Alissa C. Rothchild

The Rothchild laboratory studies the innate sentinel response by alveolar macrophages to Mycobacterium tuberculosis (Mtb) infection. Positioned at the pulmonary mucosal barrier, alveolar macrophages are often the first cells to take up inhaled pathogens. In this role, alveolar macrophages must rapidly sense foreign pathogens and alert other immune cells to assist in host defense. Our laboratory has a number of different ongoing projects to study the role of alveolar macrophages during infection.

Alveolar macrophages as innate sentinels to Mycobacterium tuberculosis

Alveolar macrophages play a critical role during Mycobacterium tuberculosis (Mtb) infection. Mtb is a respiratory pathogen that kills almost 1.5 million people each year and is one the leading cause of infection-related death worldwide. Alveolar macrophages are the very first cell to become infected after aerosol transmission and remain the dominant cell type infected through the first 10 days. Therefore, the speed and quality of the alveolar macrophage innate response influence later stages of disease and ultimately disease outcome.

Alveolar macrophage regulation by NRF2

We have found that alveolar macrophages initially respond to Mtb in a non-inflammatory manner, which is dependent on expression of the transcription factor NRF2. NRF2 is a master regulator for an antioxidant/oxidative stress response that regulates pathways such as glutathione metabolism and antioxidant production. Mtb-infected cells must eventually initiate innate cell recruitment and priming of the adaptive response, and the molecular basis for these events remains poorly understood. Using NRF2 conditional knock-out strains and NRF2 chemical agonists and antagonists, we aim to characterize how the early induction of a cell protective program by NRF2 prevents alveolar macrophages from mounting a pro-inflammatory response to Mtb infection, delaying subsequent immune events, and leading to impaired bacterial control.

Activation of alveolar macrophages by PAMPs and systemic inflammatory signals

We are also interested in understanding how alveolar macrophages serve as innate sensors, recognizing Pathogen Associated Molecular Patterns (PAMPs) from direct infection, and as inflammatory mediators, responding to inflammatory signals in the environment derived from other responding cells. We would like to know how these different roles help alveolar macrophages to maintain pulmonary homeostasis, allowing for sufficient immune responses to infection while preventing unnecessary pathology and lung damage. We are interested in understanding how the source of alveolar macrophages (fetal-liver derived versus monocyte-derived) alters the phenotype and function of these cells.

Alveolar macrophage remodeling by vaccination and prior infection

We are interrogating how different inflammatory environments alter the response of alveolar macrophages and the characteristics of their plasticity, using BCG vaccination and a murine model of contained Mtb infection. Which inflammatory signals are responsible for alveolar macrophage remodeling? How durable are those changes? What are the consequences for the host response? Working with collaborators, we are performing cross-species analyses to understand what is shared and what is unique about murine and human alveolar macrophage responses. These studies are part of the Cascade IMPAc-TB (Immune Mechanisms of Protection Against Mycobacterium tuberculosis) consortium, studying effective host immune responses across small animal models, non-human primates, and human cohorts in order to develop better vaccines and host-directed therapies.