The National Institutes of Health recently awarded $2.2 million to Alissa Rothchild, assistant professor in the Department of Veterinary and Animal Sciences at the University of Massachusetts Amherst and an expert in tuberculosis (TB) immunology, to study the very first cells that respond to Mycobacterium tuberculosis (Mtb), the bacteria causing TB.
How those initial cells, known as alveolar macrophages, or AMs, respond to the bacteria is not entirely known, though Rothchild and her lab have shown in a previous study that AMs don't respond to Mtb infection the way other macrophages do. Instead of mounting a strong inflammatory response, AMs turn on a cell-protective program that favors their survival over robust activation. Studies from the Rothchild lab and others have shown that AMs also have the capacity to be reprogrammed to mount a more robust response under different conditions. Rothchild and her colleagues will be spending the next five years trying to do just this.
To understand how Mtb infects the body, it's useful to first think about immunity. And when we think of immunity, we typically think of the adaptive immune system, which is when prior exposure to a pathogen -; either from a previous infection or from vaccination -; teaches the immune system what to guard against.
While the adaptive immune system is very effective, it is not the body's first responder -; that is the job of the innate immune system and its ranks of macrophages. Macrophages are the firstline defenders in the tissues that recognize and destroy pathogens and also call for backup. One way they do this is by turning on different inflammatory programs that can change the tissue environment.
In the case of the lungs, the sentinels in the lower airways are the AMs. They sit in the lung's alveoli, the tiny air sacs where oxygen passes into the bloodstream, constantly sampling the airway contents. But, for reasons unknown, AMs don't mount a robust immune response when they're initially infected by Mtb. This lack of response seems to be a chink in the body's armor that Mtb exploits. "Mtb seems to takes advantage of the immune response," says Rothchild, "and once AMs are infected, Mtb can replicate inside of these cells for a week or longer before backup arrives. Mtb effectively turns the AM into a Trojan Horse, where the bacteria can hide from the body's defenses."
In a previous paper, Rothchild and her colleagues showed that the AMs can be remodeled to mount different responses to Mtb, and that next-generation therapeutics could potentially leverage this plasticity to bring infection under control.
To figure out how to more precisely target the AMs, Rothchild has three aims for her NIH-supported research. First, to understand how AMs sense Mtb. Second, to understand what role interferons, specialized proteins that help host cells respond to pathogens, play in changing the AM response to Mtb. And third, to determine how altering AM responses might affect the host's response to Mtb infection without disrupting the important homeostatic balance in the lung.
One of the interesting things about TB, is that during later stages of infection, there is a very robust adaptive host response to the bacteria, but by that point, the host is playing catch-up and struggles to clear the infection without doing too much damage to the lungs. Our hypothesis is that very small, early changes could have huge downstream effects. If we can alter that initial interaction between AM and Mtb, we think we might be able to shift the outcome of the disease."
Alissa Rothchild, Assistant Professor, Department of Veterinary and Animal Sciences, University of Massachusetts Amherst
This NIH funding comes at the perfect time, because, as Rothchild points out, UMass Amherst has developed a "supergroup" of TB researchers spanning microbiology, immunology, genomics -; even computer science. "We meet monthly to share resources, ideas, and initiate joint projects," says Rothchild. "The support and expertise from the Morita, Siegrist and Green labs here at UMass Amherst have really made it possible for us to move forward with this project."
It's going to take just such collaborative work to mount an effective response to tuberculosis, which kills upwards of 1.3 million people a year, making it one of the leading causes of death by an infectious agent worldwide.
Novel anti-tuberculosis compound targets bacterial membrane protein