Pardis C Sabeti

Pardis C Sabeti
Harvard University | Harvard · Department of Organismic and Evolutionary Biology

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415
Publications
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Publications

Publications (415)
Preprint
Universities are particularly vulnerable to infectious disease outbreaks and are also ideal environments to study transmission dynamics and evaluate mitigation and surveillance measures when outbreaks occur. Here, we introduce a SARS-CoV-2 surveillance and response framework based on high-resolution, multimodal data collected during the 2020-2021 a...
Preprint
Viral genomic surveillance has been integral in the global response to the SARS-CoV-2 pandemic. Surveillance efforts rely on the availability of representative clinical specimens from ongoing testing activities. However, testing practices have recently shifted due to the widespread availability and use of rapid antigen tests, which could lead to ga...
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Full-text available
The widespread transmission and evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) call for rapid nucleic acid diagnostics that are easy to use outside of centralized clinical laboratories. Here we report the development and performance benchmarking of Cas13-based nucleic acid assays leveraging lyophilised reagents and fast s...
Article
Background The Omicron variant of SARS-CoV-2 is highly transmissible in vaccinated and unvaccinated populations. The dynamics governing its establishment and propensity towards fixation (reaching 100% frequency in the SARS-CoV-2 population) in communities remain unknown. In this work, we describe the dynamics of Omicron at three institutions of hig...
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Full-text available
Repeated emergence of SARS-CoV-2 variants with increased fitness underscores the value of rapid detection and characterization of new lineages. We have developed PyR 0 , a hierarchical Bayesian multinomial logistic regression model that infers relative prevalence of all viral lineages across geographic regions, detects lineages increasing in preval...
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Full-text available
The COVID-19 pandemic has demonstrated a clear need for high-throughput, multiplexed, and sensitive assays for detecting SARS-CoV-2 and other respiratory viruses as well as their emerging variants. Here, we present a cost-effective virus and variant detection platform, called microfluidic CARMEN (mCARMEN), that combines CRISPR-based diagnostics and...
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Full-text available
Rapid and accurate diagnosis of infections is fundamental to individual patient care and public health management. Nucleic acid detection methods are critical to this effort, but are limited either in the breadth of pathogens targeted or by the expertise and infrastructure required. We present here a high-throughput system that enables rapid identi...
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Full-text available
Design of nucleic acid-based viral diagnostics typically follows heuristic rules and, to contend with viral variation, focuses on a genome’s conserved regions. A design process could, instead, directly optimize diagnostic effectiveness using a learned model of sensitivity for targets and their variants. Toward that goal, we screen 19,209 diagnostic...
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Full-text available
The SARS-CoV-2 Delta variant rose to dominance in mid-2021, likely propelled by an estimated 40-80% increased transmissibility over Alpha. To investigate if this ostensible difference in transmissibility is uniform across populations, we partner with public health programs from all six states in New England, USA. We compare logistic growth rates du...
Preprint
Operation Outbreak (OO), an app-based, educational outbreak simulator, seeks to engage, educate, and empower citizens to prevent and better respond to infectious disease outbreaks. We examine the utility of OO for further understanding and mitigating the spread of communicable diseases. The OO smartphone app uses Bluetooth to spread a virtual patho...
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Full-text available
Amid COVID-19, many institutions deployed vast resources to test their members regularly for safe reopening. This self-focused approach, however, not only overlooks surrounding communities but also remains blind to community transmission that could breach the institution. To test the relative merits of a more altruistic strategy, we built an epidem...
Article
Full-text available
Amid COVID-19, many institutions deployed vast resources to test their members regularly for safe reopening. This self-focused approach, however, not only overlooks surrounding communities but also remains blind to community transmission that could breach the institution. To test the relative merits of a more altruistic strategy, we built an epidem...
Article
Background The Covid19 pandemic has reignited debates and discussions around healthcare systems' biosecurity vulnerabilities and cast a spotlight on the potential weaponization of biological agents. Terrorist and violent extremist groups have already attempted to incite the intentional spread of Covid19 and to use it as an improvised form of a biol...
Preprint
Full-text available
The Omicron variant of SARS-CoV-2 is transmissible in vaccinated and unvaccinated populations. Here, we describe the rapid dominance of Omicron following its introduction to three Massachusetts universities with asymptomatic surveillance programs. We find that Omicron was established and reached fixation earlier on these campuses than in Massachuse...
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Full-text available
College campuses are vulnerable to infectious disease outbreaks, and there is an urgent need to develop better strategies to mitigate their size and duration, particularly as educational institutions around the world adapt to in-person instruction during the COVID-19 pandemic. Towards addressing this need, we applied a stochastic compartmental mode...
Preprint
Full-text available
Long non-coding RNAs (lncRNAs) are pivotal mediators of systemic immune response to viral infection, yet most studies concerning their expression and functions upon immune stimulation are limited to in vitro bulk cell populations. This strongly constrains our understanding of how lncRNA expression varies at single-cell resolution, and how their cel...
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Full-text available
The global spread and continued evolution of SARS-CoV-2 has driven an unprecedented surge in viral genomic surveillance. Amplicon-based sequencing methods provide a sensitive, low-cost and rapid approach but suffer a high potential for contamination, which can undermine laboratory processes and results. This challenge will increase with the expandi...
Preprint
Full-text available
The COVID-19 pandemic has demonstrated a clear need for high-throughput, multiplexed, and sensitive assays for detecting SARS-CoV-2 and other respiratory viruses as well as their emerging variants. Here, we present microfluidic CARMEN (mCARMEN), a cost-effective virus and variant detection platform that combines CRISPR-based diagnostics and microfl...
Article
Full-text available
An outbreak of over one thousand COVID-19 cases in Provincetown, Massachusetts, in July 2021—the first large outbreak mostly in vaccinated individuals in the US—prompted a comprehensive public health response, motivating changes to national masking recommendations and raising questions about infection and transmission among vaccinated individuals....
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Full-text available
Many countries in sub-Saharan Africa have experienced lower COVID-19 caseloads and fewer deaths than countries in other regions worldwide. Under-reporting of cases and a younger population could partly account for these differences, but pre-existing immunity to coronaviruses is another potential factor. Blood samples from Sierra Leonean Lassa fever...
Preprint
Rapid and accurate diagnosis of infections is fundamental to individual patient care and public health management. Nucleic acid detection methods are critical to this effort, but are limited either in the breadth of pathogens targeted or by the expertise and infrastructure required. We present here a high-throughput system that enables rapid identi...
Preprint
Full-text available
The COVID-19 pandemic, and the recent rise and widespread transmission of SARS-CoV-2 Variants of Concern (VOCs), have demonstrated the need for ubiquitous nucleic acid testing outside of centralized clinical laboratories. Here, we develop SHINEv2, a Cas13-based nucleic acid diagnostic that combines quick and ambient temperature sample processing an...
Preprint
Multiple summer events, including large indoor gatherings, in Provincetown, Massachusetts (MA), in July 2021 contributed to an outbreak of over one thousand COVID-19 cases among residents and visitors. Most cases were fully vaccinated, many of whom were also symptomatic, prompting a comprehensive public health response, motivating changes to nation...
Article
While some variation introgressed from Neanderthals has undergone selective sweeps, little is known about its functional significance. We used a Massively Parallel Reporter Assay (MPRA) to assay 5,353 high-frequency introgressed variants for their ability to modulate the gene expression within 170bp of endogenous sequence. We identified 2,548 varia...
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Full-text available
Although some variation introgressed from Neanderthals has undergone selective sweeps, little is known about its functional significance. We used a Massively Parallel Reporter Assay (MPRA) to assay 5,353 high-frequency introgressed variants for their ability to modulate the gene expression within 170 bp of endogenous sequence. We identified 2,548 v...
Preprint
Full-text available
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant quickly rose to dominance in mid-2021, displacing other variants, including Alpha. Studies using data from the United Kingdom and India estimated that Delta was 40-80% more transmissible than Alpha, allowing Delta to become the globally dominant variant. However, it was...
Article
Objective Little is known about CSF profiles in patients with acute COVID-19 infection and neurological symptoms. Here, CSF was tested for SARS-CoV-2 RNA and inflammatory cytokines and chemokines and compared to controls and patients with known neurotropic pathogens. Methods CSF from twenty-seven consecutive patients with COVID-19 and neurological...
Preprint
Full-text available
Repeated emergence of SARS-CoV-2 variants with increased transmissibility necessitates rapid detection and characterization of new lineages. To address this need, we developed PyR 0 , a hierarchical Bayesian multinomial logistic regression model that infers relative transmissibility of all viral lineages across geographic regions, detects lineages...
Preprint
Full-text available
Despite the great success of genome-wide association studies (GWAS) in identifying genetic loci significantly associated with diseases, the vast majority of causal variants underlying disease-associated loci have not been identified. To create an atlas of causal variants, we performed and integrated fine-mapping across 148 complex traits in three l...
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Full-text available
Replacing or editing disease-causing mutations holds great promise for treating many human diseases. Yet, delivering therapeutic genetic modifiers to specific cells in vivo has been challenging, particularly in large, anatomically distributed tissues such as skeletal muscle. Here, we establish an in vivo strategy to evolve and stringently select ca...
Article
3′ untranslated region (3′UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the massively parallel reporter assay for 3′UTRs (MPRAu) to sensitively assay 12,173 3′UTR variants. We applied MPRAu to six human cell lines, focusing on genetic variants associated with genome-wide as...
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Full-text available
Effective interpretation of genome function and genetic variation requires a shift from epigenetic mapping of cis-regulatory elements (CREs) to characterization of endogenous function. We developed hybridization chain reaction fluorescence in situ hybridization coupled with flow cytometry (HCR–FlowFISH), a broadly applicable approach to characteriz...
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Full-text available
COVID-19, caused by SARS-CoV-2, can result in acute respiratory distress syndrome and multiple-organ failure1–4, but little is known about its pathophysiology. Here, we generated single-cell atlases of 23 lung, 16 kidney, 16 liver and 19 heart COVID-19 autopsy donor tissue samples, and spatial atlases of 14 lung donors. Integrated computational ana...
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Full-text available
T cell-mediated immunity plays an important role in controlling SARS-CoV-2 infection; yet the repertoire of naturally processed and presented viral epitopes on HLA class I remains uncharacterized. Here, we report the first HLA-I immunopeptidome of SARS-CoV-2 in two cell lines at different times post-infection using mass spectrometry. We found HLA-I...
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Full-text available
Developing and deploying new diagnostic tests are difficult, but the need to do so in response to a rapidly emerging pandemic such as COVID-19 is crucially important. During a pandemic, laboratories play a key role in helping healthcare providers and public health authorities detect active infection, a task most commonly achieved using nucleic acid...
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Full-text available
Dengue virus is a major and rapidly growing public health concern in tropic and subtropic regions across the globe. In late 2018, Senegal experienced its largest dengue virus outbreak to date, covering several regions. However, little is known about the genetic diversity of dengue virus (DENV) in Senegal. Here we report complete viral genomes from...
Article
We present a case of a liver transplant recipient with 2 distinct SARS-CoV-2 infections, separated by 111 days without symptoms and 2 negative test results for SARS-CoV-2 infection. The clinical course suggested reinfection, and viral genomic sequencing was used to distinguish whether the later positive samples were due to SARS-CoV-2 relapse or rei...
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Full-text available
Despite numerous viral outbreaks in the last decade, including a devastating global pandemic, diagnostic and therapeutic technologies remain severely lacking. CRISPR-Cas systems have the potential to address these critical needs in the response against infectious disease. Initially discovered as the bacterial adaptive immune system, these systems p...
Preprint
Full-text available
Amid COVID-19, many institutions deployed vast resources to test their members regularly for safe reopening. This self-focused approach, however, not only overlooks surrounding communities but also remains blind to community transmission that could breach the institution. To test the relative merits of a more altruistic strategy, we built an epidem...
Preprint
Full-text available
The rapid global spread and continued evolution of SARS-CoV-2 has highlighted an unprecedented need for viral genomic surveillance and clinical viral sequencing. Amplicon-based sequencing methods provide a sensitive, low-cost and rapid approach but suffer a high potential for contamination, which can undermine lab processes and results. This challe...
Preprint
Full-text available
The SARS-CoV-2 pandemic has caused over 1 million deaths globally, mostly due to acute lung injury and acute respiratory distress syndrome, or direct complications resulting in multiple-organ failures. Little is known about the host tissue immune and cellular responses associated with COVID-19 infection, symptoms, and lethality. To address this, we...
Article
The enormous U.S. toll of Covid-19 is attributable in part to the lack of an effective testing regimen. But by building distributed capacity and prioritizing resources appropriately, we can change our trajectory in fighting this pandemic and preempting future ones.
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Full-text available
We evaluated the incidence, distribution, and histopathologic correlates of microvascular brain lesions in patients with severe COVID-19. Sixteen consecutive patients admitted to the intensive care unit with severe COVID-19 undergoing brain MRI for evaluation of coma or neurologic deficits were retrospectively identified. Eleven patients had puncta...
Preprint
Full-text available
3'untranslated region (3'UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the Massively Parallel Reporter Assay for 3'UTRs (MPRAu) to sensitively assay 12,173 3'UTR variants. We applied MPRAu to six human cell lines, focusing on genetic variants associated with genome-wide ass...
Article
Full-text available
College campuses are highly vulnerable to infectious disease outbreaks, and there is a pressing need to develop better strategies to mitigate their size and duration, particularly as educational institutions around the world reopen to in-person instruction in the midst of the COVID-19 pandemic. Towards addressing this need, we applied a stochastic...
Article
Full-text available
Phylogenetics of superspreading One important characteristic of coronavirus epidemiology is the occurrence of superspreading events. These are marked by a disproportionate number of cases originating from often-times asymptomatic individuals. Using a rich sequence dataset from the early stages of the Boston outbreak, Lemieux et al. identified super...
Preprint
Full-text available
Harnessing genomic data and predictive models will provide activity-informed diagnostic assays for thousands of viruses and offer rapid design for novel ones. Here we develop and extensively validate new algorithms that design nucleic acid assays having maximal predicted detection activity over a virus’s full genomic diversity with stringent specif...
Preprint
Full-text available
Dengue virus is a major and rapidly growing public health concern in tropic and subtropic regions across the globe. In late 2018, Senegal experienced its largest dengue virus outbreak to date, covering several regions. However, little is known about the genetic diversity of dengue virus (DENV) in Senegal. Here we used molecular tools including meta...
Article
Full-text available
The COVID-19 pandemic has highlighted that new diagnostic technologies are essential for controlling disease transmission. Here, we develop SHINE (Streamlined Highlighting of Infections to Navigate Epidemics), a sensitive and specific diagnostic tool that can detect SARS-CoV-2 RNA from unextracted samples. We identify the optimal conditions to allo...
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Full-text available
Ebola virus (EBOV) causes epidemics with high mortality yet remains understudied due to the challenge of experimentation in high-containment and outbreak settings. Here, we used single-cell transcriptomics and CyTOF-based single-cell protein quantification to characterize peripheral immune cells during EBOV infection in rhesus monkeys. We obtained...
Article
Full-text available
T cell-mediated immunity may play a critical role in controlling and establishing protective immunity against SARS-CoV-2 infection; yet the repertoire of viral epitopes responsible for T cell response activation remains mostly unknown. Identification of viral peptides presented on class I human leukocyte antigen (HLA-I) can reveal epitopes for reco...
Article
The SARS-CoV-2 spike (S) protein variant D614G supplanted the ancestral virus worldwide, reaching near fixation in a matter of months. Here we show that D614G was more infectious than the ancestral form on human lung cells, colon cells, and on cells rendered permissive by ectopic expression of human ACE2 or of ACE2 orthologs from various mammals, i...
Article
Operation Outbreak (OO) is a simulation platform that teaches students how pathogens spread and the impact of interventions, thereby facilitating the safe re-opening of schools. In addition, OO generates data to inform epidemiological models and prevent future outbreaks. Before SARS-CoV-2 was reported we repeatedly simulated a virus with similar fe...
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Full-text available
Background Powassan virus (POWV) is an emerging cause of severe encephalitis; very little is known about human pathogenicity due to challenges in diagnosis and viral RNA recovery. We present three patients with fatal encephalitis due to POWV lineage II (deer tick virus). Methods We obtained 27 unique samples, including from brain biopsy and autops...
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Full-text available
SARS-CoV-2 has caused a severe, ongoing outbreak of COVID-19 in Massachusetts with 111,070 confirmed cases and 8,433 deaths as of August 1, 2020. To investigate the introduction, spread, and epidemiology of COVID-19 in the Boston area, we sequenced and analyzed 772 complete SARS-CoV-2 genomes from the region, including nearly all confirmed cases wi...
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Full-text available
Recent outbreaks of viral hemorrhagic fevers (VHFs), including Ebola virus disease (EVD) and Lassa fever (LF), highlight the urgent need for sensitive, deployable tests to diagnose these devastating human diseases. Here we develop CRISPR-Cas13a-based (SHERLOCK) diagnostics targeting Ebola virus (EBOV) and Lassa virus (LASV), with both fluorescent a...