Scientists have spent decades pursuing an effective vaccine for tuberculosis (TB). Now, a study published recently in the Journal of Experimental Medicine by the research group of David Russell, William Kaplan Professor of Infection Biology, illustrates how certain host cells are able to either control or promote the growth of Mycobacterium tuberculosis (Mtb) bacterium, informing a new approach to vaccine development in the fight against this global disease.

Paradigm shift

Ninety to ninety-five percent of people infected with tuberculosis live just fine with the bacteria in their systems, and will never manifest symptoms. For that minority in which the disease takes hold, TB is often deadly. “We can’t explain why that is,” says Russell. “Why is it that some people are progressing, while others are not? The immunological status between these two populations doesn’t appear to change.”

With such limited immunological understanding, it’s not surprising that we don't have an effective vaccine. In Russell’s view, “We’ve asked the questions the wrong way,” he says. “How do you design a vaccine when you have no idea what protective immunity looks like.” Previous vaccines followed a traditional paradigm—challenge the body so that it produces an adaptive immune response—usually indicated by the presence of a certain cytokines, immunological indicators of adaptive immunity. Yet, in all vaccine trials to date, individuals given these vaccines have not developed protection.

Russell sidestepped the traditional approach of only using immunological indicators as signs of protection against Mtb, and expanded the view to include the pathogen itself. To do this, his team developed bacteria fitness reporters—fluorescent Mtb bacteria that can easily be seen and analyzed within cells. Russell first examined how these glowing bacteria behaved in controlled in vitro and in vivo conditions. “I love new technologies and new ways of asking old questions, that’s why this work is so exciting to me,” says Russell.

Macrophages: protective or permissive

In his latest study, Russell and his team examined macrophages, the primary cells that TB bacteria infect in the lung. The lung has two kinds of macrophages: alveolar macrophages (AM) and interstitial macrophages (IM).

The team infected mice with the reporter Mtb bacteria, insuring that both the lung IM and AM cells had taken up the fluorescent pathogen. They then took the infected lung tissue and isolated the AM and IM cells to see how the two kinds of macrophages differed. They found that the AM cells supported growth of higher numbers of Mtb bacteria than the IM cells.

Next, the Russell team infected mice that had been depleted of AM cells. Without these more permissive macrophages in their lungs, the mice’s bacterial load decreased by over 80%. Conversely, when Russell infected mice lacking the more protective IM cells, the reverse occurred—with an almost ten-fold increase in bacteria.

Eating for two

Russell believes the reason for such a dramatic difference between these macrophage types could be driven by nutrient availability. When stressed with infection, IM cells rely on glucose for energy. AMs turn to fatty acids instead—consuming molecules like cholesterol, which is a preferred source of nutrient for Mtb bacteria in the host.

This finding could lead the way to host-directed therapeutics that would target permissive host cells like the alveolar macrophages, or target cholesterol metabolism to try to starve the TB bacteria—a concept know as nutritional immunity. Russell explains that these new findings lay groundwork for a more pragmatic approach to TB therapeutics where controlling, rather than exterminating the bacteria is the goal. “Killing the bacteria may not be as important as people assume,” he says. “Growth restriction could prove to be more effective.”

This new information about permissive and protective macrophages will help Russell as he screens millions of possible compounds as part of a $3.1 million drug discovery grant from the Gates Foundation. So far, the Russell lab has screened 1.5 million compounds for possible anti-TB properties. “We have already found that the environment within the host cell restricts bacterial metabolism, and reveals new drug targets not found in bacteria in broth culture ” says Russell. 

Armed with the latest information on the macrophage hosts, the Russell team can make even greater headway in their hunt for a viable cure for TB.

-By Lauren Cahoon Roberts