so that interested individuals can learn more about the study design, rationale, and results. For instance, information on some of the microbial community patterns identified during the Chicago hospital's construction is already available through the site.

"The idea would be that we update the findings as they come in, when they're generated," Gilbert said. "We also want to get a blog going, and we'll have a Twitter feed for this as well."

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