Lu Huang, PhD

Tuberculosis (TB) is the leading cause of death from a single infectious disease agent, accounting for around 1.3 million deaths per year worldwide. There is no doubt that a vaccine against TB would be transformative, but progress towards this goal has been painfully slow. My previous work has demonstrated that lung macrophages with distinct developmental origins have different metabolic statuses and exhibit different levels of permissiveness to Mycobacterium tuberculosis (Mtb) survival and growth. While traditional approaches to TB vaccine development have focused on the induction of optimal adaptive immune responses, our data suggest the existence of intrinsic protection against TB mediated by resident lung macrophages, perhaps independent of adaptive responses, and points to experimental strategies for investigating the underlying mechanisms. The unique metabolic activities of AMs and IMs in TB suggest that lung macrophage metabolism can be harnessed to enhance antimicrobial activity. This is in line with the recently described concept of innate memory, also known as trained immunity, where metabolic and epigenetic reprogramming enhance cytokine production and killing capacity in macrophages. Although trained immunity has been studied extensively in hematopoietic stem cells in bone marrow, it remains largely unknown whether it can be induced in tissue-resident innate immune cells. The proposed project aims to investigate whether lung macrophages from distinct lineages can generate equivalent and functional trained immunity, and if so, what are the underlying mechanisms that regulate such responses in lung macrophages? In Year 1, we demonstrated that intranasal inoculation of ß-glucan is capable of inducing trained immunity in lung resident AMs. ß-glucan-trained AMs are more immunologically active and display a higher metabolic fitness. Unexpectedly, we discovered that ß-glucan facilitates the alteration of the AM pool by recruiting monocyte-derived AMs to the lung, which exhibit higher levels of activation and glycolysis compared to trained embryonically-derived AMs. This data is intriguing and further indicates that macrophage origin may be a novel intrinsic factor to regulate trained immunity. Importantly, these alterations induced by ß-glucan lead to an enhanced anti-mycobacterial immunity in the mouse model. Lastly, ß-glucan promotes long-term metabolic reprogramming, not only in mice but also in human AMs, highlighting that trained immunity is conserved in our immune system and could be a promising therapeutic target and a novel vaccine strategy for human TB as well as other pulmonary infections.

Update: The goal of our research is to identify the mechanism that regulates trained immunity against Mycobacterium tuberculosis infection in lung resident macrophages. We discovered that ß-glucan primes lung alveolar macrophages (AMs) and induces trained immunity via metabolic reprogramming. Intriguingly, the induction of trained immunity is associated with newly generated monocyte-derived AMs, which display higher metabolic fitness and activation, implicating a more robust trained immunity in this population. Trained AMs exhibit a higher metabolic fitness in Mtb infection and correlate with a greater control of Mtb growth. Finally, ß-glucan could induce sustained metabolic changes in primary human AMs, indicating established trained immunity in human lung macrophages.