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. Understanding the host/pathogen biology of pneumonia and sepsis. Critical 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. My laboratory utilizes bulk and single cell RNA sequencing, as well as proteomic and computational methods to study the systems biology of pneumonia including COVID-19, sepsis, and the acute respiratory distress syndrome. The citations below represent key studies in this area.
2a. Spottiswoode N, Tsitsiklis A, Chu VT, Phan HV, DeVoe C, Love C, Ghale R, Bloomstein J, Zha BS, Maguire CP, Glascock A, Sarma A, Mourani PM, Kalantar KL, Detweiler A, Neff N, Haller SC; COMET Consortium; DeRisi JL, Erle DJ, Hendrickson CM, Kangelaris KN, Krummel MF, Matthay MA, Woodruff PG, Calfee CS, Langelier CR. Microbial dynamics and pulmonary immune responses in COVID-19 secondary bacterial pneumonia. Nature Communications. 2024 Oct 29;15(1):9339. PMID: 39472555.
2b. Pickering H, Schaenman J, Phan HV, Maguire C, Tsitsiklis A, Rouphael N, Higuita NIA, Atkinson MA, Brakenridge S, Fung M, Messer W; IMPACC Network; Salehi-Rad R, Altman MC, Becker PM, Bosinger SE, Eckalbar W, Hoch A, Doni Jayavelu N, Kim-Schulze S, Jenkins M, Kleinstein SH, Krammer F, Maecker HT, Ozonoff A, Diray-Arce J, Shaw A, Baden L, Levy O, Reed EF, Langelier CR. Host-microbe multiomic profiling identifies distinct COVID-19 immune dysregulation in solid organ transplant recipients. Nature Communications. 2025 Jan 10;16(1):586. PMID: 39794319.
2c. Neyton LPA, Sinha P, Sarma A, Mick E, Kalantar K, Chen S, Wu N, Delucchi K, Zhuo H, Bos LDJ, Jauregui A, Gomez A, Hendrickson CM, Kangelaris KN, Leligdowicz A, Liu KD, Matthay MA, *Langelier CR, *Calfee CS. (*co-senior authors). Host and Microbe Blood Metagenomics Reveals Key Pathways Characterizing Critical Illness Phenotypes. Am J Respir Crit Care Med. 2024 Apr 1;209(7):805-815. PMID: 38190719; PMCID: PMC10995577.
2d. 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.
2e. 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.
3. 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 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.
3a. 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.
3b. 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.
3c. 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.
3d. 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.
3e. 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.
4. Genomic studies of antimicrobial resistance. Antimicrobial resistance (AMR) presents a clear threat to human health and is responsible for increasing rates of treatment failure across diverse classes of infections. I have leveraged metagenomics to understand the impact of aging, antibiotic exposures and international travel on the microbiome and antimicrobial resistome in the lung and gut. In addition, I developed methods for genomic detection of AMR pathogens in patients with pneumonia. Finally, I have studied in-host evolution of bacterial resistance in patients exposed to long term antimicrobial therapy. The citations below represent key studies in this area.
4a. Chu VT, Tsitsiklis A, Mick E, Ambroggio L, Kalantar KL, Glascock A, Osborne CM, Wagner BD, Matthay MA, DeRisi JL, Calfee CS, Mourani PM, Langelier CR. The antibiotic resistance reservoir of the lung microbiome expands with age in a population of critically ill patients. Nature Communications. 2024. PMID: 38168095; PMCID: PMC9275031.
4b. Chu VT, Glascock A, Donnell D, Grabow C, Brown C, Ward R, Love C, Kalantar K, Cohen S, Cannon C, Woodworth M, Kelley C, Celum C, Luetkemeyer A, Langelier CR. Impact of doxycycline post-exposure prophylaxis for sexually transmitted infections on the gut microbiome and antimicrobial resistome. Nature Medicine. 2024. PMID: 39363100.
4c. 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.
4d. 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.
4e. *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.
5. Understanding the impact of aging on infection and inflammation. Older age is a leading risk factor for severe disease and mortality in patients with pneumonia, including from COVID-19. Over the past three years I have sought to understand the mechanisms underlying this striking association through multiomic profiling studies of adults and children with COVID-19 and other types of pneumonia. This work demonstrated that adults with COVID-19 have augmented and prolonged hyperinflammatory innate immune responses in the respiratory tract and blood, as well as impaired viral clearance, both of which associate with increased disease severity. The citations below represent key studies in this area.
5a. Phan HV, Tsitsiklis A, Maguire CP, Haddad EK, Becker PM, Kim-Schulze S, Lee B, Chen J, Hoch A, Pickering H, van Zalm P, Altman MC, Augustine AD, Calfee CS, Bosinger S, Cairns CB, Eckalbar W, Guan L, Jayavelu ND, Kleinstein SH, Krammer F, Maecker HT, Ozonoff A, Peters B, Rouphael N; IMPACC Network; Montgomery RR, Reed E, Schaenman J, Steen H, Levy O, Diray-Arce J, Langelier CR. Host-microbe multiomic profiling reveals age-dependent immune dysregulation associated with COVID-19 immunopathology. Science Translational Medicine. 2024 Apr 17;16. PMID: 38630846.
5b. 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 Jul 8;13(1):3937. PMID: 35803954; PMCID: PMC9263813.
5c. Chu VT, Tsitsiklis A, Mick E, Ambroggio L, Kalantar KL, Glascock A, Osborne CM, Wagner BD, Matthay MA, DeRisi JL, Calfee CS, Mourani PM, Langelier CR. The antibiotic resistance reservoir of the lung microbiome expands with age in a population of critically ill patients. Nature Communications. 2024. PMID: 38168095; PMCID: PMC9275031.