Mycobacterium tuberculosis (Mtb) is a strict human pathogen that has adapted a facultative intracellular lifestyle with, among others, macrophages serving as host cells. The bacterium is able to manipulate the host cell by secreting protein and releasing lipid effectors (Augenstreich and Briken, 2020). The focus of my lab is to discover novel host cell pathways manipulated by Mtb (Shah et al. 2013; Banks et al. 2019) and then to elucidate the molecular mechanisms of this host cell manipulation (Miller et al 2012). A common approach in my lab in order to characterize bacterial factors is to perform genetic screens and we are using the mouse model of tuberculosis in order to study the importance of Mtb genes for virulence of the bacteria (Velmurugan et al. 2007; Srinivasan et al. 2016).

Research Interest 1: How does Mtb manipulate host cell death signaling? 
Mtb, after infection of macrophages, is able to inhibit host cell apoptosis induced by either mitochondria (Mito) or death receptor -mediated pathways (Srinivasan et al, 2014). We identified the Mtb protein NuoG as being important for host cell apoptosis inhibition and that determined that this capacity is important for the full virulence of the bacteria during in vivo infections in the mouse model of tuberculosis (Velmurugan et al. 2007; Miller et al. 2010).
At some point Mtb needs to escape the host cell in order to disseminate and it does so by inducing host cell necrosis, a cell death pathway that leads to the lysis of the cell membrane. We identified a transcription factor (Rv3167c) of Mtb that regulates the cell death inducing capacity of Mtb by repressing transcription of genes important for the cell wall lipid PDIM (Srinivasan et al. 2016; Quigley et al. 2017).

Research Interest 2: How does Mtb inhibit the host cell inflammasome and is it important for virulence of the bacteria?
Pathogen/Danger Associated Molecular Patterns (D/PAMP) can be recognized by cytosolic pattern recognition receptors such as AIM2 and lead to the formation of an active inflammasome complex which induces the maturation and subsequent secretion of the cytokine IL-1b and pyroptotic host cell death (Briken et al. 2013). We identified the capacity of Mtb to inhibit the AIM2 inflammasome complex activation (Shah et al. 2013). In unpublished data we furthermore show that Mtb also inhibits the NLRP3 inflammasome activation. A genetic screen identified the serine/threonine protein kinase gene, PknF, to be important for this capacity of Mtb (Rastogi et al. submitted). 

Research Interest 3: How does Mtb inhibit host cell IFN-b signaling and is it important for virulence of the bacteria?
We discovered the capacity of Mtb to inhibit IFN-b signaling and determined that this inhibition happens upstream of STAT1 in the signal transduction pathway (Banks et al. 2019). Furthermore, we showed that overriding the inhibition by adding higher doses of IFN-b leads to a decreased intracellular growth of Mtb due to the generation of nitric oxide (Banks et al. 2019). We are planning to perform genetic screens and biochemical approaches in order to identify the protein or lipid of Mtb involved in IFN-b signaling inhibition.