MedicalResearch: What is the background for this study?
Dr. Desvignes: This study is the result of a collaboration at NYU Langone Medical Center, between the laboratories of Dr. Stefan Feske and Dr. Joel Ernst, my mentor. Dr. Feske and colleagues had developed a mouse model of rare, inherited mutations he had identified in infants. These mutations occur in the genes for STIM1 and ORAI1, which are crucial for calcium flux in cells of the immune system. The young patients affected by these mutations suffer from severe, recurrent and chronic infections that often cause death before their first birthday. In particular, some of these patients cannot control infection with BCG, which is a normally innocuous strain of mycobacteria administered to protect against tuberculosis (TB). TB is a chronic infection and one of the leading causes of infection-related death worldwide. Going into this study, Dr. Feske and colleagues knew that without functional calcium channels, immune cells do not function properly. However, they did not fully understand how these channels contribute to immune responses to infectious pathogens in a living organism and in particular, for pathogens that cause chronic infections such as TB. This is why Dr. Ernst and I collaborated with Dr. Feske and provided him with our clinical and research expertise in TB.
MedicalResearch: What are the main findings?
Dr. Desvignes: Dr. Feske’s mice are genetically engineered to lack STIM1 in a certain type of immune cells, known as T cells or T lymphocytes. We infected these mice with Mycobacterium tuberculosis, the bacterium causing TB. Mycobacterium tuberculosis causes chronic infection by manipulating the immune system even in healthy people. The first very surprising result of our study was that mice lacking calcium flux in T cells handled acute TB fairly well. Only during the chronic phase of infection did they become unable to control mycobacterial growth and developed a strong inflammation in their lungs, which was due to an infiltration by different types of immune cells, including T cells. We discovered that the accumulation of STIM1-deficient T cells in the lungs resulted from the cells’ inability to die, which is a normal mechanism to limit an immune response and prevent excessive inflammation.
Another immune control mechanism that failed in the absence of STIM1 is mediated by a subset of T cells called induced regulatory T cells, or iTreg cells. These cells are essential to prevent normal immune responses from going “overboard” by suppressing the functions of other immune cells, including T cells. We found that calcium signals are required for the development of iTreg cells and that their numbers were strongly reduced in the lungs of infected STIM1-deficient mice. We therefore think that the lack of iTreg cells in the absence of STIM1 contributes to the severe lung inflammation in chronic TB.
The third finding that really surprised us was that T cells accumulating in the lungs of STIM1-deficient mice produced large amounts of a protein called interferon gamma. While interferon gamma is required to control Mycobacterium tuberculosis, it is also a very potent promoter of inflammation and too much of it can lead to tissue damage. Dr. Feske and colleagues had previously observed that calcium fluxes promote the production of interferon gamma in T cells cultured in vitro and we expected the STIM1-deficient T cells to be defective in the production of that protein. During chronic TB, however, calcium signaling turned out to be not only dispensable for the production of interferon gamma by T cells but it was actually required to limit its production and thus, to control inflammation.
MedicalResearch: What should clinicians and patients take away from your report?
Dr. Desvignes: Our research is primarily aimed at understanding the fundamental mechanisms of how calcium channels regulate the immune response to chronic inflammation and infections, and we think that our findings may help other scientists to develop new drugs and vaccines that improve immune responses to infections. Of course, we hope that this study helps clinicians understand, and maybe treat, the infectious diseases observed in those rare patients with mutations in STIM1 and ORAI1.
From a drug discovery perspective, it is important to note that several pharmaceutical companies are currently exploring applications for calcium channel blockers, for instance in the treatment of autoimmune or inflammatory diseases, like Multiple Sclerosis, psoriasis or chronic obstructive pulmonary disease (COPD). Inhibition of calcium channels is an effective strategy to suppress certain forms of inflammation. Based on our results, inhibition of calcium channels may however suppress important immune regulatory mechanisms that are required to prevent an overwhelming immune response. During chronic or latent infections such as TB, hepatitis or with herpes viruses, constant triggering of the immune system, without appropriate shutdown mechanisms when calcium channels are inhibited, could result in harmful inflammation.
MedicalResearch: What recommendations do you have for future research as a result of this study?
Dr. Desvignes: There are pressing and exciting avenues that should be explored as a direct follow up to our study. For example, we have experimental evidence that inhibition of calcium channels, by genetic deletion or pharmacological inhibition of STIM1 or ORAI1 proteins, prevents the development of T cell-mediated autoimmune diseases such as Multiple Sclerosis and Crohn’s disease in mice. To assess the safety of calcium channel inhibition in patients with these diseases, it will be necessary to test if the degree of inhibition required for treatment increases the risk of reactivating latent or chronic infections such as TB.
TB remains a global health issue and we are in dire need of a new, more efficacious vaccine. In this respect, our study serves as a cautionary tale and provides ideas to develop better vaccines. For example, a vaccine preparation that would induce large amounts of interferon gamma may seem like a good idea to control Mycobacterium tuberculosis but it could result in uncontrolled, harmful inflammation, and even fuel the infection. Now that we understand better some of the players and the mechanisms of the immune response to TB, we can target specific elements of the immune response that will help fight the infection while limiting its deleterious effects.