Alexander L. Greninger, MD, PhD, MS, MPhil
Disclosures:
OMB No. 0925-0046, Biographical Sketch Format Page

 

OMB No. 0925-0001 and 0925-0002 (Rev. 03/2020 Approved Through 02/28/2023)

BIOGRAPHICAL SKETCH

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NAME: Alexander L. Greninger

eRA COMMONS USER NAME (credential, e.g., agency login): gerbix

POSITION TITLE: Assistant Professor in Laboratory Medicine

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)

INSTITUTION AND LOCATION

DEGREE

(if applicable)

 

Completion Date

MM/YYYY

 

FIELD OF STUDY

 

Stanford University

B.A.

01/2004

International Relations

Stanford University

B.S.

01/2004

Biological Sciences

Stanford University

M.S.

01/2004

Microbiology/Immunology

Cambridge University

M.Phil.

7/2005

Epidemiology

University of California-San Francisco

University of California-San Francisco

Ph.D.

M.D.

3/2013

5/2015

Microbiology/Immunology

Medicine

University of Washington

Residency

6/2018

Clinical Pathology

 

A.              Personal Statement

I have a long-standing interest in understanding the clinical aspects and fundamental biology associated with RNA viruses. I previously spent a combined decade receiving training on the use of unbiased technologies such as metagenomic sequencing and proteomics to characterize the pathogenesis and epidemiology of RNA viruses in the laboratories of Drs. Joseph L. DeRisi and Charles Y. Chiu at the University of California San Francisco. I have spent the last 4.5 years applying these tools in the clinical virology laboratory at the University of Washington, where I serve as assistant clinical director, publishing more than 100 manuscripts on viral evolution, clinical virology, and viral genomics. During this time, I also completed a residency in laboratory medicine and am board-certified in clinical pathology, such that I understand the requirements for accurate, validated laboratory testing for clinical use.

The SARS-CoV-2 pandemic has allowed the University of Washington to showcase its considerable skills at responding to infectious diseases. Our academic clinical lab at UW Virology was one of the first in the country to perform SARS-CoV-2 testing. We have performed testing on more than 2,100,000 specimens in the past nine months, detecting more than 115,000 infections. We were also one of the first laboratories to bring on accurate serological testing, publishing one of the first large-scale clinical validations of serological testing in the country. Our laboratory was also the central laboratory for the Janssen, Novavax, and ACTIV trials for SARS-CoV-2 qPCR, sequencing, and serology. We have considerable expertise in the tests required for the proposed work. Selected publications on understand viral diagnostics and evolution and human coronavirus evolution from a total of 192 publications:

  1. Addetia A, Crawford KHD, Dingens A, Zhu H, Roychoudhury P, Huang ML, Jerome KR, Bloom JD, Greninger AL*. Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery vessel outbreak with high attack rate. J Clin Microbiol. 2020 Aug 21:JCM.02107-20.
  2. Bryan A, Pepper G, Wener MH, Fink SL, Morishima C, Chaudhary A, Jerome KR, Mathias PC, Greninger AL*. Performance Characteristics of the Abbott Architect SARS-CoV-2 IgG Assay and Seroprevalence in Boise, Idaho. J Clin Microbiol. 2020 May 7:JCM.00941-20.
  3. Lieberman NAP, Peddu V, Xie H, Shrestha L, Huang ML, Mears MC, Cajimat MN, Bente DA, Shi PY, Bovier F, Roychoudhury P, Jerome KR, Moscona A, Porotto M, Greninger AL*. In vivo antiviral host response to SARS-CoV-2 by viral load, sex, and age. PLoS Biol. 2020 Sep 8;18(9):e3000849.
  4. Nalla AK, Casto AM, Huang MW, Perchetti GA, Sampoleo R, Shrestha L, Wei Y, Zhu H, Jerome KR, Greninger AL*. Comparative Performance of SARS-CoV-2 Detection Assays using Seven Different Primer/Probe Sets and One Assay Kit. J Clin Microbiol. 2020 Apr 8:JCM.00557-20.

 

B.              Positions and Honors

Positions and Employment

2004                                                        Emerging and New Dangerous Pathogens Program, World Health Organization, Geneva

2005-2015                                          Medical Scientist Training Program, University of California-San Francisco

2014-2015                                          Post-doctoral associate, laboratory of Charles Chiu, UCSF

2014-2015                                          NGS Consultant to California Department of Public Health, Richmond, CA

2015-2018                                          Resident, Department of Laboratory Medicine, University of Washington

2017-2019                                          Junior Member, Clinical Practice Committee, Association of Molecular Pathology

2017-present                            NGS Consultant to the Washington State Public Health Lab, Seattle, WA

2017-present                            Member, Multiplex Testing Working Group, Association of Molecular Pathology

2018-present                            Assistant Professor, Department of Laboratory Medicine, University of Washington

2018-present                            Assistant Director, Clinical Virology Laboratory, University of Washington

 

Honors

2003                            Firestone Medal for Excellence in Research for International Security Studies

2003                            Genentech Scholar

2004                            Churchill Scholar for study at Cambridge University

2005                            George J. Mitchell Scholar (declined)

2005-2015                            Medical Scientist Training Program, University of California-San Francisco

2007                            President, Associated Students of University of California-San Francisco

2012                            Travel Award, American Society of Virology

2016                            Marco Escobar Award, American Society of Microbiology

2016                            Young Investigator Award, American Clinical Laboratory Physicians and Scientists

2016                                                        Platform Presentation, Association for Molecular Pathology

2017                                                        Outstanding Abstract, HHV6 & 7 Conference, Berlin

2017                                                        American Society of Clinical Pathologists “40 under 40”

2017                                                        Full Physician’s License, state of Washington

2017                                                        Travel Award, University of Washington Office of Postdoctoral Affairs

2017                                                        Travel Award, 4th International RSV Vaccines for the World

2018                            PASCV Young Investigator Pioneer Award

2018                            Strandjord-Clayson Award, Department of Laboratory Medicine

2019                            Koichi Yamanishi Young Investigator Award for Excellence in Basic Science in HHV-6

2020                            Pathologist PowerList

2020                            UW Medicine Inventor of the Year

 

 

C.              Contributions to Science

1. Response to the SARS-CoV-2 pandemic

              SARS-CoV-2 chose to make landing in Seattle and the first front of battle in the United States. The University of Washington clinical virology laboratory was as ready as we could be. Thanks to NIH support of clinical trials which preserved our personnel’s considerable expertise, we went live with one of the first clinical tests for SARS-CoV-2, protecting our healthcare workers and community. We shared SARS-CoV-2 samples with approximately one hundred clinical laboratories across the country, helping them to bring on testing. We evaluated multiple RT-PCR and serological tests, publishing some of the first comparative evaluations of these tests in the country. Washington State successfully flattened the curve and has consistently performed among the best states in the country in SARS-CoV-2 response as we await what comes next.

  1. Bryan A, Pepper G, Wener MH, Fink SL, Morishima C, Chaudhary A, Jerome KR, Mathias PC, Greninger AL*. Performance Characteristics of the Abbott Architect SARS-CoV-2 IgG Assay and Seroprevalence in Boise, Idaho. J Clin Microbiol. 2020 May 7:JCM.00941-20.
  2. Addetia A, Crawford KHD, Dingens A, Zhu H, Roychoudhury P, Huang ML, Jerome KR, Bloom JD, Greninger AL*. Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery vessel outbreak with high attack rate. J Clin Microbiol. 2020 Aug 21:JCM.02107-20.
  3. Peddu V, Shean RC, Xie H, Shrestha L, Perchetti GA, Minot SS, Roychoudhury P, Huang ML, Nalla A, Reddy SB, Phung Q, Reinhardt A, Jerome KR*, Greninger AL*. Metagenomic analysis reveals clinical SARS-CoV-2 infection and bacterial or viral superinfection and colonization. Clin Chem. 2020 May 7:hvaa106.
  4. Nalla AK, Casto AM, Huang MW, Perchetti GA, Sampoleo R, Shrestha L, Wei Y, Zhu H, Jerome KR, Greninger AL*. Comparative Performance of SARS-CoV-2 Detection Assays using Seven Different Primer/Probe Sets and One Assay Kit. J Clin Microbiol. 2020 Apr 8:JCM.00557-20.

 

2. Rapid metagenomic next-generation sequencing for detection and recovery of whole genomes for transmission tracking

              As there are not many human pathogens that remain to be discovered, I have focused on extending the method of metagenomics for viral discovery to whole genome recovery of known human pathogens for transmission tracking. In 2010, I published one of the original papers on the use of metagenomics to characterize known viruses in the initial 2009 H1N1 influenza cases in Mexico, California, and Canada. I published a paper on the 2014 enterovirus D68 outbreak in California and Colorado that showed that viral sequences recovered from acute flaccid myelitis clustered with outbreak strains from patients whose sole presentation was respiratory infection. We also demonstrated no other causes of encephalitis could be identified metagenomically from EV-D68 infected individuals. More recently, I have been using metagenomics to rapidly recover sequence from hospital-acquired viral infections to rule-in or rule-out a single source to the chain of transmission, including more than 1,000 genomes in the SARS-CoV-2 pandemic in Seattle.

1. Greninger AL, Naccache SN, Messacar K, Clayton A, Yu G, Somasekar S, Federman S, Stryke D, Anderson C, Yagi S, Messenger S, Wadford D, Xia D, Watt JP, Van Haren K, Dominguez SR, Glaser C, Aldrovandi G, Chiu CY. A novel outbreak enterovirus D68 strain associated with acute flaccid myelitis cases in the USA (2012-14): a retrospective cohort study. The Lancet. Infectious diseases. 2015; 15(6):671-82.

2. Greninger AL, Zerr DM, Qin X, Adler AL, Sampoleo R, Kuypers JM, Englund JA, Jerome KRRapid metagenomic next-generation sequencing during an investigation of hospital-acquired human parainfluenza virus 3 infections. Journal of clinical microbiology. 2016;

3. Greninger AL, Chen EC, Sittler T, Scheinerman A, Roubinian N, Yu G, Kim E, Pillai DR, Guyard C, Mazzulli T, Isa P, Arias CF, Hackett J, Schochetman G, Miller S, Tang P, Chiu CY.  A metagenomic analysis of pandemic influenza A (2009 H1N1) infection in patients from North America. PloS one. 2010; 5(10):e13381.

4. Peddu V, Shean RC, Xie H, Shrestha L, Perchetti GA, Minot SS, Roychoudhury P, Huang ML, Nalla A, Reddy SB, Phung Q, Reinhardt A, Jerome KR*, Greninger AL*. Metagenomic analysis reveals clinical SARS-CoV-2 infection and bacterial or viral superinfection and colonization. Clin Chem. 2020 May 7:hvaa106.

 

3. Understanding human viral diversity and evolution

              In addition to first genomes, I have established used the rich sample banks at the clinical virology laboratories at the University of Washington to substantially expand the number of publically available clinical relevant viral genomes, focusing on the human parainfluenza viruses and human herpesviruses.  Until our work with the present collaborators, viral genome sequencing has overwhelmingly focused on HIV and influenza viruses as well as emerging viruses such as Ebola virus or Zika virus, leaving out most of the viruses we detect clinical virology laboratory.  In the context of our collaboration with the Moscona group, these sequences have uncovered how these viruses evolve in human populations and when they grow in cell culture, allowing us to establish cell culture models that better reflect selective forces in humans.  We have also developed freely available bioinformatic tools that rapidly annotate viral annotation for submission to NCBI GenBank to enable data sharing and remove one of the pain points from sequence submission.

  1. Greninger AL, Knudsen GM, Roychoudhury P, Hanson DJ, Sedlak RH, Xie H, Guan J, Nguyen T, Boeckh M, Huang ML, Cook L, Depledge DP, Zerr DM, Koelle DM, Gantt S, Yoshikawa T, Caserta M, Hill JA, Jerome KR. Comparative genomic, transcriptomic, and proteomic reannotation of human herpesvirus 6.  BMC Genomics.  2018 Mar 20;19(1):204.
  2. Casto AM, Roychoudhury P, Xie H, Selke S, Perchetti GA, Wofford H, Huang ML, Verjans GMGM, Gottlieb GS, Wald A, Jerome KR, Koelle DM, Johnston C, Greninger AL. Large, stable, contemporary interspecies recombination events in circulating human herpes simplex viruses.J Infect Dis. 2019 Apr 23.
  3. Iketani S, Shean R, Ferren M, Makhsous N, Aquino D, des Georges A, Rima B, Mathieu C, Porotto M, Moscona A, Greninger AL. Viral entry properties required for fitness in humans are lost through rapid genomic change during viral isolation.  mBio. 2018, Jul 3;9(4).
  4. Porotto M, Ferren M, Chen Y-W, Siu Y, Makhsous N, Rima B, Briese T, Greninger AL, Snoeck H-W, Moscona A. Authentic modeling of human respiratory virus infection in human pluripotent stem cell-derived lung organoids. MBio. 2019 May 7;10(3). pii: e00723-19. doi: 10.1128/mBio.00723-19. PMID: 31064833

 

4. Discovery of Druggable Novel Viral-Host Protein-Protein Interactions

              In addition to genomics, I have used affinity purification-mass spectrometry to agnostically discover novel virus-host protein-protein interactions.  The most important of these was the discovery that multiple picornaviruses, including the medically-relevant enterovirus/rhinoviruses, use their 3A protein to bind ACBD3 to recruit/activate PI4KB for PI4P generation for viral replication.  We went on to show that two radically different genera of picornaviruses have evolved radically different strategies to bind ACBD3 to alter PI4KB activity.  These discoveries form the basis for a novel class of 3A inhibitors that interrupt binding to ACBD3 to treat enterovirus/rhinovirus infections, similar to the NS5A inhibitors that are currently used in hepatitis C virus therapy.  I have also used affinity-purification mass spectrometry to find novel host protein interactions with the herpesviruses and foot and mouth disease virus.

1. Greninger AL, Knudsen GM, Betegon M, Burlingame AL, Derisi JL. The 3A protein from multiple picornaviruses utilizes the golgi adaptor protein ACBD3 to recruit PI4KIIIβ.

Journal of virology. 2012; 86(7):3605-16.

2. Greninger AL, Knudsen GM, Betegon M, Burlingame AL, DeRisi JL.  ACBD3 interaction with TBC1 domain 22 protein is differentially affected by enteroviral and kobuviral 3A protein binding.

mBio. 2013; 4(2):e00098-13.

3. Greninger AL. Picornavirus--host interactions to construct viral secretory membranes. Progress in molecular biology and translational science. 2015; 129:189-212.

4. Morris JH, Knudsen GM, Verschueren E, Johnson JR, Cimermancic P, Greninger AL, Pico AR. Affinity purification-mass spectrometry and network analysis to understand protein-protein interactions.  Nature protocols. 2014; 9(11):2539-54.

 

5. Discovery and characterization of new human viral pathogens

              My primary scientific passion is the discovery of new human pathogens through metagenomic sequencing.  My PhD work involved the discovery of salivirus, a novel and as-yet-unculturable picornavirus associated with up to 4% of pediatric diarrhea.  Serological screens indicated that most American blood donors are infected at a young age with salivirus and that only one serotype exists.  Attempts to culture salivirus virus have proven unsuccessful, so it has been characterized to date via culture-independent methods.  The same cohort in which salivirus was discovered was also used to discover Saffold virus, another novel human picornavirus that has been found in cases of pediatric encephalitis, diarrhea, and respiratory disease, with high levels of infection at a young age.  I am also a co-discoverer of a novel human polyomavirus as well as an avian bornavirus that is associated with proventricular dilatation disease.

1. Greninger AL, Runckel C, Chiu CY, Haggerty T, Parsonnet J, Ganem D, DeRisi JL. The complete genome of klassevirus - a novel picornavirus in pediatric stool.  Virology journal. 2009; 6:82.

2. Greninger AL, Holtz L, Kang G, Ganem D, Wang D, DeRisi JL. Serological evidence of human klassevirus infection. Clinical and vaccine immunology : CVI. 2010; 17(10):1584-8.

3. Yu G, Greninger AL, Isa P, Phan TG, Martínez MA, de la Luz Sanchez M, Contreras JF, Santos-Preciado JI, Parsonnet J, Miller S, DeRisi JL, Delwart E, Arias CF, Chiu CY. Discovery of a novel polyomavirus in acute diarrheal samples from children. PloS one. 2012; 7(11):e49449.

4. Chiu CY, Greninger AL, Kanada K, Kwok T, Fischer KF, Runckel C, Louie JK, Glaser CA, Yagi S, Schnurr DP, Haggerty TD, Parsonnet J, Ganem D, DeRisi JL. Identification of cardioviruses related to Theiler's murine encephalomyelitis virus in human infections. Proceedings of the National Academy of Sciences of the United States of America. 2008; 105(37):14124-9.

 

Complete List of Published Work in MyBibliography:  

https://www.ncbi.nlm.nih.gov/sites/myncbi/alex.greninger.1/bibliography/41271270/public/?sort=date&direction=ascending

 

D.              Additional Information: Research Support and/or Scholastic Performance

 

UM1AI068618 (McElrath)                                                         8/1/2020-6/30/2021 (NCE) 0.38 calendar

NIH/HIAID                                                                                                  $602,213 (sub only)

HVTN Laboratory Center CoVPN 5001/HVTN 406

To provide specialized diagnostic virology laboratory services for the study of the immune response to acute SARS-CoV-2 infection.

Role: Co-Inv

 

R01 AI132599 (Jerome)                                                                      06/12/2018 – 05/31/2023              0.44 Calendar

Fred Hutch through National Institute of Health

Endonuclease-mediated disruption of latent HSV as curative therapy

The primary objective of our study is to optimize and evaluate our approach to eliminate latent HSV infection in vivo using a murine model of HSV latent infection. Moreover, our results will be directly applicable in efforts to cure varicella zoster virus, another alphaherpesvirus that like HSV establishes latency in sensory neurons. Furthermore, the data generated will be highly relevant to the development of a cure of other chronic or latent viral infections such as hepatitis B virus, HIV, or human papillomavirus.

Role: Co-Investigator

 

R01 AI141222 (Plemper)                                                                      01/01/2019 – 12/31/2021              0.57 Calendar

Georgia State through NIH                                                       

Development of a Broad-Spectrum Inhibitor against Seasonal and Highly-Pathogenic Influenza Viruses

This subaward proposal covers testing of clinical samples via whole genome sequencing for a clinical trial of a novel polymerase-directed antiviral. Through whole genome sequencing of clinical samples containing influenza A virus, we will be able to detect potential resistance mutations against the antiviral agent in vivo as well as mechanisms of inhibition that affect viral genome replication.

Role: Sub PI

 

U19 AI144133 (Wald)                                                                      3/1/2019-2/29/24                            1.20 Calendar

National Institute of Health             

University of Washington (UW) Sexually Transmitted Infections (STI) Cooperative Research Center (CRC) - Syphilis vaccine to protect against local and disseminated T. pallidum infection

UW aims to meet this public health need by proposing a Sexually Transmitted Infection Cooperative Research Center (STI CRC) application focussed on syphilis vaccine development. The goal of our STI CRC is to develop an effective syphilis vaccine by the end of the 5 year grant timeframe that provides significant protection against T. pallidum infection and is in a format that is ready for human clinical trials.

Role: Genomics Core PI

 

UM1 AI148573 ( (Wald)                                                                      12/01/2019-11/30/2021              0.45 Calendar

National Institute of Health                                                       

University of Washington Vaccine and Treatment Evaluation Unit

The VTEU site award is a designation of the site for future clinical trials through the VTEU mechanism. The initial site award does not include trial-specific funding.

Role: Key Personnel

 

R01 AI147309 (Frenkel)                                                                      7/1/2019-6/30/2024                            0.90 Calendar

Seattle Children’s Research Institute             

Drug Resistance Genotypic and Phenotypic Correlates of Efavirenz and Dolutegravir Based Treatment Outcomes across Non-B HIV Subtypes

Our studies will clarify (1) the risks of specific DRM and MV across of non-B subtypes for VF; (2) interactions between DRM that determine phenotypic resistance associated with VF; (3) mutations selected by various regimens at VF; and (4) the combination of DRM that can be used for an effective point-of-care diagnostic assay. The long-term goal of this proposal is to provide data to enable best care practices in resource-limited-settings (RLS) in Africa and Asia

Role: Subaward Co-Investigator