- Pediatric Infectious Diseases
Assistant Professor, Pediatrics - Infectious Diseases
Honors & Awards
Basic Science Research Faculty Award - Early Career, Stanford Department of Pediatrics (2022)
K08 Mentored Clinical Scientist Career Development Award, NIAID (2019)
Alpha-Omega-Alpha Postgraduate Fellowship, AOA Honor Medical Society (2017)
PIDS Stanley A. Plotkin Sanofi Pasteur Fellowship, Pediatric Infectious Diseases Society (2016)
Ernest and Amelia Gallo Endowed Postdoctoral Fellowship, Maternal and Child Health Research Institute (2015)
Consulting Fellow Teaching Award, Stanford University Pediatrics Residency Program (2015)
Letter of Teaching Distinction in Pediatrics Clerkship, Stanford University School of Medicine (2012)
Board Certification, American Board of Pediatrics, Pediatric Infectious Diseases (2017)
Board Certification, American Board of Pediatrics, General Pediatrics (2014)
Fellowship: Lucile Packard Children's Hospital at Stanford University Medical Center (2017) CA
Residency, Stanford University School of Medicine, Pediatrics (2014)
M.D., University of California, San Francisco, Medicine
Ph.D., University of California, San Francisco, Cell Biology/Immunology
B.S., University of California, San Diego, Biochemistry and Cell Biology
Current Research and Scholarly Interests
Uncovering mechanisms of tissue immunity and immunophysiology during persistent infection
The immune system safeguards the health of complex organisms by rapidly eliminating invading pathogens, curbing infection-induced tissue disruptions, and maintaining tissue homeostasis. Many bacterial pathogens evade host antimicrobial mechanisms and persist in infected tissues at low levels for long periods of time even in the presence of innate and adaptive immune resistance. During persistent infection, the immune system simultaneously orchestrates antimicrobial responses to contain the pathogen, repairs damaged tissue, regulates nutrient resources, and maintains other tissue physiologic functions to ensure host survival. Failure of any of these tasks leads to uncontrolled infection, devastating disease, and even death. The goals of our research are to understand:
1)What are the innate and adaptive immune cellular mechanisms that contain pathogens during persistent infection?
2)How are tissue physiological functions, such as tissue repair and nutrient regulation, maintained during persistent infection?
3)How do pathogens survive innate and adaptive antimicrobial mechanisms in infected tissues?
4)How does persistent infection impact host immunity to secondary infections of a similar or different pathogen?
Through investigating these fundamental questions, we may be able to decode the underlying cellular and molecular mechanisms that can be harnessed to eradicate infections and help restore health after an infectious insult.
Current areas of research:
•Development, maintenance, and plasticity of macrophage functional diversity in infected tissue
•Tissue repair and nutrient regulation during persistent infection
•Cellular dynamics and bacterial persistence in lymphoid organs
We are looking for highly motivated individuals who are passionate about making impactful scientific discoveries to join our team at all levels. Interested undergraduate, graduate, and medical students, postdocs, clinical trainees, and life science research associates, please send your CV and cover letter to email@example.com!
Turning foes into permissive hosts: manipulation of macrophage polarization by intracellular bacteria.
Current opinion in immunology
2023; 84: 102367
Macrophages function as tissue-immune sentinels and mediate key antimicrobial responses against bacterial pathogens. Yet, they can also act as a cellular niche for intracellular bacteria, such as Salmonella enterica, to persist in infected tissues. Macrophages exhibit heterogeneous activation or polarization, states that are linked to differential antibacterial responses and bacteria permissiveness. Remarkably, recent studies demonstrate that Salmonella and other intracellular bacteria inject virulence effectors into the cellular cytoplasm to skew the macrophage polarization state and reprogram these immune cells into a permissive niche. Here, we review mechanisms of macrophage reprogramming by Salmonella and highlight manipulation of macrophage polarization as a shared bacterial pathogenesis strategy. In addition, we discuss how the interplay of bacterial effector mechanisms, microenvironmental signals, and ontogeny may shape macrophage cell states and functions. Finally, we propose ideas of how further research will advance our understanding of macrophage functional diversity and immunobiology.
View details for DOI 10.1016/j.coi.2023.102367
View details for PubMedID 37437470
Single-cell profiling identifies ACE+ granuloma macrophages as a nonpermissive niche for intracellular bacteria during persistent Salmonella infection.
2023; 9 (1): eadd4333
Macrophages mediate key antimicrobial responses against intracellular bacterial pathogens, such as Salmonella enterica. Yet, they can also act as a permissive niche for these pathogens to persist in infected tissues within granulomas, which are immunological structures composed of macrophages and other immune cells. We apply single-cell transcriptomics to investigate macrophage functional diversity during persistent S. enterica serovar Typhimurium (STm) infection in mice. We identify determinants of macrophage heterogeneity in infected spleens and describe populations of distinct phenotypes, functional programming, and spatial localization. Using an STm mutant with impaired ability to polarize macrophage phenotypes, we find that angiotensin-converting enzyme (ACE) defines a granuloma macrophage population that is nonpermissive for intracellular bacteria, and their abundance anticorrelates with tissue bacterial burden. Disruption of pathogen control by neutralizing TNF is linked to preferential depletion of ACE+ macrophages in infected tissues. Thus, ACE+ macrophages have limited capacity to serve as cellular niche for intracellular bacteria to establish persistent infection.
View details for DOI 10.1126/sciadv.add4333
View details for PubMedID 36608122
- Near-fatal Legionella pneumonia in a neonate linked to home humidifier by metagenomic next generation sequencing. Med (New York, N.Y.) 2022
A Salmonella Typhi RNA thermosensor regulates virulence factors and innate immune evasion in response to host temperature.
2021; 17 (3): e1009345
Sensing and responding to environmental signals is critical for bacterial pathogens to successfully infect and persist within hosts. Many bacterial pathogens sense temperature as an indication they have entered a new host and must alter their virulence factor expression to evade immune detection. Using secondary structure prediction, we identified an RNA thermosensor (RNAT) in the 5' untranslated region (UTR) of tviA encoded by the typhoid fever-causing bacterium Salmonella enterica serovar Typhi (S. Typhi). Importantly, tviA is a transcriptional regulator of the critical virulence factors Vi capsule, flagellin, and type III secretion system-1 expression. By introducing point mutations to alter the mRNA secondary structure, we demonstrate that the 5' UTR of tviA contains a functional RNAT using in vitro expression, structure probing, and ribosome binding methods. Mutational inhibition of the RNAT in S. Typhi causes aberrant virulence factor expression, leading to enhanced innate immune responses during infection. In conclusion, we show that S. Typhi regulates virulence factor expression through an RNAT in the 5' UTR of tviA. Our findings demonstrate that limiting inflammation through RNAT-dependent regulation in response to host body temperature is important for S. Typhi's "stealthy" pathogenesis.
View details for DOI 10.1371/journal.ppat.1009345
View details for PubMedID 33651854
Salmonella-Driven Polarization of Granuloma Macrophages Antagonizes TNF-Mediated Pathogen Restriction during Persistent Infection.
Cell host & microbe
Many intracellular bacteria can establish chronic infection and persist in tissues within granulomas composed of macrophages. Granuloma macrophages exhibit heterogeneous polarization states, or phenotypes, that may be functionally distinct. Here, we elucidate a host-pathogen interaction that controls granuloma macrophage polarization and long-term pathogen persistence during Salmonella Typhimurium (STm) infection. We show that STm persists within splenic granulomas that are densely populated by CD11b+CD11c+Ly6C+ macrophages. STm preferentially persists in granuloma macrophages reprogrammed to an M2 state, in part through the activity of the effector SteE, which contributes to the establishment of persistent infection. We demonstrate that tumor necrosis factor (TNF) signaling limits M2 granuloma macrophage polarization, thereby restricting STm persistence. TNF neutralization shifts granuloma macrophages toward an M2 state and increases bacterial persistence, and these effects are partially dependent on SteE activity. Thus, manipulating granuloma macrophage polarization represents a strategy for intracellular bacteria to overcome host restriction during persistent infection.
View details for DOI 10.1016/j.chom.2019.11.011
View details for PubMedID 31883922
Salmonella Effector SteE Converts the Mammalian Serine/Threonine Kinase GSK3 into a Tyrosine Kinase to Direct Macrophage Polarization.
Cell host & microbe
Many Gram-negative bacterial pathogens antagonize anti-bacterial immunity through translocated effector proteins that inhibit pro-inflammatory signaling. Inaddition, the intracellular pathogen Salmonella enterica serovar Typhimurium initiates an anti-inflammatorytranscriptional response in macrophages through its effector protein SteE. However, the target(s) and molecular mechanism of SteE remain unknown. Here, we demonstrate that SteE converts both the amino acid and substrate specificity of the host pleiotropic serine/threonine kinase GSK3. SteE itself is a substrate of GSK3, and phosphorylationof SteE is required for its activity. Remarkably, phosphorylated SteE then forces GSK3 to phosphorylate the non-canonical substrate signal transducer and activator of transcription 3 (STAT3) on tyrosine-705. This results in STAT3 activation, which along with GSK3 is required for SteE-mediated upregulation of the anti-inflammatory M2 macrophage marker interleukin-4Ralpha (IL-4Ralpha). Overall, the conversion of GSK3 to a tyrosine-directed kinase representsa tightly regulated event that enables a bacterial virulence protein to reprogram innate immune signaling and establish an anti-inflammatory environment.
View details for DOI 10.1016/j.chom.2019.11.002
View details for PubMedID 31862381
A Gut Commensal-Produced Metabolite Mediates Colonization Resistance to Salmonella Infection.
Cell host & microbe
The intestinal microbiota provides colonization resistance against pathogens, limiting pathogen expansion and transmission. These microbiota-mediated mechanisms were previously identified by observing loss of colonization resistance after antibiotic treatment or dietary changes, which severely disrupt microbiota communities. We identify a microbiota-mediated mechanism of colonization resistance against Salmonella enterica serovar Typhimurium (S. Typhimurium) by comparing high-complexity commensal communities with different levels of colonization resistance. Using inbred mouse strains with different infection dynamics and S. Typhimurium intestinal burdens, we demonstrate that Bacteroides species mediate colonization resistance against S. Typhimurium by producing the short-chain fatty acid propionate. Propionate directly inhibits pathogen growth invitro by disrupting intracellular pH homeostasis, and chemically increasing intestinal propionate levels protects mice from S.Typhimurium. In addition, administering susceptible mice Bacteroides, but not a propionate-production mutant, confers resistance to S. Typhimurium. This work provides mechanistic understanding into the role of individualized microbial communities in host-to-host variability of pathogen transmission.
View details for PubMedID 30057174
Well-Appearing Newborn With a Vesiculobullous Rash at Birth.
A term, appropriate-for-gestational-age, male infant born via normal spontaneous vaginal delivery presented at birth with a full-body erythematous, vesiculobullous rash. He was well-appearing with normal vital signs and hypoglycemia that quickly resolved. His father had a history of herpes labialis. His mother had an episode of herpes zoster during pregnancy and a prolonged rupture of membranes that was adequately treated. The patient underwent a sepsis workup, including 2 attempted but unsuccessful lumbar punctures, and was started on broad-spectrum antibiotics and acyclovir, given concerns about bacterial or viral infection. The rash evolved over the course of several days. Subsequent workup, with particular attention to his history and presentation, led to his diagnosis.
View details for PubMedID 29437933
Pseudogenization of the Secreted Effector Gene sseI Confers Rapid Systemic Dissemination of S. Typhimurium ST313 within Migratory Dendritic Cells.
Cell host & microbe
2017; 21 (2): 182-194
Genome degradation correlates with host adaptation and systemic disease in Salmonella. Most lineages of the S. enterica subspecies Typhimurium cause gastroenteritis in humans; however, the recently emerged ST313 lineage II pathovar commonly causes systemic bacteremia in sub-Saharan Africa. ST313 lineage II displays genome degradation compared to gastroenteritis-associated lineages; yet, the mechanisms and causal genetic differences mediating these infection phenotypes are largely unknown. We find that the ST313 isolate D23580 hyperdisseminates from the gut to systemic sites, such as the mesenteric lymph nodes (MLNs), via CD11b(+) migratory dendritic cells (DCs). This hyperdissemination was facilitated by the loss of sseI, which encodes an effector that inhibits DC migration in gastroenteritis-associated isolates. Expressing functional SseI in D23580 reduced the number of infected migratory DCs and bacteria in the MLN. Our study reveals a mechanism linking pseudogenization of effectors with the evolution of niche adaptation in a bacterial pathogen.
View details for DOI 10.1016/j.chom.2017.01.009
View details for PubMedID 28182950
View details for PubMedCentralID PMC5325708
DOCK8 is essential for T-cell survival and the maintenance of CD8(+) T-cell memory
EUROPEAN JOURNAL OF IMMUNOLOGY
2011; 41 (12): 3423-3435
Deficiency in the guanine nucleotide exchange factor dedicator of cytokinesis 8 (DOCK8) causes a human immunodeficiency syndrome associated with recurrent sinopulmonary and viral infections. We have recently identified a DOCK8-deficient mouse strain, carrying an ethylnitrosourea-induced splice-site mutation that shows a failure to mature a humoral immune response due to the loss of germinal centre B cells. In this study, we turned to T-cell immunity to investigate further the human immunodeficiency syndrome and its association with decreased peripheral CD4(+) and CD8(+) T cells. Characterisation of the DOCK8-deficient mouse revealed T-cell lymphopenia, with increased T-cell turnover and decreased survival. Egress of mature CD4(+) thymocytes was reduced with increased migration of these cells to the chemokine CXCL12. However, despite the two-fold reduction in peripheral naïve T cells, the DOCK8-deficient mice generated a normal primary CD8(+) immune response and were able to survive acute influenza virus infection. The limiting effect of DOCK8 was in the normal survival of CD8(+) memory T cells after infection. These findings help to explain why DOCK8-deficient patients are susceptible to recurrent infections and provide new insights into how T-cell memory is sustained.
View details for DOI 10.1002/eji.201141759
View details for Web of Science ID 000297465000009
View details for PubMedID 21969276
GRK2-Dependent S1PR1 Desensitization Is Required for Lymphocytes to Overcome Their Attraction to Blood
2011; 333 (6051): 1898-1903
Lymphocytes egress from lymphoid organs in response to sphingosine-1-phosphate (S1P); minutes later they migrate from blood into tissue against the S1P gradient. The mechanisms facilitating cell movement against the gradient have not been defined. Here, we show that heterotrimeric guanine nucleotide-binding protein-coupled receptor kinase-2 (GRK2) functions in down-regulation of S1P receptor-1 (S1PR1) on blood-exposed lymphocytes. T and B cell movement from blood into lymph nodes is reduced in the absence of GRK2 but is restored in S1P-deficient mice. In the spleen, B cell movement between the blood-rich marginal zone and follicles is disrupted by GRK2 deficiency and by mutation of an S1PR1 desensitization motif. Moreover, delivery of systemic antigen into follicles is impaired. Thus, GRK2-dependent S1PR1 desensitization allows lymphocytes to escape circulatory fluids and migrate into lymphoid tissues.
View details for DOI 10.1126/science.1208248
View details for Web of Science ID 000295365800059
View details for PubMedID 21960637
View details for PubMedCentralID PMC3267326
Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning
JOURNAL OF EXPERIMENTAL MEDICINE
2010; 207 (1): 17-27
Lymphocyte egress from lymph nodes (LNs) is dependent on sphingosine-1-phosphate (S1P), but the cellular source of this S1P is not defined. We generated mice that expressed Cre from the lymphatic vessel endothelial hyaluronan receptor 1 (Lyve-1) locus and that showed efficient recombination of loxP-flanked genes in lymphatic endothelium. We report that mice with Lyve-1 CRE-mediated ablation of sphingosine kinase (Sphk) 1 and lacking Sphk2 have a loss of S1P in lymph while maintaining normal plasma S1P. In Lyve-1 Cre+ Sphk-deficient mice, lymphocyte egress from LNs and Peyer's patches is blocked. Treatment with pertussis toxin to overcome Galphai-mediated retention signals restores lymphocyte egress. Furthermore, in the absence of lymphatic Sphks, the initial lymphatic vessels in nonlymphoid tissues show an irregular morphology and a less organized vascular endothelial cadherin distribution at cell-cell junctions. Our data provide evidence that lymphatic endothelial cells are an in vivo source of S1P required for lymphocyte egress from LNs and Peyer's patches, and suggest a role for S1P in lymphatic vessel maturation.
View details for DOI 10.1084/jem.20091619
View details for Web of Science ID 000273690800003
View details for PubMedID 20026661
View details for PubMedCentralID PMC2812554
Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice
JOURNAL OF CLINICAL INVESTIGATION
2009; 119 (7): 1871-1879
Maintenance of vascular integrity is critical for homeostasis, and temporally and spatially regulated vascular leak is a central feature of inflammation. Sphingosine-1-phosphate (S1P) can regulate endothelial barrier function, but the sources of the S1P that provide this activity in vivo and its importance in modulating different inflammatory responses are unknown. We report here that mutant mice engineered to selectively lack S1P in plasma displayed increased vascular leak and impaired survival after anaphylaxis, administration of platelet-activating factor (PAF) or histamine, and exposure to related inflammatory challenges. Increased leak was associated with increased interendothelial cell gaps in venules and was reversed by transfusion with wild-type erythrocytes (which restored plasma S1P levels) and by acute treatment with an agonist for the S1P receptor 1 (S1pr1). S1pr1 agonist did not protect wild-type mice from PAF-induced leak, consistent with plasma S1P levels being sufficient for S1pr1 activation in wild-type mice. However, an agonist for another endothelial cell Gi-coupled receptor, Par2, did protect wild-type mice from PAF-induced vascular leak, and systemic treatment with pertussis toxin prevented rescue by Par2 agonist and sensitized wild-type mice to leak-inducing stimuli in a manner that resembled the loss of plasma S1P. Our results suggest that the blood communicates with blood vessels via plasma S1P to maintain vascular integrity and regulate vascular leak. This pathway prevents lethal responses to leak-inducing mediators in mouse models.
View details for DOI 10.1172/JCI38575
View details for Web of Science ID 000267694300016
View details for PubMedID 19603543
Cortical sinus probing, S1P(1)-dependent entry and flow-based capture of egressing T cells
2009; 10 (1): 58-65
The cellular dynamics of the egress of lymphocytes from lymph nodes are poorly defined. Here we visualized the branched organization of lymph node cortical sinuses and found that after entry, some T cells were retained, whereas others returned to the parenchyma. T cells deficient in sphingosine 1-phosphate receptor type 1 probed the sinus surface but failed to enter the sinuses. In some sinuses, T cells became rounded and moved unidirectionally. T cells traveled from cortical sinuses into macrophage-rich sinus areas. Many T cells flowed from medullary sinuses into the subcapsular space. We propose a multistep model of lymph node egress in which cortical sinus probing is followed by entry dependent on sphingosine 1-phosphate receptor type 1, capture of cells in a sinus region with flow, and transport to medullary sinuses and the efferent lymph.
View details for DOI 10.1038/ni.1682
View details for Web of Science ID 000261788800012
View details for PubMedID 19060900
S1P(1) receptor signaling overrides retention mediated by G alpha(i)-coupled receptors to promote T cell egress
2008; 28 (1): 122-133
The mechanism by which sphingosine-1-phosphate receptor-1 (S1P1) acts to promote lymphocyte egress from lymphoid organs is not defined. Here, we showed that CCR7-deficient T cells left lymph nodes more rapidly than wild-type cells did, whereas CCR7-overexpressing cells were retained for longer. After treatment with FTY720, an agonist that causes downmodulation of lymphocyte S1P1, CCR7-deficient T cells were less effectively retained than wild-type T cells. Moreover, treatment with pertussis toxin to inactivate signaling via G alpha i-protein-coupled receptors restored egress competence to S1P1-deficient lymphocytes. We also found that T cell accumulation in lymph node cortical sinusoids required intrinsic S1P1 expression and was antagonized by CCR7. These findings suggest a model where S1P1 acts in the lymphocyte to promote lymph node egress by overcoming retention signals mediated by CCR7 and additional G alpha i-coupled receptors. Furthermore, by simultaneously upregulating S1P1 and downregulating CCR7, T cells that have divided multiple times switch to a state favoring egress over retention.
View details for DOI 10.1016/j.immuni.2007.11.017
View details for Web of Science ID 000252627300016
View details for PubMedID 18164221
View details for PubMedCentralID PMC2691390
Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell-mediated innate resistance to cytomegalovirus infection
2005; 37 (6): 593-599
Experimental infection with mouse cytomegalovirus (MCMV) has been used to elucidate the intricate host-pathogen mechanisms that determine innate resistance to infection. Linkage analyses in F(2) progeny from MCMV-resistant MA/My (H2 (k)) and MCMV-susceptible BALB/c (H2 (d)) and BALB.K (H2 (k)) mouse strains indicated that only the combination of alleles encoded by a gene in the Klra (also called Ly49) cluster on chromosome 6, and one in the major histocompatibility complex (H2) on chromosome 17, is associated with virus resistance. We found that natural killer cell-activating receptor Ly49P specifically recognized MCMV-infected cells, dependent on the presence of the H2 (k) haplotype. This binding was blocked using antibodies to H-2D(k) but not antibodies to H-2K(k). These results are suggestive of a new natural killer cell mechanism implicated in MCMV resistance, which depends on the functional interaction of the Ly49P receptor and the major histocompatibility complex class I molecule H-2D(k) on MCMV-infected cells.
View details for DOI 10.1038/ng1564
View details for Web of Science ID 000229495300012
View details for PubMedID 15895081