About

Katherine Siddle is an assistant professor in the Department of Molecular Microbiology and Immunology at Brown University, with a primary appointment in the department and affiliations with the Center for Computational Biology and the Pandemic Center. Her research focuses on understanding how pathogens, particularly viruses, emerge, spread, and evolve, and the selective pressures this exerts on infected hosts. Her work integrates the analysis of large biological data sets, experimentation, and fieldwork to investigate the genetic diversity of emerging viruses and the role of host and pathogen genetic variation in disease severity. Siddle joined Brown University in January 2023 after completing her postdoctoral fellowship at the Broad Institute of MIT and Harvard in Pardis Sabeti's lab. She holds a BA and MPhil in Biological Anthropology from the University of Cambridge and a Ph.D. in human immunogenomics from the Institut Pasteur and the Université Pierre et Marie Curie in Paris.

Research topics

• Medicine
• Biology
• Virology
• Genetics
• Pathology
• Political Science
• Geography
• Evolutionary biology
• Immunology
• Computer Science
• Internal medicine
• Demography
• Environmental health
• Engineering
• Law
• Development economics
• Physics
• Paleontology
• Computational biology
• Economics
• Bioinformatics

Selected publications

• Oral and plasma microbiome in the context of acute febrile illness

  medRxiv · 2026-04-20

  articleOpen accessSenior author

  Abstract Emerging infectious diseases and antimicrobial resistance (AMR) have surfaced as two major public health threats over the past two decades. Consequently, integrative surveillance systems capable of detecting both emerging pathogens and resistance-carrying bacteria are crucial. With advances in next-generation sequencing, simultaneous detection of pathogens and AMR is increasingly feasible. In this study, we used short-read metatranscriptomics complemented by total 16S rRNA metagenomic long-read sequencing to analyze paired oral and plasma samples from a cohort of febrile individuals at two locations in Senegal. Oral microbiomes differed in community composition between locations, and reduced diversity and richness were significantly associated with high fever. We identified at least one known pathogen in 15.33 % (23/150) of samples, with Borrelia crocidurae as the most frequently detected pathogen. We detected both pathogenic and non-pathogenic viruses in oral (10/72) and plasma (09/78) samples. Finally, we observed a high frequency of genes associated with resistance and virulence: 10% of samples expressed at least one AMR gene (ARG), and 24% expressed virulence factor genes. Resistance to widely used beta-lactam antibiotics was the most prevalent. Our findings provide critical data on oral and plasma microbiomes in the context of acute febrile illness in Senegal while expanding understanding of circulating ARGs.

  PublisherDOI

• Genomic epidemiology as a tool for understanding drivers of hepatitis A community outbreaks in Massachusetts and New Hampshire

  medRxiv · 2026-05-19

  articleOpen access

  Abstract Despite the existence of an effective vaccine, the United States continues to experience outbreaks of hepatitis A, including in Massachusetts (MA) and New Hampshire (NH) in 2018 and again in MA in 2023. To clarify the relationship between these outbreaks and better understand their drivers, we generated hepatitis A virus whole genome sequences from reported cases and analyzed them using open-source genotyping tools developed and released as part of this study. We found that the 2018 and 2023 outbreaks were caused by distinct viral strains, despite affecting individuals with similar demographic characteristics and reported risk factors. Detailed analysis of genomic and epidemiologic data further resolved transmission patterns within and across outbreaks, showing that experiencing homelessness and prior use of drugs were associated with increased transmission while also revealing transmission between individuals with and without these risk factors, as well as spread across state borders. Together, these findings demonstrate the value of broadly accessible genomic tools for understanding hepatitis A outbreaks and illustrate how whole genome analysis can complement epidemiological investigation by resolving transmission patterns and outbreak drivers that can inform public health interventions.

  PublisherOA PDFDOI

• Best practices when benchmarking CATCH for the design of genome enrichment probes

  Bioinformatics · 2026-01-12 · 1 citations

  articleOpen access
  PublisherDOI

• Enhancing SARS-CoV-2 response capacity in Africa and other centers for research in emerging infectious diseases centres through a collaborative training programme

  Clinical Microbiology and Infection · 2025-10-11

  letterOpen access
  PublisherOA PDFDOI

• Genomic surveillance reveals age-structured SARS-CoV-2 transmission across demographics and settings

  medRxiv · 2025-04-06

  preprintOpen access

  Despite intensive study, gaps remain in our understanding of SARS-CoV-2 transmission patterns during the COVID-19 pandemic, in part due to limited contextual metadata accompanying most large genomic surveillance datasets. We analyzed over 130,000 SARS-CoV-2 genomes, over 85,000 with matched epidemiological data, collected in Massachusetts from November 2021 to January 2023, to investigate viral transmission dynamics at high resolution. The data were drawn from diagnostic testing at >600 facilities representing schools, workplaces, public testing, and other sectors, and encompass the emergence of six major viral lineages, each representing a new outbreak. We found urban areas as key hubs for new lineage introduction and interurban transmission as facilitating spread throughout the state. Young adults, especially those on college campuses, served as early indicators of emerging lineage dominance. Resident-aged populations in college campuses and nursing homes exhibited a higher likelihood of being linked to within-facility transmission, while staff-aged at those facilities were more linked to their surrounding community. Individuals with recent vaccine doses, including boosters, had a lower likelihood of initiating transmission. This dataset shows the value of linking genomic and epidemiologic data at scale for higher resolution insights into viral dynamics and their implication for public health strategy.

  PublisherOA PDFDOI

• SARS-CoV-2 Serosurveillance Reveals Pre-pandemic Cross-Reactivity and Pandemic Seroprevalence Trends in Senegal

  medRxiv · 2025-10-21

  preprintOpen access

  The relatively mild impact of COVID-19 in sub-Saharan Africa has raised questions about the role of pre-existing immunity in the region. One hypothesis for this unexpected observation is the presence of pre-existing cross-protective immunity, potentially induced by prior exposure to seasonal and zoonotic coronaviruses. However, the prevalence and functional relevance of such antibodies in the Senegalese population are not fully known. To investigate this, we conducted a cross-sectional seroprevalence study using 822 plasma samples collected in Senegal before (2017-2019) and during (2020-2022) the pandemic, across regions of high (Kédougou) and low (Thiès) malaria endemicity. Samples were screened for anti-SARS-CoV-2 spike 1 IgG using enzyme-linked immunosorbent assay (ELISA), and a subset of the pre-pandemic IgG-positive samples was further tested for neutralizing activity using a surrogate virus neutralization test (sVNT). Pre-pandemic SARS-CoV-2 IgG positivity was 39.1% [34.6 - 43.7]. No significant differences were observed in terms of age, sex, region, or malaria status. However, only 5.1% of pre-pandemic IgG-positive samples showed neutralizing activity, with 1.3% [0.1 - 6.7] in Kédougou and 9.2% [4.5 - 17.8] in Thiès. During the pandemic, IgG seroprevalence increased from the baseline around 40% in 2020 (37.3 % [27.7 - 48.1] in Kedougou and 50%[29.03 - 70.9%] in Thies), peaking near 99% of the study population by 2022 with 98.2% [93.8 - 99.5] in Kedougou and 98.8% [93.6 - 99.7] in Thies. These results indicate widespread pre-pandemic cross-reactivity to SARS-CoV-2 in Senegal, likely driven by exposure to related coronaviruses. However, their poor neutralizing activity implies limited cross-protection. These findings highlight the need for further investigation into the origins, nature, and immunological significance of these cross-reactive antibody responses.

  PublisherOA PDFDOI

• Investigating the etiologies of non-malarial febrile illness in Senegal using metagenomic sequencing

  Nature Communications · 2024-01-25 · 14 citations

  articleOpen accessSenior author

  The worldwide decline in malaria incidence is revealing the extensive burden of non-malarial febrile illness (NMFI), which remains poorly understood and difficult to diagnose. To characterize NMFI in Senegal, we collected venous blood and clinical metadata in a cross-sectional study of febrile patients and healthy controls in a low malaria burden area. Using 16S and untargeted sequencing, we detected viral, bacterial, or eukaryotic pathogens in 23% (38/163) of NMFI cases. Bacteria were the most common, with relapsing fever Borrelia and spotted fever Rickettsia found in 15.5% and 3.8% of cases, respectively. Four viral pathogens were found in a total of 7 febrile cases (3.5%). Sequencing also detected undiagnosed Plasmodium, including one putative P. ovale infection. We developed a logistic regression model that can distinguish Borrelia from NMFIs with similar presentation based on symptoms and vital signs (F1 score: 0.823). These results highlight the challenge and importance of improved diagnostics, especially for Borrelia, to support diagnosis and surveillance.

  PublisherOA PDFDOI

• Genome-wide association study identifies human genetic variants associated with fatal outcome from Lassa fever

  Nature Microbiology · 2024-02-07 · 10 citations

  articleOpen access

  Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays. We analysed Lassa fever susceptibility and fatal outcomes in 533 cases of Lassa fever and 1,986 population controls recruited over a 7 year period in Nigeria and Sierra Leone. We detected genome-wide significant variant associations with Lassa fever fatal outcomes near GRM7 and LIF in the Nigerian cohort. We also show that a haplotype bearing signatures of positive selection and overlapping LARGE1, a required LASV entry factor, is associated with decreased risk of Lassa fever in the Nigerian cohort but not in the Sierra Leone cohort. Overall, we identified variants and genes that may impact the risk of severe Lassa fever, demonstrating how GWAS can provide insight into viral pathogenesis.

  PublisherOA PDFDOI

• Polyphonia: detecting inter-sample contamination in viral genomic sequencing data

  Bioinformatics · 2024-11-28 · 1 citations

  articleOpen access

  SUMMARY: In viral genomic research and surveillance, inter-sample contamination can affect variant detection, analysis of within-host evolution, outbreak reconstruction, and detection of superinfections and recombination events. While sample barcoding methods exist to track inter-sample contamination, they are not always used and can only detect contamination in the experimental pipeline from the point they are added. The underlying genomic information in a sample, however, carries information about inter-sample contamination occurring at any stage. Here, we present Polyphonia, a tool for detecting inter-sample contamination directly from deep sequencing data without the need for additional controls, using intrahost variant frequencies. We apply Polyphonia to 1102 SARS-CoV-2 samples sequenced at the Broad Institute and already tracked using molecular barcoding for comparison. AVAILABILITY AND IMPLEMENTATION: Polyphonia is available as a standalone Docker image and is also included as part of viral-ngs, available in Dockstore. Full documentation, source code, and instructions for use are available at https://github.com/broadinstitute/polyphonia.

  PublisherOA PDFDOI

• High-depth sequencing characterization of viral dynamics across tissues in fatal COVID-19 reveals compartmentalized infection

  Nature Communications · 2023-02-02 · 23 citations

  articleOpen accessCorresponding

  SARS-CoV-2 distribution and circulation dynamics are not well understood due to challenges in assessing genomic data from tissue samples. We develop experimental and computational workflows for high-depth viral sequencing and high-resolution genomic analyses from formalin-fixed, paraffin-embedded tissues and apply them to 120 specimens from six subjects with fatal COVID-19. To varying degrees, viral RNA is present in extrapulmonary tissues from all subjects. The majority of the 180 viral variants identified within subjects are unique to individual tissue samples. We find more high-frequency (>10%) minor variants in subjects with a longer disease course, with one subject harboring ten such variants, exclusively in extrapulmonary tissues. One tissue-specific high-frequency variant was a nonsynonymous mutation in the furin-cleavage site of the spike protein. Our findings suggest adaptation and/or compartmentalized infection, illuminating the basis of extrapulmonary COVID-19 symptoms and potential for viral reservoirs, and have broad utility for investigating human pathogens.

  PublisherOA PDFDOI

Frequent coauthors

• Pardis C. Sabeti

  339 shared

• S. F. Schaffner

  Broad Institute

  125 shared

• Bronwyn MacInnis

  Broad Institute

  91 shared

• Jacob E. Lemieux

  Massachusetts General Hospital

  71 shared

• Christian T. Happi

  Redeemer's University

  69 shared

• Gordon Adams

  Broad Institute

  68 shared

• Kayla G. Barnes

  Broad Institute

  67 shared

• Erica Normandin

  Center for Systems Biology

  66 shared

Labs

• Molecular Microbiology and ImmunologyPI

Education

• Ph.D., human immunogenomics

  Institut Pasteur and Université Pierre et Marie Curie

• Other, Biological Anthropology

  University of Cambridge

• B.A., Biological Anthropology

  University of Cambridge

Awards & honors

• COBRE Computational Biology of Human Disease pilot award (20…