Our Projects
Our laboratory uses two evolutionarily related microbes: Chlamydia trachomatis and Akkermansia muciniphila to understanding the molecular mechanisms underlying pathogenesis and commensalism.
Akkermansia
We seek to understand the cell biology of beneficial-host microbe interactions and how microbes like Akkermansia muciniphila impact the function of intestinal epithelial cells and mucosal immunity.
The Genetic Basis of Host Colonization by Akkermansia
We develop genetic tools to study Akkermanisa and apply TnSeq methodologies to identify Akkermansia genes that are required to colonize diverse sites on the GI in germ-free animals and in the context of complex microbiotas and transgenic mouse models.
Molecular Mechanisms of Mucin Utilization by Akkermansia
Akkermansia has adapted to use host mucin as a sole source of carbon, thus allowing it to occupy unique niches within the mammalian gastrointestinal tract. Through genetic approaches we have identified genes required for the transport of host-derived proteoglycans into bacterial intracellular compartments.
The Impact of Natural Diversity of Human Akkermansia On Health and Disease Outcomes
The abundance of Akkermansia in the GI is linked to protection from metabolic diseases, neurological disorders, and improved outcomes after cancer immunotherapies. We survey the diversity and abundance of Akkermansia species among diverse patient populations to draw better association between Akkermansia genes and clinical outcomes.
Methods to Characterize Genetically "Intractable" Microbes
Many of the microbes that associate with vertebrate animals and influence their physiology are not amenable to routine experimentation because of their lack of molecular genetic tools. We develop deep DNA sequencing-based methods and molecular genetic tools to experimentally test the function of genes from interesting members of vertebrate microbiotas.
Chlamydia
We explore the biology of the obligate intracellular bacterial pathogen Chlamydia trachomatis with a focus on its interactions with epithelial surfaces and the molecular basis for the evasion of host defenses
Chlamydia Type III Secreted Effector Proteins
Chlamydia manipulates multiple host cellular functions, including the engagement of anti-bacterial innate immune defenses, by secreting “effector” proteins directly into the host cytoplasm and membranes. We characterize the molecular function of effectors that are delivered early during cell invasion and those secreted later to maintain the Chlamydia inclusion (pathogen-containing vacuole). We study how these effectors are regulated and how they interact with each other to promote bacterial fitness within the host.
Organoid and Mouse Models of Chlamydia Infection
Chlamydia trachomatis has evolved to infect tissues of the conjunctiva and the upper genital tract. We have developed endometrial organoids to mimic the properties and cell diversity of cells and tissues that are targeted by Chlamydia during natural infections. We apply organoids as experimentally tractable systems to explore the cell biology and innate immunity of tissue infections and scRNAseq approaches to understand the dynamics of immune cell infiltration and transcriptional responses during acute infections and what factors lead to the onset of fibrotic disease.
The Cell Biology of Chlamydia Infections
Through a combination of live cell microscopy, molecular and biochemical approaches, we study how Chlamydia exploits the cytoskeleton, signaling pathways and endomembrane transport systems to invade and establish residence within epithelial cells. We are also interested in how Chlamydia reprograms junctional complexes in polarized epithelia, how it manipulates membrane transport to limit innate immune signaling, and inhibits the activation of host-protective cell death pathways.
Maintenance of the Chlamydia-containing Vacuole
Chlamydia goes to great lengths to maintain the integrity of the vacuole in which it resides to escape recognition by cell autonomous antimicrobial defense mechanisms. Multiple proteins on the pathogen vacuoles (inclusion membrane proteins- Incs) regulate membrane trafficking, the cytoskeleton, and cell death pathways to ensure vacuole integrity throughout the Chlamydia infectious cycle. We are interested in identifying the molecular targets of these Incs and how they participate in maintenance of the Chlamydia vacuole and evade the activation of cell death programs