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Principal Investigator: Nevan J Krogan
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2023
Award: $2,489,172
Funding agency: National Institute of Allergy and Infectious Diseases
THE HOST PATHOGEN MAP INITIATIVE 2.0
OVERALL SUMMARY
The Host-Pathogen Map Initiative (HPMI) 2.0 is an interdisciplinary program that aims to improve our
understanding of the interactions between host cellular systems and respiratory pathogens and builds upon the
success of its previous iteration. The ultimate goals are identifying therapeutic targets, treatment modalities, and
predicting disease severity. HPMI 2.0 will focus its efforts on the bacterial pathogen Mycobacterium tuberculosis
(Mtb) and viral respiratory pathogens such as SARS-CoV-2 and variants of concern, e.g. omicron and delta, as
well as influenza, parainfluenza virus, and respiratory syncytial virus, among other RNA viruses. We will use
proteomics, genetics and structural biology approaches to study the host factors relevant to these infectious
diseases in disease-relevant cell models and patient samples, and combine our data with existing -omic
datasets. Network and structure modeling approaches will be used to integrate these datasets to make testable
predictions about proteins, complexes and pathways in the host regulating infection as well as disease prognosis.
Our proposal will be centered on the profiling of human samples to decipher networks underlying infectious
respiratory diseases. To generate clinically relevant datasets on viral respiratory disease, we will use human
lung primary cells and three-dimensional human airway organoids (HAO) for systems biology analyses,
determine the global proteome of plasma samples from SARS-CoV-2-infected patients, and integrate our data
with clinical datasets. To uncover the determinants of the heterogeneity of susceptibility to TB, we will utilize
genome-wide association studies (GWAS) for TB susceptibility genes combined with whole genome sequences
of the infecting Mtb strain in a cohort of TB patients in Vietnam at the Oxford University Clinical Research Unit
(OUCRU). We will further profile alveolar macrophages and peripheral blood derived macrophages from healthy
donors to understand mechanisms of innate immune responses to Mtb infection and cell-type specific features.
We hypothesize that different TB clinical outcomes are regulated by specific molecular networks in infected
macrophages. Our models for the identification of combinatorial biomarkers to predict disease outcomes will be
assessed on the Mtb-infected cohort in Vietnam and COVID-19 patients at UCSF. Lastly, we will explore potential
commonalities between Mtb and SARS-CoV-2, as severe forms of TB and COVID-19 are accompanied by
exacerbated inflammatory responses and “cytokine storms”.
A better molecular understanding of the functions and mechanisms of host-pathogen complexes may reveal new
therapeutic strategies for intervention, including strategies of host-directed therapies that circumvent the
limitations of current drug regimens using antibiotics or antivirals where mutations in the pathogen proteins can
diminish drug efficacy. Our host-pathogen cell maps will help build interpretable deep learning systems using
state-of-the-art modeling approaches for prediction of infectious disease risk, disease severity and combinatorial
risk factors for M. tuberculosis and SARS-CoV-2 infection in clinical settings.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><3-D><3-Dimensional><3D><Airway infections><Alveolar Macrophages><Animal Model><Animal Models and Related Studies><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antiviral Agents><Antiviral Drugs><Antivirals><Automobile Driving><Bacterial Genes><Bacterial Genome><Binding><Bio-Informatics><Bioinformatics><Biologic Sciences><Biological Markers><Biological Sciences><Bioscience><Blood Plasma><Blood Serum><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 infected patient><COVID-19 infection><COVID-19 patient><COVID-19 positive patient><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 virus infection><COVID19><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 virus><CV-19><CV19><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell model><Cells><Cellular Assay><Cellular model><Chromosome Mapping><Clinical><Clinical Data><Clinical Research><Clinical Study><CoV-2><CoV2><Collaborations><Collection><Communicable Diseases><Communication><Complex><Critical Paths><Critical Pathways><Cytokines and Inflammatory Response><Data><Data Set><Disease><Disease Outcome><Disease Progression><Disorder><Drugs><Environment><Event><Fostering><Funding><GWA study><GWAS><Gene Combinations><Gene Localization><Gene Mapping><Gene Mapping Genetics><Generalized Growth><Genetic><Genetic Alteration><Genetic Change><Genetic Screening><Genetic analyses><Genetic defect><Goals><Grippe><Growth><Heterogeneity><Host Factor><Host Factor Protein><Human><Human Genome><In Vitro><Infection><Infectious Agent><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammatory><Inflammatory Response Pathway><Influenza><Information Networks><Innate Immune Response><Integration Host Factors><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Leadership><Life Sciences><Linkage Mapping><Lung><Lung Respiratory System><M tb><M tuberculosis><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><Macrophage><Maps><Medication><Miscellaneous Antibiotic><Mission><Modality><Modeling><Modern Man><Molecular><Molecular Interaction><Mutation><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Mφ><NIAID><National Institute of Allergy and Infectious Disease><Organoids><Outcome><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Pharmaceutic Preparations><Pharmaceutical Preparations><Plasma><Plasma Serum><Population><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Predisposition><Predisposition gene><Protein Modification><Protein Secretion><Proteins><Proteome><Proteomics><Pulmonary Macrophages><RNA Viruses><Regimen><Research Resources><Resistance><Resources><Respiration><Respiratory Disease><Respiratory Infections><Respiratory System Disease><Respiratory System Disorder><Respiratory Therapy><Respiratory Tract Infections><Respiratory syncytial virus><Reticuloendothelial System, Serum, Plasma><Risk><Risk Factors><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Series><Serum><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Severity of illness><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Susceptibility><Susceptibility Gene><System><Systems Biology><TB infection><Technology><Therapeutic><Tissue Growth><Total Human and Non-Human Gene Mapping><Tuberculosis><Universities><Viet Nam><Vietnam><Viral><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Viral Respiratory Tract Infection><Virus Diseases><Virus Replication><Wuhan coronavirus><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antiviral compound><antiviral medication><antiviral therapeutic><bacteria pathogen><bacterial pathogen><bio-markers><biologic marker><biological signal transduction><biomarker><cell assay><cell dimension><cell type><clinical relevance><clinically relevant><co-infection><cohort><coinfection><combinatorial><conference><convention><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cytokine release syndrome><cytokine storm><data integration><data management><deep learning><disease prognosis><disease prognostication><disease risk><disease severity><disorder risk><disseminated TB><disseminated tuberculosis><diversity, equity, and inclusiveness><driving><drug efficacy><drug/agent><entire genome><equity, diversity, and inclusion><full genome><genetic analysis><genetic mapping><genome mutation><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><global gene expression><global transcription profile><hCoV19><human whole genome><identification of viruses><improved><in vivo><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><infection due to Mycobacterium tuberculosis><infectious organism><innate immune mechanisms><innovate><innovation><innovative><interventional strategy><lectures><model of animal><mtb><nCoV2><network models><new technology><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel technologies><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ontogeny><outreach><parainfluenza virus><pathogen><pathogenic bacteria><pathogenic virus><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><peripheral blood><permissiveness><predisposing gene><programs><protein complex><pulmonary><resistance to therapy><resistant><resistant to therapy><respiratory mechanism><respiratory pathogen><respiratory virus><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><social role><spatiotemporal><structural biology><success><summit><susceptibility allele><susceptibility locus><susceptibility variant><symposia><symposium><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapeutic target><therapy resistant><three dimensional><tool><transcriptome><transcriptomics><treatment resistance><tuberculosis infection><tuberculous spondyloarthropathy><variants of concern><viral infection><viral multiplication><viral pathogen><viral replication><viral resistance><viral respiratory infection><virus identification><virus infection><virus multiplication><virus pathogen><virus protein><virus resistance><virus-induced disease><whole genome><whole genome association analysis><whole genome association studies><whole genome association study>