1. Integrating host gene expression profiling and unbiased microbe detection to advance infectious disease diagnosis in patients with critical illness. Effectively treating patients with infectious diseases depends on rapid and accurate detection of the etiologic pathogens and the ability to differentiate infectious from other acute inflammatory illnesses that can appear clinically similar. Existing diagnostics, however, are unable to provide a microbiologic diagnosis in a high proportion of cases, resulting in empirical, as opposed to targeted, treatment and leading adverse outcomes. To address this, our work has focused on developing novel metagenomic next-generation sequencing (mNGS) methods that screen for a broad range of potential pathogens while simultaneously profiling host immune gene expression markers of infection. By applying machine learning methods to high dimensional datasets, the laboratory has developed a new approach for diagnosing lower respiratory tract infections (LRTI) based on profiling the host response and differentiating pathogens from commensal microbiota. These methods are currently being used to advance the diagnosis of pediatric LRTI, COVID-19 and sepsis. The citations below represent key studies in this area.
1a. Mick E, Tsitsiklis A, Kamm J, Kalantar KL, Caldera S, Lyden A, Tan M, Detweiler AM, Neff N, Osborne CM, Williamson KM, Soesanto V, Leroue M, Maddux AB, Simões EA, Carpenter TC, Wagner BD, DeRisi JL, Ambroggio L, Mourani PM, Langelier CR. Integrated host/microbe metagenomics enables accurate lower respiratory tract infection diagnosis in critically ill children. J Clin Invest. 2023 Apr 3;133(7):e165904. PMID: 37009900; PMCID: PMC10065066.
1b. Kalantar KL, Neyton L, Abdelghany M, Mick E, Jauregui A, Caldera S, Serpa PH, Ghale R, Albright J, Sarma A, Tsitsiklis A, Leligdowicz A, Christenson SA, Liu K, Kangelaris KN, Hendrickson C, Sinha P, Gomez A, Neff N, Pisco A, Doernberg SB, Derisi JL, Matthay MA, Calfee CS, Langelier CR. Integrated host-microbe plasma metagenomics for sepsis diagnosis in a prospective cohort of critically ill adults. Nature Microbiology. 2022 Nov;7(11):1805-1816. PMID: 36266337; PMCID: PMC9613463.
1c. Mick E, Kamm J, Pisco AO, Ratnasiri K, Babik JM, Calfee CS, Castaneda G, DeRisi JL, Detweiler AM, Hao S, Kangelaris KN, Kumar GR, Li LM, Mann SA, Neff N, Prasad PA, Serpa PH, Shah SJ, Spottiswoode N, Tan M, Christenson SA, Kistler A, Langelier C. Upper airway gene expression differentiates COVID-19 from other acute respiratory illnesses and reveals suppression of innate immune responses by SARS-CoV-2. Nature Communications. 2020. PMID: 32511476; PMCID: PMC7673985
1d. Langelier C, Kalantar KL, Moazed F, Wilson MR, Crawford ED, Deiss T, Belzer A, Bolourchi S, Caldera S, Fung M, Jauregui A, Malcolm K, Lyden A, Khan L, Vessel K, Quan J, Zinter M, Chiu CY, Chow ED, Wilson J, Miller S, Matthay MA, Pollard KS, Christenson S, Calfee CS, DeRisi JL. Integrating host response and unbiased microbe detection for lower respiratory tract infection diagnosis in critically ill adults. Proc Natl Acad Sci U S A. 2018. PMID: 30482864; PMCID: PMC6310811.
2. Emerging pathogen surveillance. Rapid and comprehensive assessment of novel pathogens and suspected outbreaks is essential for implementing effective infection control measures. Further, molecular epidemiologic surveillance for emerging pathogens is essential for characterizing the etiology of infectious s syndromes both locally and globally. The lab work in this area has contributed to the genomic characterization of novel respiratory and sepsis pathogens and has demonstrated the utility of both whole genome sequencing and culture-independent mNGS for rapid assessment of outbreaks, allowing for targeted infection control interventions and an improved understanding of transmission networks. UCSF is the only medical center in California, and one of the few in the United States, to routinely incorporate real-time whole genome sequencing for hospital infection control, via a unique collaboration with the Langelier laboratory. The citations below represent key studies in this area.
2a. Chu VT, Nafees S, Waltari E, McNeil N, Caughell C, Sanchez-Guerrero E, Wang L, Stanley K, Cunningham G, Wong J, Phelps M, Tato CM, Miller S, DeRisi JL, Yokoe DS, Ramirez-Avila L, Langelier CR. Whole-genome sequencing rule-out of suspected hospital-onset Rhizopus outbreaks. Infect Control Hosp Epidemiol. 2023 Jun 13:1-3. doi: 10.1017/ice.2023.85. Epub ahead of print. PMID: 37308466.
2b. Spottiswoode N, Bloomstein J, Caldera S, Sessolo A, Byanyima P, Zawedde J, Kalantar K, Kaswabuli S, Rutishauser RL, Davis L, Jan A, Moore J, Iwai S, Shenoy M, Sanyu I, DeRisi JL, Lynch SV, Worodria W. Huang L, Langelier C. Pneumonia Surveillance in Ugandans with HIV Through the Lens of Culture- Independent Metatranscriptomics: A Cross Sectional Study. Lancet Microbe. 2022. PMID: 35544096.
2c. Tsitsiklis A, Osborne CM, Kamm J, Williamson K, Kalantar KL, Dudas G, Caldera S, Lyden A, Tan M, Neff, N, Soesanto V, Harris JK, Ambroggio L, Maddux AB, Carpenter, TC, Sontag MK, Reeder RW, Locandro C, Simões, E, Leroue MK, Hall MW, Zuppa AF, Carcillo J, Meert KL, Sapru A, Pollack MM, McQuillen P Notterman DA, Dean JM, Zinter M, Wagner BD, DeRisi JL, *Mourani PM, *Langelier C. Etiology of Lower Respiratory Tract Infections in Children Requiring Mechanical Ventilation: A Multicenter Prospective Surveillance Study Incorporating Airway Metagenomics. Lancet Microbe. 2022. PMID: 35544065; PMCID: PMC9446282.
2d. Crawford E, Kamm J, Miller S, Li LM, Caldera S, Lyden A, Yokoe D, Nichols A, Tran NK, Barnard SE, Conner PM, Nambiar A, Zinter MS, Moayeri M, Serpa PH, Prince BC, Quan J, Sit R, Tan M, Phelps M, DeRisi JL, Tato CM, Langelier C. Investigating Transfusion-Related Sepsis using Culture-Independent Metagenomic Sequencing. Clinical Infectious Diseases. 2019. PMID: 31563940; PMCID: PMC7442849.
2e. Langelier C, Fung M, Caldera S, Deiss T, Lyden A, Prince BC, Hayakawa Serpa P, Moazed F, Chin-Hong P, DeRisi JL, Calfee CS. Detection of Pneumonia Pathogens from Plasma Cell-Free DNA. Am J Respir Crit Care Med. 2019. PMID: 31647702; PMCID: PMC7049928.
3. Systems biology of COVID-19 and other severe respiratory diseases. COVID-19 and other severe infectious diseases are characterized by a dysregulated host inflammatory response to infection. Identifying the aberrant signaling pathways driving disease pathophysiology affords an opportunity to advance understanding of the underlying biology, identify novel therapeutics, and distinguish patient subphenotypes with different outcome or treatment response trajectories. The laboratory utilizes bulk and single cell RNA sequencing, as well as proteomic and computational methods to study the systems biology of COVID-19, other lower respiratory tract infections, and the acute respiratory distress syndrome. The citations below represent key studies in this area.
3a. Sarma A, Christenson S, Mick E, Deiss T, DeVoe C, Pisco A, Ghale R, Jauregui A, Byrne A, Moazed F, Spottiswoode N, Sinha P, Zha B, Neff N, Tan M, Serpa PH, Ansel KM, Wilson J, Leligdowicz A, Seigel E, Sirota M, DeRisi J, Matthay M, Consortium C, Hendrickson C, Kangelaris K, Krummel M, Woodruff P, Erle D, *Calfee CS, *Langelier C. (*co-senior) Tracheal aspirate RNA sequencing identifies distinct immunological features of COVID19 ARDS. Nature Communications. 2021. PMID: 34446707; PMCID: PMC8390461.
3b. Mick E, Kamm J, Pisco AO, Ratnasiri K, Babik JM, Calfee CS, Castaneda G, DeRisi JL, Detweiler AM, Hao S, Kangelaris KN, Kumar GR, Li LM, Mann SA, Neff N, Prasad PA, Serpa PH, Shah SJ, Spottiswoode N, Tan M, Christenson SA, Kistler A, Langelier C. Upper airway gene expression differentiates COVID-19 from other acute respiratory illnesses and reveals suppression of innate immune responses by SARS-CoV-2. Nature Communications. 2020. PMID: 32511476; PMCID: PMC7273244.
3c. Mick E, Tsitsiklis A, Spottiswoode N, Caldera S, Serpa P, Detweiler A, Neff N, Pisco AO, Li L, Retallack H, Ratnasiri K, Williamson K, Soesanto V, Simões E, Kistler A, Wagner B, DeRisi J, Ambroggio L, Mourani P, Langelier C. Upper airway gene expression reveals a more robust innate and adaptive immune response to SARS-CoV-2 in children compared with older adults. Nature Communications. 2022. PMID: 35803954.
3d. Dugger DT, Fung M, Zlock L, Caldera S, Sharp L, Hays SR, Singer JP, Leard LE, Golden JA, Shah RJ, Kukreja J, Gordon E, Finkbeiner W, Kleinhenz ME, Langelier C, Greenland JR. Cystic Fibrosis Lung Transplant Recipients Have Suppressed Airway Interferon Responses during Pseudomonas Infection. Cell Reports Medicine. 2020. PMID: 32754722; PMCID: PMC7402593.
4. Genomic assessment of antimicrobial resistance. Antimicrobial resistance (AMR) presents a clear threat to human health and is responsible for increasing rates of treatment failure. Rapid and accurate detection of pathogen resistance is critical for effective and targeted treatment interventions, however is often not possible due to the lengthy time requirements and low yield of existing culture-based methods. To address the need for improved AMR detection and culture-independent surveillance tools, the group has developed and applied mNGS-based approaches for identifying clinically relevant AMR genes from patient specimens. In particular, we developed FLASH (Finding Low Abundance Sequences by Hybridization), a technique that uses the CRISPR/Cas9 sequence-specific nuclease to enrich for low-abundance target sequences such as AMR genes by several orders of magnitude. This has allowed for identification of otherwise undetectable, but clinically important, AMR genes thereby affording rapid detection of drug-resistant respiratory pathogens. The citations below represent key studies in this area.
4a. Hayakawa Serpa P, Deng Xianding, Abdelghany M, Crawford E, Malcolm K, Caldera S, Fung M, McGeever A, Kalantar KL, Lyden A, Ghale R, Deiss T, Neff N, Miller SA, Doernberg SB, Chiu CY, DeRisi JL, Calfee CS, Langelier CR. Metagenomic Prediction of Antimicrobial Resistance in Critically Ill Patients with Lower Respiratory Tract Infections. Genome Medicine. 2022. PMID: 35818068; PMCID: PMC9275031.
4b. Langelier C, Graves M, Kalantar K, Caldera S, Durrant R, Fisher M, Backman R, Tanner W, DeRisi JL, Leung DT. Microbiome and Antimicrobial Resistance Gene Dynamics in International Travelers. Emerging Infectious Diseases. 2019. PMID: 31211676; PMCID: PMC6590773.
4c. *Quan J, *Langelier C, *Kuchta A, Batson J, Teyssier N, Lyden A, Caldera S, McGeever A, Dimitrov B, King R, Wilheim J, Murphy M, Ares LP, Travisano KA, Sit R, Amato R, Mumbengegwi DR, Smith JL, Bennett A, Gosling R, Mourani PM, Calfee CS, Neff NF, Chow ED, Kim PS, Greenhouse B, DeRisi JL, Crawford ED. FLASH: a next-generation CRISPR diagnostic for multiplexed detection of antimicrobial resistance sequences. Nucleic Acids Research. 2019. PMID: 31114866; PMCID: PMC6698650.
4d. Hao S, Abdelghany M, Lyden A, Sit R, Tan M, Tato CM, DeRisi JL, Miller S, Doernberg SB, Langelier C. Genomic Profiling of Evolving Daptomycin Resistance in a Patient with Recurrent Staphylococcus argenteus Sepsis. Antimicrobial Agents Chemotherapy. 2020. PMID: 32601156; PMCID: PMC7508626.