Understanding Tuberculosis from the Bacterium’s Point of View

Over a quarter of humanity is thought to be infected with or previously exposed to the tuberculosis bacterium, one of the deadliest microbes on Earth. Why the pathogen is so pervasive, despite an existing vaccine and medications, is due to how well it has learned to read and exploit our biology. The earliest evidence of tuberculosis in people dates back over 9,000 years, giving the bacteria millennia to develop effective strategies to adapt and spread.

This ability to survive is what makes Mycobacterium tuberculosis (Mtb) such an intriguing bacterium, says Shumin Tan, associate professor of molecular biology and microbiology at Tufts University School of Medicine. Her lab is dedicated to understanding the tactics Mtb uses to exploit its host to survive and grow. The group’s recent discoveries include evidence that subsets of bacteria within a single host “see” different cues depending on where they are present and respond and adapt their growth accordingly, a phenomenon referred to as “infection heterogeneity.”

Tan’s research caught the attention of an organization supporting early stage, high-risk, high-reward science called the Hypothesis Fund, which doesn’t accept grant applications; instead, the organization’s scientist scouts identify and nominate especially bold research projects to fund. Tan was selected to receive a grant to build an experimental platform that will let scientists observe, in detail, the molecular tactics tuberculosis bacteria deploy in various biological situations.

“Her work may lead to major advances in our understanding of what Mtb metabolic heterogeneity looks like, literally and figuratively, in infections,” says Dianne Newman, a scientist scout for the Hypothesis Fund and professor at California Institute of Technology, who nominated Tan for the grant. “This project has the right mix of risk and reward, and has the potential to be highly impactful, not only for the Mtb community but for the field of host-microbe interactions more broadly.”

“One feels very privileged to have received this opportunity, as it has provided the impetus to do a project that’s been percolating in my head for years, but required too many upfront resources to obtain the proof-of-principle data necessary to get funding from traditional means,” says Tan, who used the grant in part to bring on postdoctoral scholar Anna-Lisa Lawrence to lead the initiative. “The commitment of the Hypothesis Fund to investing in and building a community that cares about doing fundamental science is really exciting.”

The Bacterium’s Point of View

Tan, who grew up in Singapore, decided she wanted to be a scientist during her first year in high school, after having the opportunity to participate in a research program in a university lab. Tan applied to colleges in the United States, initially looking to study the link between human genetics and disease. She was accepted into Washington University in St. Louis, where a mentor helped place her with a group researching the bacterial genetics of Helicobacter pylori, a common stomach bug that is also the causative agent of gastric cancer. That experience led to her decision to pursue microbiology for her Ph.D. studies instead of human genetics.

After earning a Ph.D. at Stanford University studying H. pylori-host interactions, Tan decided on a different direction for her postdoctoral research. Mtb caught her interest because of its continuing impact on public health, and its ability to live in our bodies for decades without causing any active disease. Tan knew from studying H. pylori that pathogens invest energy in activities that help them grow and survive, so she was interested to find out how Mtb exploits host signals so that it can better colonize us.

“If you look at things only from the host’s perspective, but you don’t understand what’s in it for the bacteria, then you miss a key aspect of how these actions are truly connected,” says Tan. “Upon exploration, you may see, for example, that the response from our immune system may result in a cue that the bacteria are able to utilize as a ‘GPS signal’ as to its location in the host, so it has evolved to detect and respond to such signals to enable appropriate adaptation and continued survival.”

Since joining Tufts University as a faculty member in 2016, Tan’s lab has searched for the environmental cues Mtb “cares” about. One significant discovery was that changes in the levels of chloride and potassium, electrically charged molecules whose concentrations differ depending on location within tissue or a host cell and can be altered by our immune response, are sensed and responded to by the tuberculosis pathogen.

Her group has also shown how Mtb living throughout the lung “see” different host signals and have different growth states. If bacteria exist in different states throughout the body, this means some can remain out of sight from our immune system or medications. For example, drugs directed at killing only actively growing bacteria are going to be less effective.

“As we’ve improved our ability to analyze things at the single cell level in spatial context, we’re seeing that bacteria, even those in adjacent spaces, can vary in sensitivity to therapies,” Tan says. “It affects the way we think about how to manage the disease, pushing us to better understand the basic biology to figure out how we can try and perturb it.”

The Hypothesis Fund Grant

An airborne pathogen like SARS-CoV-2, tuberculosis has been responsible for an estimated 1.2 to 2 million deaths annually for decades. Despite the disease’s prevalence and toll on human health, the Stop TB Partnership reported that the investment in COVID-19 vaccines dwarfed that for tuberculosis by ~1000:1, with funding for Mtb research coming mostly from governments and nonprofits.

The Hypothesis Fund’s support will enable Tan to tackle the complexity of Mtb by creating a platform that can measure changes in the bacteria over space and time. Such a tool would make it possible to probe how individual bacterial cells in the lung and other tissue respond during infection and relate it to the host’s response. The data will reveal how mixing molecular cues can shift the infection in favor of Mtb or the host.

The team will need to tackle some technical challenges, such as designing a strategy that will enable probe penetration through the tuberculosis bacterium’s extremely complex and thick cell wall to report accurately on a single cell’s internal state, but Tan is optimistic about the progress of the project. 

“What’s fun about science is that you don’t always know what you might discover as your research progresses,” Tan says. “It’s been a crazy journey, but if we get this methodology to work, it will advance not just our understanding of Mycobacterium tuberculosis, but have utility for many other infections of interest.”