Pediatric Infectious Diseases

Flores
Streptococcal
Laboratory

Advancing our understanding of streptococcal pathogenesis, antimicrobial resistance, and epidemiology to develop better prevention and treatment strategies.

AF
Anthony R. Flores, MD, MPH, PhD
Principal Investigator
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Research Area 01
Group A Streptococcus
LiaFSR · SpxA2 · emm4 Emergence
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Research Area 02
Group B Streptococcus
Capsular Polysaccharide Type V · ST1 · Adult Disease
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Research Area 03
Epidemiology of Gram-Positive Pathogens
Clinical Epidemiology · Genomic Epidemiology · Surveillance
Contact the Lab
Inquiries — Collaborations & Opportunities
anthony.flores@vumc.org
50+
Peer-Reviewed
Publications
3
Active Research
Programs
NIH
Funded
Research
20+
Years of
Research
Research Area 01

Group A
Streptococcus

Streptococcus pyogenes (Group A Streptococcus, GAS) causes more than 700 million infections and over 500,000 deaths annually. Our laboratory investigates three integrated research programs focused on gene regulatory systems, transcriptional regulators, and epidemic clonal emergence.

  • Cell envelope stress signaling through the LiaFSR three-component system
  • Distinct roles of Spx family transcriptional regulators (SpxA1, SpxA2) in virulence
  • Carbonic anhydrase-mediated epidemic clonal emergence in emm4 GAS
  • Host inflammatory response manipulation and immune cell interactions
  • Global transcriptome regulation and virulence gene expression
Major Research Themes
Gene Regulatory SystemsTwo-component and three-component systems responding to host antimicrobial stress
Transcriptional RegulatorsSpx paralogs that distinctly modulate gene expression and host immune responses
Epidemic Clone EmergenceHow novel emm4 strains replaced circulating isolates over two decades in North America
Host Immune EvasionGAS manipulation of macrophage and neutrophil responses to promote survival
Current Project — NIH-Funded
LiaFSR: Cell Envelope Stress Response and Pathogenesis
The LiaFSR three-component system (3CS) is unique to Gram-positive bacteria and responds to host antimicrobial peptide (AMP)-induced cell envelope stress. A single amino acid change in LiaS significantly alters the GAS phenotype, trading decreased virulence for enhanced colonization and persistence. We are advancing our understanding of LiaFSR’s mechanism of activation, downstream gene regulatory network, and role in GAS pathogenesis.
Major Themes
  • LiaFSR responds to AMP-induced cell envelope stress and regulates a gene network that includes the transcriptional regulator SpxA2
  • LiaF localizes within the functional membrane microdomain (ExPortal); its cytoplasmic C-terminal domain governs interaction with LiaS
  • Cardiolipin (CL) in the GAS membrane is essential for LiaS localization to the ExPortal; specific CL-binding motifs in LiaS determine membrane topology and activation
  • Disruption of LiaFSR alters virulence factor transcription and in vivo pathogenesis across multiple infection models
  • High conservation of LiaFSR across Gram-positive pathogens positions findings as broadly translatable to novel anti-infective targets
Current Project — NIH-Funded
SpxA1 and SpxA2: Defining the Contribution of Spx Paralogs to GAS Pathogenesis
GAS encodes two Spx family paralogs (SpxA1, SpxA2) that interact with the α-CTD of RNA polymerase to regulate global gene expression. Only SpxA2 is regulated by LiaR, and changes in SpxA2 levels associate with phosphorylation of CovR, a master virulence regulator. Our preliminary data reveal distinct transcriptomes associated with each paralog, indicating independent and divergent regulatory roles in GAS biology and host immune interaction.
Major Themes
  • SpxA1 and SpxA2 regulate distinct transcriptomes in response to oxidative and AMP-induced cell envelope stress
  • Amino acid differences in the C-terminal α-helix determine divergent σ-factor interactions and gene regulatory outputs of each paralog
  • SpxA2 expression is tightly linked to the LiaFSR pathway; SpxA1 operates in an independent regulatory circuit
  • Spx paralogs differentially modulate innate immune cell responses (neutrophils, macrophages) and cytokine output to GAS infection
  • Spatially resolved transcriptomics (GeoMx®) reveals tissue-level host immune regulons associated with individual Spx paralog activity in vivo
Current Project — NIH-Funded
emm4 GAS Epidemic Clonal Emergence: The Role of Carbonic Anhydrase
Our group described epidemic clone emergence within emm4 GAS in which a novel lineage progressively replaced ancestral strains over 20 years in North America. Paradoxically, emergent strains show downregulation of key virulence factors (including nga/slo) yet are more virulent in human blood and murine models. We discovered that a mutation eliminating carbonic anhydrase (CA) activity is the key driver of this emergent phenotype, positioning our work as a new paradigm for understanding bacterial epidemic emergence.
Major Themes
  • Loss of CA activity distinguishes emergent from historical emm4 GAS and drives clonal replacement dynamics over two decades
  • Emergent strains downregulate nga/slo and classical virulence factors, yet survive better inside macrophages — challenging the prevailing model of ever-increasing virulence
  • Absence of CA activity alters the global GAS transcriptome, including virulence factor expression during interaction with human immune cells
  • The emergent phenotype is linked to altered macrophage IL-1β response, implicating inflammasome-mediated pathways in clonal success
  • Provides a new paradigm: epidemic GAS emergence can be driven by adaptation favoring host cell survival over overt cytotoxicity
Research Area 02

Group B
Streptococcus

Streptococcus agalactiae (Group B Streptococcus, GBS) remains a leading cause of neonatal sepsis and meningitis and is now the most frequent cause of invasive bacterial disease in non-pregnant adults — with over 30,000 cases annually in the United States. Our laboratory investigates the mechanisms underlying adult GBS invasive disease, with emphasis on capsular polysaccharide type V (CPS V) and ST1 emergence.

  • Population genomics of CPS V GBS causing adult invasive disease
  • ST1 predominance: gene content, global gene regulation, and enhanced virulence
  • Two-component regulatory system RDF_0314/0315 under strong host selective pressure
  • Molecular mechanisms distinguishing major GBS sequence types
  • Emergence and clonal replacement dynamics in GBS adult populations
Major Research Themes
Adult GBS DiseaseDefining pathophysiology and virulence mechanisms in a growing, understudied patient population
Capsular Type V BiologyCPS V has become the most frequent type in adult invasive disease, preferentially infecting adults over young infants
ST1 Clonal EmergenceST1 now predominates among CPS V adult isolates; regulatory evolution drives this clonal success
Regulatory DiversityTCS RDF_0314/0315 is under strong host selective pressure and is hypothesized critical to ST1 pathogenesis
Current Project — NIH-Funded
CPS V GBS: Emergence and Pathogenesis of ST1 in Adult Invasive Disease
GBS capsular polysaccharide type V (CPS V) was first recognized clinically in the 1990s and by 2009 had become the most frequent CPS type causing adult GBS disease (~30% of isolates). Our group performed one of the only phylogenomic studies of CPS V adult invasive isolates, demonstrating that over 200 WGS-characterized strains are almost exclusively ST1 and evolve through small genetic changes rather than large-scale recombination. A putative TCS, RDF_0314/0315, emerged as among the most highly polymorphic loci under strong host selective pressure.
Major Themes
  • ST1 CPS V GBS has progressively displaced non-ST1 strains; early (pre-1990s) isolates were more commonly non-ST1, while contemporary isolates are overwhelmingly ST1
  • Distinct gene content, global gene expression, and enhanced virulence in model systems collectively distinguish ST1 from non-ST1 CPS V GBS
  • TCS RDF_0314/0315 is conserved across GBS serotypes but carries serotype V-specific polymorphisms; it putatively regulates surface proteins BibA and pilus 2a and the arginine deiminase pathway
  • Population genomic analysis of >800 GBS genomes reveals distinct ST-defined subpopulations with divergent regulatory gene mutation profiles, suggesting regulatory evolution as a key driver of adult disease emergence
  • CPS V adult disease serves as a model for understanding GBS evolution across age groups and informs future vaccine and therapeutic target prioritization
Program Context
Evolving GBS Disease Epidemiology
GBS adult invasive disease incidence has risen steadily over three decades. CDC ABCs data estimate over 30,000 invasive GBS cases annually in the US, with the majority now in non-pregnant adults rather than neonates. Macrolide resistance among infant invasive isolates has similarly evolved over 50+ years (1970–2021), reflecting ongoing population-level genomic change. Our epidemiological and genomic work directly characterizes these trends and identifies their molecular drivers.
Research Area 03

Epidemiology of
Gram-Positive
Pathogens

The Flores laboratory has a long-standing program in clinical and genomic epidemiology of Gram-positive pathogens — principally GAS and GBS, but also S. pneumoniae, S. aureus, and the S. anginosus group. We integrate population-based surveillance with whole-genome sequencing to characterize disease burden, track emerging strains, and detect clonal replacement events.

  • Population-based surveillance for invasive streptococcal disease in children and adults
  • Secular trends in disease incidence and impact of population-level events (e.g., COVID-19)
  • WGS-based population genomics and phylogenomics
  • Clonal replacement events across GAS emm types and GBS serotypes
  • Antibiotic resistance epidemiology and genomic surveillance of resistance determinants
Program Highlights
Clinical SurveillancePediatric and adult invasive disease incidence, risk factors, and outcomes at single-center and national levels
Genomic EpidemiologyWGS integrated with epidemiological data to characterize population structure, clonal emergence, and resistance evolution
Multi-Pathogen ScopeGAS, GBS, S. pneumoniae, S. aureus, and the Streptococcus anginosus group
Public Health TranslationDirectly informing CDC surveillance, antibiotic stewardship, and clinical guidelines

Clinical Epidemiology
Population-based studies and retrospective clinical analyses characterizing the incidence, risk factors, and outcomes of invasive Gram-positive infections in pediatric and adult populations. Key work includes documenting the impact of COVID-19 on non-SARS-CoV-2 invasive bacterial infections, defining pediatric invasive GAS disease trends, and characterizing emerging clinical syndromes.
Pediatric Invasive GAS
Invasive Group A Streptococcus in Infants <1 Year of Age, 2012–2022: Single-Center Experience
J Pediatric Infect Dis Soc · 2023
Pandemic Epidemiology
Indirect Impact of the SARS-CoV-2 Pandemic on Invasive GAS, S. pneumoniae, and S. aureus Infections in Houston Area Children
Pediatr Infect Dis J · 2021
National Surveillance
Toward an Understanding of Group A Streptococcal Transmission Dynamics Using National-Level Surveillance
Clin Infect Dis · 2020
Pediatric GAS Strains
Capsule-Negative emm Types Are an Increasing Cause of Pediatric Group A Streptococcal Infections at a Large Pediatric Hospital in Texas
J Pediatric Infect Dis Soc · 2019
Emerging Infections
Increasing Incidence of Streptococcus anginosus Group Intracranial Infections Associated With Sinusitis, Otitis Media, and Mastoiditis in Children
Pediatr Infect Dis J · 2024
GBS Resistance Epidemiology
Evolving Antibiotic Resistance in Group B Streptococci Causing Invasive Infant Disease: 1970–2021
Pediatr Res · 2022

Genomic Epidemiology
Whole-genome sequencing applied to the population structure of streptococcal pathogens, tracking clonal replacement events and defining the genomic determinants of epidemic emergence. Work spans GAS emm type populations and GBS serotypes in collaboration with domestic and international partners.
GAS Population Genomics
Population Genomics of emm4 Group A Streptococcus Reveals Progressive Replacement with a Hypervirulent Clone in North America
mSystems · 2021
GBS Population Genomics
Population Genomics Reveals Distinct Temporal Association with the Emergence of ST1 Serotype V GBS and Macrolide Resistance in North America
Antimicrob Agents Chemother · 2021
GAS Clonal Emergence
Emergent emm4 GAS Evidences a Survival Strategy During Interaction with Immune Effector Cells
Infect Immun · 2024
GBS Serotype IV
Emergence of Serotype IV GBS Adult Invasive Disease in Manitoba and Saskatchewan, Canada, Driven by Clonal ST459 Strains
J Clin Microbiol · 2021
GAS Transcriptomics
Transcriptome Remodeling Contributes to Epidemic Disease Caused by the Human Pathogen Streptococcus pyogenes
mBio · 2020
GAS Virulence Genomics
The Majority of 9,729 Group A Streptococcus Strains Causing Disease Secrete SpeB Cysteine Protease: Pathogenesis Implications
Infect Immun · 2021
PubMed-Sourced

Publications

Peer-reviewed publications from the Flores Streptococcal Laboratory. Data sourced directly from PubMed. Click any DOI link to view the full article.

All GAS GBS Epidemiology AMR Host–Pathogen
2025
Comparison of cytokine responses to group B Streptococcus infection in a human maternal-fetal interface organ-on-a-chip system and culture model of human gestational membranes.
GBSHost–Pathogen
Infect Immun · 2025DOI ↗PubMed ↗
2024
Acute Rheumatic Fever During a Surge of Group A Streptococcus Disease in a US Children’s Hospital System.
GASEpidemiology
J Pediatric Infect Dis Soc · 2024PubMed ↗
Postpandemic Surges Proving the Mettle of Group A Streptococcus — Rising to the Occasion.
GASEpidemiology
JAMA Netw Open · 2024PubMed ↗
LiaR-dependent gene expression contributes to antimicrobial responses in group A Streptococcus.
GASAMRHost–Pathogen
Antimicrob Agents Chemother · 2024PubMed ↗
Increasing Incidence of Streptococcus anginosus Group Intracranial Infections Associated With Sinusitis, Otitis Media, and Mastoiditis in Children.
Epidemiology
Pediatr Infect Dis J · 2024DOI ↗PubMed ↗
Emergent emm4 Group A Streptococcus evidences a survival strategy during interaction with immune effector cells.
GASEpidemiologyHost–Pathogen
Infect Immun · 2024DOI ↗PubMed ↗
2023
Invasive Group A Streptococcus in Infants Less Than 1-year of Age From 2012 to 2022: A Single-Center Experience.
GASEpidemiology
J Pediatric Infect Dis Soc · 2023DOI ↗PubMed ↗
Gestational diabetes augments group B Streptococcus infection by disrupting maternal immunity and the vaginal microbiota.
GBSHost–Pathogen
Nat Commun · 2023PubMed ↗
Identification of distinct impacts of CovS inactivation on the transcriptome of acapsular group A streptococci.
GASHost–Pathogen
J Bacteriol · 2023PubMed ↗
Hyperphosphorylation of the Group A Streptococcal Control of Virulence Regulator Increases Promoter Occupancy Specifically at Virulence Genes.
GASHost–Pathogen
J Bacteriol · 2023PubMed ↗
2022
Evolving antibiotic resistance in Group B Streptococci causing invasive infant disease: 1970–2021.
GBSAMREpidemiology
Pediatr Res · 2022DOI ↗PubMed ↗
Increases in group A streptococcal infections in the pediatric population in Houston, TX, 2022.
GASEpidemiology
Clin Infect Dis · 2022PubMed ↗
The Integrative Conjugative Element ICESpyM92 Contributes to Pathogenicity of Emergent Antimicrobial-Resistant Group A Streptococcus.
GASAMR
Infect Immun · 2022PubMed ↗
Use of whole-genome sequencing to detect transmission of group A Streptococcus in Houston, TX.
GASEpidemiology
Access Microbiol · 2022PubMed ↗
CovS inactivation reduces CovR promoter binding at diverse virulence factor encoding genes in group A Streptococcus.
GASHost–Pathogen
Mol Microbiol · 2022PubMed ↗
Hematopoietic stem and progenitor cells improve survival from sepsis by boosting immunomodulatory cells.
Host–Pathogen
JCI Insight · 2022PubMed ↗
2021
Population Genomics Reveals Distinct Temporal Association with the Emergence of ST1 Serotype V Group B Streptococcus and Macrolide Resistance in North America.
GBSAMREpidemiology
Antimicrob Agents Chemother · 2021DOI ↗PubMed ↗
Characterization of the Type I Restriction Modification System Broadly Conserved among Group A Streptococci.
GASHost–Pathogen
mSphere · 2021DOI ↗PubMed ↗
Emergence of Serotype IV Group B Streptococcus Adult Invasive Disease in Manitoba and Saskatchewan, Canada, Is Driven by Clonal Sequence Type 459 Strains.
GBSEpidemiology
J Clin Microbiol · 2021PubMed ↗
The majority of 9,729 group A streptococcus strains causing disease secrete SpeB cysteine protease: pathogenesis implications.
GASHost–Pathogen
Infect Immun · 2021PubMed ↗
Population Genomics of emm4 Group A Streptococcus Reveals Progressive Replacement with a Hypervirulent Clone in North America.
GASEpidemiology
mSystems · 2021DOI ↗PubMed ↗
The Indirect Impact of the SARS-CoV-2 Pandemic on Invasive Group A Streptococcus, Streptococcus pneumoniae and Staphylococcus aureus Infections in Houston Area Children.
GASEpidemiology
Pediatr Infect Dis J · 2021DOI ↗PubMed ↗
For a complete list of publications, visit PubMed ↗ or Google Scholar ↗.
Flores Streptococcal Laboratory

Lab Members

The Flores Streptococcal Laboratory brings together physician-scientists, research faculty, and trainees united by a shared interest in streptococcal biology, genomics, and infectious disease epidemiology.

AF
Anthony R. Flores, MD, MPH, PhD
Principal Investigator
Physician-scientist in Pediatric Infectious Diseases. Research focused on GAS and GBS pathogenesis, gene regulation, and epidemiology. NIH-funded investigator.
MS
Misu Sanson, MD, PhD
Research Assistant Professor
Vanderbilt University Medical Center. Co-investigator on emm4 epidemic clonal emergence and carbonic anhydrase biology projects.
GM
Gretchen Morrison
Graduate Student
Project: Roles of SpxA1/SpxA2 in GAS pathogenesis.
NO
Nicholas Obremskey, MD
Fellow, Pediatric Infectious Diseases
Mechanisms of bacterial dissemination in musculoskeletal infections.
CO
Chioma Odo, PhD
Graduate Student · 2019–2024
PhD, Microbiology and Infectious Diseases, MD Anderson–UTHealth Houston Graduate School of Biomedical Sciences. Co-mentored with Dr. Samuel Shelburne.
VM
Vicki Mercado, MD/PhD
MD/PhD Student · 2022–2024
Co-mentored with Dr. Katy Patras, Baylor College of Medicine. Currently MS3 at Baylor College of Medicine.
GS
Gaby Segura, MD
Postdoctoral Fellow, Pediatric ID · 2022–2024
Currently Assistant Professor and Attending Pediatric Infectious Diseases Physician, Children's Memorial Hermann Hospital and McGovern Medical School at UTHealth Houston.
KB
Kyle Buchan, PhD
Postdoctoral Fellow · 2022–2024
Currently Postdoctoral Fellow, School of Public Health at UTHealth Houston.
AA
Aya Aboulhosn, MD
Postdoctoral Fellow · 2022–2024
Currently PGY-2 Resident in Pediatrics, Cleveland Clinic.
PM
Piyali Mukherjee, PhD
Postdoctoral Fellow · 2022–2024
BS
Bharat Singh, PhD
Postdoctoral Fellow · 2022–2023
Currently Research Associate, MD Anderson Cancer Center, Houston, TX.
IF
Ian Francis, MD, PhD
Postdoctoral Fellow · 2021–2023
Co-mentored with Dr. Katy Patras, BCM/TCH Pediatric Scientist Training and Development Program. Currently PGY-5 Pediatric Critical Care Medicine, The Ohio State University.
ES
Elizabeth Sabroske, MD
Postdoctoral Fellow, Neonatology · 2021–2023
Currently Assistant Professor, Division of Neonatal Medicine, McGovern Medical School at UTHealth Houston.
CT
Christy Tabarani, MD
Postdoctoral Fellow, Pediatric ID · 2020–2022
Currently Attending Physician and Pediatric Infectious Diseases Consultant, East Tennessee Children's Hospital.
MC
Maria Belen Cubria, MD
Research Fellow · 2019–2021
Currently PGY-4 Pediatric Critical Care Fellow, McGovern Medical School, Houston, TX.
ZA
Zain Alamarat, MD
Postdoctoral Fellow, Pediatric ID · 2018–2021
Currently Assistant Professor, Pediatric Infectious Diseases, University of Arkansas Medical School.
LV
Luis Alberto Vega, PhD
Postdoctoral Fellow · 2018–2021
Supported by T32 TPAMR fellowship. Currently Research Assistant Professor, McGovern Medical School at UTHealth Houston.
CF
Catherine Foster, MD
Postdoctoral Fellow, Pediatric ID · 2016–2018
Currently Assistant Professor and Fellowship Program Director, Pediatric Infectious Diseases, Baylor College of Medicine and Texas Children's Hospital.
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Jennifer A. Gaddy, PhD
Vanderbilt University Medical Center
Bacterial pathogenesis, innate immunity, and reproductive immunology, with a focus on host responses to GBS infection of the reproductive tract in the context of pregnancy.
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Thomas A. Hooven, MD
University of Pittsburgh / UPMC Children's Hospital of Pittsburgh
GBS neonatal pathogenesis, bacterial genetics and bioinformatics, CRISPR-based functional genomics, and the influence of the neonatal microbiome on susceptibility to infectious disease.
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J. Chase McNeil, MD
Baylor College of Medicine / Texas Children's Hospital
Epidemiology, antimicrobial susceptibility, and management of pediatric bacterial pathogens, with a focus on GAS, S. aureus, and pediatric bone and joint infections.
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Kathryn A. Patras, PhD
Baylor College of Medicine
Vaginal microbiota, GBS colonization and host-pathogen interactions in the female urogenital tract, and women's reproductive health and pregnancy.
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Jonathan G. Schoenecker, MD, PhD
Vanderbilt University Medical Center
Pediatric orthopaedic surgery, musculoskeletal infections, and the integrated role of coagulation and inflammation in orthopaedic wound healing and bone biology.
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Samuel A. Shelburne, MD, PhD
MD Anderson Cancer Center
emm4 population genomics, CovRS biology, GAS virulence regulation, and WGS-based epidemiology.
Opportunities
Join the Laboratory
We welcome inquiries from prospective graduate students, postdoctoral fellows, and clinical research trainees interested in streptococcal pathogenesis, genomics, and infectious disease epidemiology. Interested applicants should contact Dr. Flores directly and include a CV and brief statement of research interests. For clinical resources and contact information, contact Dr. Flores by email at anthony.flores@vumc.org.

Principal
Investigator

Dr. Anthony R. Flores is a physician-scientist and principal investigator in the Division of Pediatric Infectious Diseases. His laboratory pursues NIH-funded, hypothesis-driven research on the pathogenesis, gene regulation, and epidemiology of streptococcal infections. With more than 50 peer-reviewed publications, his program integrates bacterial genetics, functional genomics, in vivo infection models, and population-level whole-genome sequencing to address clinically important questions about Group A and Group B Streptococcal disease. The laboratory’s long-term mission is to understand how Gram-positive pathogens sense and respond to host defenses, evolve to cause epidemic disease, and drive clinical morbidity with the ultimate goal of informing improved vaccines, diagnostics, and therapeutics.

  • MD — Medical Degree
  • MPH — Master of Public Health
  • PhD — Doctoral Research Training
  • Pediatric Infectious Diseases — Clinical Specialty
  • NIH-Funded Principal Investigator

Contact & Lab Info

Principal Investigator
Anthony R. Flores, MD, MPH, PhD
Department
Pediatric Infectious Diseases
Research Focus
Streptococcal Pathogenesis, Gene Regulation & Epidemiology
Funding
National Institutes of Health
Opportunities
Graduate students, postdoctoral fellows, and clinical research trainees are encouraged to inquire about available positions.