Manuel Amieva, MD, PhD

Interim Division Chief, Pediatric Infectious Diseases | Tashia and John Morgridge Endowed Faculty Scholar in Pediatric Translational Medicine | Professor

Infectious Diseases

Mary L. Johnson Specialty Services
Pediatric Infectious Disease
730 Welch Road, 2nd Fl
Palo Alto, CA 94304

Maps, Directions & Parking
Phone: (650) 721-5805

Locations

Mary L. Johnson Specialty Services
Pediatric Infectious Disease
730 Welch Road, 2nd Fl
Palo Alto, CA 94304
Maps, Directions & Parking
Phone: (650) 721-5805

Services

Infectious Diseases

Work and Education

Professional Education
Stanford University School of Medicine, Palo Alto, CA, 06/01/1997
Residency
Stanford Health Care at Lucile Packard Children's Hospital, Palo Alto, CA, 06/30/1999
Fellowship
Stanford University Pediatric Infectious Disease Fellowship, Stanford, CA, 06/30/2004
Internship
Stanford Health Care at Lucile Packard Children's Hospital, Palo Alto, CA, 06/30/1998
Board Certifications
Pediatric Infectious Diseases, American Board of Pediatrics, 2023

Publications

Accessible homeostatic gastric organoids reveal secondary cell type-specific host-pathogen interactions in Helicobacter pylori infections.

Nature communications
Hofer, M., Kim, Y., Broguiere, N., Gorostidi, F., Klein, J. A., Amieva, M. R., Lutolf, M. P. 2025; 16 (1): 2767

Abstract
Despite the high prevalence of gastric diseases like gastric cancer and peptic ulcer disease attributed to Helicobacter pylori infections, there is still only a limited understanding of the underlying mechanisms. Existing in vitro models are either two-dimensional systems lacking the structural complexity of the gastric architecture, or complex three-dimensional systems that pose challenges for experimental access. In this study, we introduce a patterned homeostatic human gastric organoid-on-a-chip system with bilateral access that is capable of modeling H. pylori niche establishment and persistent colonization of the gastric epithelium. We show that in physiological apical acidic conditions, our organ-on-a-chip can generate pit cells of higher maturity in contrast to traditionally grown organoids. Upon infection with H. pylori for up to 6 days, these mature pit cells exhibit a distinctive response from other cell types, which was previously uncharacterized. Beyond its application in studying H. pylori infection, the increased structural and functional relevance of our model offers broader significance as a versatile platform for advancing our understanding of gastric epithelial cell interactions, gastric mucosal immunity, and host-pathogen interactions.

View details for DOI 10.1038/s41467-025-57131-y
View details for PubMedID 40113752
View details for PubMedCentralID 502139

A spatial transcriptomic signature of 26 genes resolved at single-cell resolution characterizes high-risk gastric cancer precursors.

NPJ precision oncology
Huang, R. J., Wichmann, I. A., Su, A., Sathe, A., Shum, M. V., Grimes, S. M., Meka, R., Almeda, A., Bai, X., Shen, J., Nguyen, Q., Luo, I., Han, S. S., Amieva, M. R., Hwang, J. H., Ji, H. P. 2025; 9 (1): 52

Abstract
Gastric cancer precursors demonstrate highly-variable rates of progression toward neoplasia. Certain high-risk precursors, such as gastric intestinal metaplasia with advanced histologic features, may be at up to 30-fold increased risk for progression compared to lower-risk intestinal metaplasia. The biological differences between high- and low-risk lesions have been incompletely explored. In this study, we use several clinical cohorts to characterize the microenvironment of advanced gastric cancer precursors relative to low-risk lesions using bulk, spatial, and single-cell gene expression assays. We identified a 26-gene panel which is associated with advanced lesions, localizes to metaplastic glands on histopathology, and is expressed in aberrant mature and immature intestinal cells not normally present in the healthy stomach. This gene expression signature suggests an important role of the immature intestinal lineages in promoting carcinogenesis in the metaplastic microenvironment. These findings may help to inform future biomarker development and strategies of gastric cancer prevention.

View details for DOI 10.1038/s41698-025-00816-w
View details for PubMedID 40000871
View details for PubMedCentralID 5879496

The Landscape of Helicobacter pylori-related Gastric Carcinogenesis.

Journal of gastrointestinal and liver diseases : JGLD
Assumpção, P. P., Genta, R. M., Camargo, M. C., Silva, J. M., Amieva, M. R., Rugge, M. 2024; 33 (4): 524-534

Abstract
The relationship between Helicobacter pylori (H. pylori) and humans remains a complex enigma. While other factors contribute to gastric cancer (GC), their impact pales in comparison to the central role of H. pylori. Various cofactors, such as dietary carcinogens and Epstein-Barr virus infection, can lead to GC independently of H. pylori. However, it is likely the combination of mechanisms, especially those driven by H. pylori, that represents the primary force behind GC development. Identifying individuals at high risk of developing H. pylori-related GC or detecting the disease in its earliest stages remains a significant challenge. To address this, we aim to refine the existing gastric carcinogenic model by incorporating molecular data, oncological concepts common to many cancers, and data from innovative experimental approaches. This updated model, applicable to both intestinal and diffuse GC, builds on Pelayo Correa's carcinogenesis pathway while expanding our understanding of H. pylori's role in gastric carcinogenesis. It not only emphasizes the direct cellular effects of H. pylori virulence factors but also integrates underrecognized carcinogenic mechanisms, including the interactions between H. pylori and stem cells, providing a more comprehensive view of H. pylori's contribution. By acknowledging additional molecular drivers in GC and recognizing H. pylori's potential involvement in these processes, this model could offer more precise interpretations of GC development and open new avenues for clinical interventions.

View details for DOI 10.15403/jgld-5959
View details for PubMedID 39733312

Gut regulatory T cells mediate immunological tolerance in Salmonella-infected superspreader hosts.

Di Luccia, B., Massis, L., Ruddle, S., Narasimhan, R., Pham, T., Vilches-Moure, J., Amieva, M. R., Monack, D. M. 2023

Mechanosensitive extrusion of Enterovirus A71-infected cells from colonic organoids.

Nature microbiology
Moshiri, J., Craven, A. R., Mixon, S. B., Amieva, M. R., Kirkegaard, K. 2023

Abstract
Enterovirus A71 causes severe disease upon systemic infection, sometimes leading to life-threatening neurological dysfunction. However, in most cases infection is asymptomatic and limited to the gastrointestinal tract, where virus is amplified for transmission. Picornaviruses have previously been shown to exit infected cells via either cell lysis or secretion of vesicles. Here we report that entire Enterovirus A71-infected cells are specifically extruded from the apical surface of differentiated human colon organoids, as observed by confocal microscopy. Differential sensitivity to chemical and peptide inhibitors demonstrated that extrusion of virus-infected cells is dependent on force sensing via mechanosensitive ion channels rather than apoptotic cell death. When isolated and used as inoculum, intact virus-containing extruded cells can initiate new infections. In contrast, when mechanical force sensing is inhibited, large amounts of free virus are released. Thus, extrusion of live, virus-infected cells from intact epithelial tissue is likely to benefit both the integrity of host tissues and the protected spread of this faecal-oral pathogen within and between hosts.

View details for DOI 10.1038/s41564-023-01339-5
View details for PubMedID 36914754

Approaches to integrating online videos into health professions curricula: educators' perspectives from multiple institutions.

MedEdPublish (2016)
Aluri, K., Sow, M., Amieva, M., Chen, S. 2022; 12: 52

Abstract
Background: The COVID-19 pandemic has accelerated a transition from lecture-based classes to blended and online learning, increasing the need to integrate publicly available online educational videos. Although online videos are widely available, it is challenging for educators to effectively integrate them into a curriculum. Years before the pandemic, educators from different institutions integrated videos from a library of microbiology and immunology resources into different curricula. Their experiences may inform current educators on the approach to incorporating external resources into their unique curricula. Methods: We interviewed US health professions instructors or course directors who had previously requested access to online microbiology and immunology videos. Using thematic analysis, we organized prominent themes into an existing framework for curriculum development. We then reflected on the meaning of the themes using the same conceptual framework. Results: We found that educators from different schools were able to integrate the same publicly available videos into varying contexts. Most used them as preparation for interactive sessions. For integrating videos, educators felt success when the following actions occurred. 1) Educators integrated videos as a tool to enhance active-learning activities. 2) Educators created activities that focused on clinical applications of knowledge, taught critical thinking, and developed enthusiasm for the subject. 3) They tested students on knowledge application and major concepts rather than solely on content for high-stakes exams. 4) Educators worked with administrators who understood the goals of integrating external videos and supported educators with time and resources to develop effective blended learning. Conclusion: Our study suggests that educators integrating external resources into their curricula may benefit from first establishing their goals and aspirations for their students. These goals then become the anchor for other curricular elements, including external videos, in-class activities, and assessments. Our study highlights the need for dedicated time to develop experienced and enthusiastic educators.

View details for DOI 10.12688/mep.19179.2
View details for PubMedID 37588412
View details for PubMedCentralID PMC10425914

The Gastric Cancer Registry: A Genomic Translational Resource for Multidisciplinary Research in Gastric Cancer.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Almeda, A. F., Grimes, S. M., Lee, H., Greer, S., Shin, G., McNamara, M., Hooker, A. C., Arce, M. M., Kubit, M., Schauer, M. C., Van Hummelen, P., Ma, C., Mills, M. A., Huang, R. J., Hwang, J. H., Amieva, M. R., Han, S. S., Ford, J. M., Ji, H. P. 2022

Abstract
Gastric cancer (GC) is a leading cause of cancer morbidity and mortality. Developing information systems which integrate clinical and genomic data may accelerate discoveries to improve cancer prevention, detection, and treatment. To support translational research in GC, we developed the GC Registry (GCR), a North American repository of clinical and cancer genomics data. Participants self-enrolled online. Entry criteria into the GCR included the following: (1) diagnosis of GC, (2) history of GC in a first- or second-degree relative, or (3) known germline mutation in the gene CDH1. Participants provided demographic and clinical information through a detailed survey. Some participants provided specimens of saliva and tumor samples. Tumor samples underwent exome sequencing, whole genome sequencing and transcriptome sequencing. From 2011-2021, 567 individuals registered and returned the clinical questionnaire. For this cohort 65% had a personal history of GC, 36% reported a family history of GC and 14% had a germline CDH1 mutation. 89 GC patients provided tumor samples. For the initial study, 41 tumors were sequenced using next generation sequencing. The data was analyzed for cancer mutations, copy number variations, gene expression, microbiome, neoantigens, immune infiltrates, and other features. We developed a searchable, web-based interface (the GCR Genome Explorer) to enable researchers access to these datasets. The GCR is a unique, North American GC registry which integrates clinical and genomic annotation. Available for researchers through an open access, web-based explorer, the GCR Genome Explorer will accelerate collaborative GC research across the United States and world.

View details for DOI 10.1158/1055-9965.EPI-22-0308
View details for PubMedID 35771165

An infection-induced oxidation site regulates legumain processing and tumor growth.

Nature chemical biology
Kovalyova, Y., Bak, D. W., Gordon, E. M., Fung, C., Shuman, J. H., Cover, T. L., Amieva, M. R., Weerapana, E., Hatzios, S. K. 2022

Abstract
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

Controlling the polarity of human gastrointestinal organoids to investigate epithelial biology and infectious diseases.

Nature protocols
Co, J. Y., Margalef-Catala, M., Monack, D. M., Amieva, M. R. 2021

Abstract
Human epithelial organoids-3D spheroids derived from adult tissue stem cells-enable investigation of epithelial physiology and disease and host interactions with microorganisms, viruses and bioactive molecules. One challenge in using organoids is the difficulty in accessing the apical, or luminal, surface of the epithelium, which is enclosed within the organoid interior. This protocol describes a method we previously developed to control human and mouse organoid polarity in suspension culture such that the apical surface faces outward to the medium (apical-out organoids). Our protocol establishes apical-out polarity rapidly (24-48 h), preserves epithelial integrity, maintains secretory and absorptive functions and allows regulation of differentiation. Here, we provide a detailed description of the organoid polarity reversal method, compatible characterization assays and an example of an application of the technology-specifically the impact of host-microbe interactions on epithelial function. Control of organoid polarity expands the possibilities of organoid use in gastrointestinal and respiratory health and disease research.

View details for DOI 10.1038/s41596-021-00607-0
View details for PubMedID 34663962

Engineered Matrices Enable the Culture of Human Patient-Derived Intestinal Organoids.

Advanced science (Weinheim, Baden-Wurttemberg, Germany)
Hunt, D. R., Klett, K. C., Mascharak, S., Wang, H., Gong, D., Lou, J., Li, X., Cai, P. C., Suhar, R. A., Co, J. Y., LeSavage, B. L., Foster, A. A., Guan, Y., Amieva, M. R., Peltz, G., Xia, Y., Kuo, C. J., Heilshorn, S. C. 2021; 8 (10): 2004705

Abstract
Human intestinal organoids from primary human tissues have the potential to revolutionize personalized medicine and preclinical gastrointestinal disease models. A tunable, fully defined, designer matrix, termed hyaluronan elastin-like protein (HELP) is reported, which enables the formation, differentiation, and passaging of adult primary tissue-derived, epithelial-only intestinal organoids. HELP enables the encapsulation of dissociated patient-derived cells, which then undergo proliferation and formation of enteroids, spherical structures with polarized internal lumens. After 12 rounds of passaging, enteroid growth in HELP materials is found to be statistically similar to that in animal-derived matrices. HELP materials also support the differentiation of human enteroids into mature intestinal cell subtypes. HELP matrices allow stiffness, stress relaxation rate, and integrin-ligand concentration to be independently and quantitatively specified, enabling fundamental studies of organoid-matrix interactions and potential patient-specific optimization. Organoid formation in HELP materials is most robust in gels with stiffer moduli (G' ≈ 1 kPa), slower stress relaxation rate (t1/2 ≈ 18 h), and higher integrin ligand concentration (0.5 × 10-3-1 × 10-3 m RGD peptide). This material provides a promising in vitro model for further understanding intestinal development and disease in humans and a reproducible, biodegradable, minimal matrix with no animal-derived products or synthetic polyethylene glycol for potential clinical translation.

View details for DOI 10.1002/advs.202004705
View details for PubMedID 34026461
View details for PubMedCentralID PMC8132048