“Tuberculosis is the single largest infectious disease killer in the world,” says David G. Russell, Microbiology and Immunology. “It’s a huge problem in Southern Africa, Asia, and Eastern Europe. There’s a tremendous underappreciation in the Western world for how big a problem it really is.”
Russell studies infectious diseases, and a large portion of his work revolves around tuberculosis (TB). There is no vaccine for the disease. Researchers lack understanding of immune correlates, or measurable signs of protection from Mycobacterium tuberculosis (Mtb) bacterium, which is one reason why a vaccine continues to elude them. “We don’t understand what immune protection from TB is,” Russell says, “nor what failure of immune protection is.” He and his collaborators decided to start over in the pursuit of a vaccine by looking at the factors that determine the progression of the disease.
Why Don’t People Know They Have TB?
“More than 90 percent of people infected with TB don’t go on to present the disease,” Russell says. “They’ll die of something else without ever knowing they’re TB positive. Why is this? What dictates disease progression in some individuals when the majority of people control the infection?” In an effort to answer that question, the Russell lab developed fluorescent strains of Mtb. By fluorescing under certain conditions, the bacterium can report to the researchers its fitness and its ability to replicate in various environments within the macrophage host cells of mouse models. The goal is to see which host cell phenotypes control the disease and which allow it to progress.
“We’ve identified different macrophage subsets that allow bacterial growth or control it,” Russell says. “These subsets coexist within the infected mouse at the same time, so we think that it’s the ratio, or balance, of these host cell subsets that determines the progression or control of the disease.”
Russell is working with collaborators in South Africa and Malawi, who are testing the reporter bacterial strains on tissue and cells taken from TB-infected human patients in those countries. The next step will be to tie the basic science work done on mouse models in the Russell lab together with human subjects work in Africa. That will require a limited testing of the reporter bacterium strains in primate models. “We can work up the procedures in mouse models, but mice are not a great model for human disease,” Russell says. “Having a limited amount of primate work is very important to test and validate the system.”
Disease Progression and Drug Discovery
Russell has just received a grant for $3.8 million from the National Institutes of Health (NIH) to pursue the integration of mouse-primate-human work, with the goal of further understanding TB disease progression. This grant joins the many others Russell and his collaborators have already received from the NIH and the Bill & Melinda Gates Foundation to fund various aspects of their TB research.
One of the earlier grants, $2.5 million from the Gates Foundation, is funding another facet of Russell’s work: TB-related drug discovery. Creating a vaccine for TB is the ultimate goal, but currently the disease is treated by antibiotics that must be taken for eight to nine months. A common problem is noncompliance or failure of the treatment, as patients go off the medication too soon or don’t take it regularly. Added to that is the alarming increase in antibiotic-resistant bacteria and the trend for pharmaceutical companies to close down their antimicrobial divisions, resulting in no new antibiotics being developed.
“If you invent an antibiotic that cures someone of an infection, then that person doesn’t have to take the drug anymore.” Russell says. “Yet the pharmaceutical companies have to spend the same amount of money developing an antibiotic as they do developing something like an anti-cholesterol medication that a person has to take for life. For companies that must make profits, this does not make fiscal sense. So they’ve stopped doing antibiotic discovery. It’s a huge problem. We are moving toward a post-antibiotic era where we’re going to have infections we can’t treat. At the moment we have TB. What are we going to do about that?”
“Our drug discovery platform found this new target pathway. Before, there were no inhibitors out there for cholesterol metabolism in TB bacteria. This is a totally new drug target.”
An Effective Drug Discovery Platform, a Collaborative Effort
Working with the California Institute for Biomedical Research (Calibr), a not-for-profit organization that seeks to discover and develop therapies for unmet medical needs, the Russell lab is screening Calibr’s library of compounds, looking for those that negatively affect Mtb inside the host cell. So far they’ve screened 1.5 million compounds. The Gates Foundation grant funds this drug discovery component of the Russell lab with the understanding that any resulting drugs will be co-owned between Cornell and Calibr and developed and shared with the world. The Gates Foundation also de-emphasizes the publication requirement that is usual with most grant funders. “I’ve hired people specifically to do drug discovery with the view that there will not necessarily be publications at the end of this but with the hope that there will be drugs,” says Russell.
The Russell lab initially identified a panel of compounds that affected Mtb’s ability to metabolize cholesterol. This led to the discovery that Mtb is genetically wired to realign its metabolism to cholesterol and fatty acids when it’s inside the host cell. Not only do these components of the host nourish the bacterium, allowing it to thrive and reproduce, but they also serve as environmental signals, telling the bacterium where it is and how to modify its metabolism. “Our drug discovery platform found this new target pathway,” Russell says. “Before, there were no inhibitors out there for cholesterol metabolism in TB bacteria. This is a totally new drug target.”
The researchers have now identified several promising compounds that inhibit Mtb’s ability to breakdown cholesterol when it is inside the macrophage cell of an infected mouse model. “Whether these compounds develop into proper drugs, we’ll have to wait and see,” Russell says, “but they do restrict bacterial growth.”
The TB-HIV Connection
Along with work on TB, Russell also spends a portion of his time studying human immunodeficiency virus (HIV) and the connection between it and TB. “TB is the largest single cause of death in people living with HIV,” he says. “In Malawi, about 85 percent of the TB cases in hospital are HIV positive. There’s a collision between the two infections in sub-Saharan Africa.” Currently Russell and his collaborators in Malawi are studying the presence of Mtb and HIV in alveolar macrophages in the lung.
Working on TB and HIV in Africa for more than 20 years has given Russell a different perspective on his work. He says, “There’s been a transition for me from an intellectual pursuit to something much, much deeper. Spending time in Africa has had a huge impact on my attitude toward my research. I believe Western universities need to step up to fill the void that’s been left by pharmaceutical companies in the drug discovery arena. Universities have a responsibility. It’s not just about education, or about research for research’s sake. It is about addressing real world problems that kill people.”