Connie received her B.S. in Microbiology, Immunology, and Molecular Genetics from UCLA, where she conducted research on how the eukaryotic parasite Toxoplasma gondii invades and replicates inside host cells in the lab of Dr. Peter Bradley. Subsequently, she obtained her Ph.D. in Microbiology & Immunology from Stanford University with Dr. Manuel Amieva. Her thesis research involved the use of high-resolution microscopy to study how the bacterium Helicobacter pylori establishes and maintains persistent colonization of the gastric epithelium. Connie joined Dr. Michael Howitt's lab as a postdoctoral research fellow in 2019 and is currently investigating how tuft cells, specialized taste-chemosensory cells, modulate epithelial cell function and mucosal immunity in response to intestinal parasites and commensals.
Honors & Awards
A.P. Giannini Foundation Postdoctoral Research Fellowship, A.P. Giannini Foundation (2021-2024)
Maternal & Child Health Research Institute Postdoctoral Fellowship, Stanford School of Medicine (2021)
Dean's Postdoctoral Fellowship, Stanford School of Medicine (2020)
Office of Graduate Education Travel Grant, Stanford School of Medicine (2016, 2017)
NSF Graduate Research Fellowship, National Science Foundation (2014-2017)
Stanford Graduate Fellowship, Stanford University (2012-2017)
Doctor of Philosophy, Stanford University, Microbiology & Immunology (2019)
Bachelor of Science, University of California, Los Angeles, Microbiology, Immunology, and Molecular Genetics (2012)
Tuft cells mediate commensal remodeling of the small intestinal antimicrobial landscape.
Proceedings of the National Academy of Sciences of the United States of America
2023; 120 (23): e2216908120
Succinate produced by the commensal protist Tritrichomonas musculis (T. mu) stimulates chemosensory tuft cells, resulting in intestinal type 2 immunity. Tuft cells express the succinate receptor SUCNR1, yet this receptor does not mediate antihelminth immunity nor alter protist colonization. Here, we report that microbial-derived succinate increases Paneth cell numbers and profoundly alters the antimicrobial peptide (AMP) landscape in the small intestine. Succinate was sufficient to drive this epithelial remodeling, but not in mice lacking tuft cell chemosensory components required to detect this metabolite. Tuft cells respond to succinate by stimulating type 2 immunity, leading to interleukin-13-mediated epithelial and AMP expression changes. Moreover, type 2 immunity decreases the total number of mucosa-associated bacteria and alters the small intestinal microbiota composition. Finally, tuft cells can detect short-term bacterial dysbiosis that leads to a spike in luminal succinate levels and modulate AMP production in response. These findings demonstrate that a single metabolite produced by commensals can markedly shift the intestinal AMP profile and suggest that tuft cells utilize SUCNR1 and succinate sensing to modulate bacterial homeostasis.
View details for DOI 10.1073/pnas.2216908120
View details for PubMedID 37253002
Tuft cell-derived acetylcholine regulates epithelial fluid secretion.
bioRxiv : the preprint server for biology
Tuft cells are solitary chemosensory epithelial cells that can sense lumenal stimuli at mucosal barriers and secrete effector molecules to regulate the physiology and immune state of their surrounding tissue. In the small intestine, tuft cells detect parasitic worms (helminths) and microbe-derived succinate, and signal to immune cells to trigger a Type 2 immune response that leads to extensive epithelial remodeling spanning several days. Acetylcholine (ACh) from airway tuft cells has been shown to stimulate acute changes in breathing and mucocilliary clearance, but its function in the intestine is unknown. Here we show that tuft cell chemosensing in the intestine leads to release of ACh, but that this does not contribute to immune cell activation or associated tissue remodeling. Instead, tuft cell-derived ACh triggers immediate fluid secretion from neighboring epithelial cells into the intestinal lumen. This tuft cell-regulated fluid secretion is amplified during Type 2 inflammation, and helminth clearance is delayed in mice lacking tuft cell ACh. The coupling of the chemosensory function of tuft cells with fluid secretion creates an epithelium-intrinsic response unit that effects a physiological change within seconds of activation. This response mechanism is shared by tuft cells across tissues, and serves to regulate the epithelial secretion that is both a hallmark of Type 2 immunity and an essential component of homeostatic maintenance at mucosal barriers.
View details for DOI 10.1101/2023.03.17.533208
View details for PubMedID 36993541
View details for PubMedCentralID PMC10055254
An infection-induced oxidation site regulates legumain processing and tumor growth.
Nature chemical biology
Oxidative stress is a defining feature of most cancers, including those that stem from carcinogenic infections. Reactive oxygen species can drive tumor formation, yet the molecular oxidation events that contribute to tumorigenesis are largely unknown. Here we show that inactivation of a single, redox-sensitive cysteine in the host protease legumain, which is oxidized during infection with the gastric cancer-causing bacterium Helicobacter pylori, accelerates tumor growth. By using chemical proteomics to map cysteine reactivity in human gastric cells, we determined that H. pylori infection induces oxidation of legumain at Cys219. Legumain oxidation dysregulates intracellular legumain processing and decreases the activity of the enzyme in H. pylori-infected cells. We further show that the site-specific loss of Cys219 reactivity increases tumor growth and mortality in a xenograft model. Our findings establish a link between an infection-induced oxidation site and tumorigenesis while underscoring the importance of cysteine reactivity in tumor growth.
View details for DOI 10.1038/s41589-022-00992-x
View details for PubMedID 35332331
A Tuft Act to Follow: Leukotrienes Take the Stage in Anti-worm Immunity.
2020; 52 (3): 426–28
Tuft cells are specialized taste-chemosensory cells that detect the presence of intestinal parasites and orchestrate type 2 immunity. In this issue of Immunity, McGinty et al. discover that parasitic worms, but not commensal protists, stimulate tuft cells to release cysteinyl leukotrienes to amplify anti-helminth immunity in the small intestine.
View details for DOI 10.1016/j.immuni.2020.02.011
View details for PubMedID 32187512
High-resolution mapping reveals that microniches in the gastric glands control Helicobacter pylori colonization of the stomach.
2019; 17 (5): e3000231
Lifelong infection of the gastric mucosa by Helicobacter pylori can lead to peptic ulcers and gastric cancer. However, how the bacteria maintain chronic colonization in the face of constant mucus and epithelial cell turnover in the stomach is unclear. Here, we present a new model of how H. pylori establish and persist in stomach, which involves the colonization of a specialized microenvironment, or microniche, deep in the gastric glands. Using quantitative three-dimensional (3D) confocal microscopy and passive CLARITY technique (PACT), which renders tissues optically transparent, we analyzed intact stomachs from mice infected with a mixture of isogenic, fluorescent H. pylori strains with unprecedented spatial resolution. We discovered that a small number of bacterial founders initially establish colonies deep in the gastric glands and then expand to colonize adjacent glands, forming clonal population islands that persist over time. Gland-associated populations do not intermix with free-swimming bacteria in the surface mucus, and they compete for space and prevent newcomers from establishing in the stomach. Furthermore, bacterial mutants deficient in gland colonization are outcompeted by wild-type (WT) bacteria. Finally, we found that host factors such as the age at infection and T-cell responses control bacterial density within the glands. Collectively, our results demonstrate that microniches in the gastric glands house a persistent H. pylori reservoir, which we propose replenishes the more transient bacterial populations in the superficial mucosa.
View details for PubMedID 31048876
A Toxoplasma Palmitoyl Acyl Transferase and the Palmitoylated Armadillo Repeat Protein TgARO Govern Apical Rhoptry Tethering and Reveal a Critical Role for the Rhoptries in Host Cell Invasion but Not Egress
2013; 9 (2)
Apicomplexans are obligate intracellular parasites that actively penetrate their host cells to create an intracellular niche for replication. Commitment to invasion is thought to be mediated by the rhoptries, specialized apical secretory organelles that inject a protein complex into the host cell to form a tight-junction for parasite entry. Little is known about the molecular factors that govern rhoptry biogenesis, their subcellular organization at the apical end of the parasite and subsequent release of this organelle during invasion. We have identified a Toxoplasma palmitoyl acyltransferase, TgDHHC7, which localizes to the rhoptries. Strikingly, conditional knockdown of TgDHHC7 results in dispersed rhoptries that fail to organize at the apical end of the parasite and are instead scattered throughout the cell. While the morphology and content of these rhoptries appears normal, failure to tether at the apex results in a complete block in host cell invasion. In contrast, attachment and egress are unaffected in the knockdown, demonstrating that the rhoptries are not required for these processes. We show that rhoptry targeting of TgDHHC7 requires a short, highly conserved C-terminal region while a large, divergent N-terminal domain is dispensable for both targeting and function. Additionally, a point mutant lacking a key residue predicted to be critical for enzyme activity fails to rescue apical rhoptry tethering, strongly suggesting that tethering of the organelle is dependent upon TgDHHC7 palmitoylation activity. We tie the importance of this activity to the palmitoylated Armadillo Repeats-Only (TgARO) rhoptry protein by showing that conditional knockdown of TgARO recapitulates the dispersed rhoptry phenotype of TgDHHC7 knockdown. The unexpected finding that apicomplexans have exploited protein palmitoylation for apical organelle tethering yields new insight into the biogenesis and function of rhoptries and may provide new avenues for therapeutic intervention against Toxoplasma and related apicomplexan parasites.
View details for DOI 10.1371/journal.ppat.1003162
View details for Web of Science ID 000315648900016
View details for PubMedID 23408890
View details for PubMedCentralID PMC3567180
Toxoplasma ISP4 is a central IMC Sub-compartment Protein whose localization depends on palmitoylation but not myristoylation
MOLECULAR AND BIOCHEMICAL PARASITOLOGY
2012; 184 (2): 99-108
Apicomplexan parasites utilize a peripheral membrane system called the inner membrane complex (IMC) to facilitate host cell invasion and parasite replication. We recently identified a novel family of Toxoplasma IMC Sub-compartment Proteins (ISP1/2/3) that localize to sub-domains of the IMC using a targeting mechanism that is dependent on coordinated myristoylation and palmitoylation of a series of residues in the N-terminus of the protein. While the precise functions of the ISPs are unknown, deletion of ISP2 results in replication defects, suggesting that this family of proteins plays a role in daughter cell formation. Here we have characterized a fourth ISP family member (ISP4) and discovered that this protein localizes to the central IMC sub-compartment, similar to ISP2. Like ISP1/3, ISP4 is dispensable for the tachyzoite lytic cycle as the disruption of ISP4 does not produce any gross replication or growth defects. Surprisingly, targeting of ISP4 to the IMC membranes is dependent on residues predicted for palmitoylation but not myristoylation, setting its trafficking apart from the other ISP proteins and demonstrating distinct mechanisms of protein localization to the IMC membranes, even within a family of highly related proteins.
View details for DOI 10.1016/j.molbiopara.2012.05.002
View details for Web of Science ID 000306626300005
View details for PubMedID 22659420
View details for PubMedCentralID PMC3383393