About

Cressida Madigan earned her Ph.D. in microbiology and molecular genetics at Harvard Medical School, where she studied TB lipid chemistry in Branch Moody's lab at Brigham and Women's Hospital. As an NRSA Postdoctoral Fellow, she studied infection biology in zebrafish with Lalita Ramakrishnan at the University of Washington, and completed her training at UCLA in the labs of Alvaro Sagasti, Robert Modlin, and Stephen Smale. She joined the Molecular Biology faculty at UCSD in 2018. Her research uses genetic and imaging tools to study mechanisms of infection-mediated inflammation and neurological injury, utilizing zebrafish as a model host to observe infections at difficult-to-access sites in humans. Her current focus is on understanding how mycobacteria that cause leprosy and tuberculosis induce neurological injury, with the aim of identifying pathways of central nervous system inflammation that can be targeted by host-directed therapies.

Research topics

• Genetics
• Biology
• Medicine
• Computational biology
• Immunology
• Microbiology
• Chemistry
• Pathology
• Internal medicine
• Virology

Selected publications

• Review 1: "Innate Immune Responses to Plasmodium falciparum Disrupt the Blood–Brain Barrier"

  2026-01-15

  peer-reviewOpen access1st authorCorresponding

  Reviewers find that the manuscript provides reliable evidence that Plasmodium falciparum–activated immune cells can directly disrupt the blood–brain barrier through inflammatory activation and leukocyte adhesion, even without sequestration of infected red blood cells.

  PublisherOA PDFDOI

• Reviews of "Innate Immune Responses to Plasmodium falciparum Disrupt the Blood–Brain Barrier"

  2026-01-15

  peer-reviewOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Mycobacteria trehalose dimycolate interactions with host Mincle remodel blood-brain barrier junctions for brain invasion

  Cell Reports · 2025-12-01 · 1 citations

  articleOpen accessSenior author

  Tuberculous meningitis is unique among bacterial meningitides because it occurs in two temporally separated steps: mycobacteria first invade the brain, then form infected macrophage aggregates called Rich foci, which later erode the meninges. Here, using transparent zebrafish larvae, we detail the first step-brain invasion. We find that whereas elsewhere in the body mycobacteria disseminate within phagocytes, only extracellular mycobacteria reach the brain microvasculature. There, they adhere to the microvascular endothelium and grow into microcolonies. These microcolonies induce endothelial tight junction reorganization, creating transient gaps through which bacteria enter the brain and infect microglia to initiate Rich foci. This reorganization is induced by mycobacterial surface glycolipid trehalose dimycolate interacting with its receptor, Mincle. Strikingly, the pathogens Mycobacterium tuberculosis and Mycobacterium marinum and the saprophyte Mycobacterium smegmatis can all invade the brain via this pathway. Thus, M. tuberculosis initiates meningitis, the deadliest form of tuberculosis, using an ancestral determinant important for environmental fitness.

  PublisherDOI

• The mevalonate pathway of isoprenoid biosynthesis supports metabolic flexibility in <i>Mycobacterium marinum</i>

  Journal of Bacteriology · 2025-10-30 · 1 citations

  articleOpen access

  ABSTRACT Isoprenoids are a diverse class of natural products that are essential in all domains of life. Most bacteria synthesize isoprenoids through either the methylerythritol phosphate (MEP) pathway or the mevalonate (MEV) pathway, while a small subset encodes both pathways, including the pathogen Mycobacterium marinum (Mm). It is unclear whether the MEV pathway is functional in Mm, or why Mm encodes seemingly redundant metabolic pathways. Here, we show that the MEP pathway is essential in Mm, while the MEV pathway is dispensable in culture, with the ΔMEV mutant having no growth defect in axenic culture but a competitive growth defect compared to WT Mm. We found that the MEV pathway does not play a role in ex vivo or in vivo acute infection but does play a role in survival of peroxide stress. Metabolite profiling revealed that modulation of the MEV pathway causes compensatory changes in the concentration of MEP intermediates DOXP and CDP-ME, suggesting that the MEV pathway is functional and that the pathways interact at the metabolic level. Finally, the MEV pathway is upregulated early in the shift down to hypoxia, suggesting that it may provide metabolic flexibility to this bacterium. Interestingly, we found that our complemented strains, which vary in copy number of the polyprenyl synthetase idsB2 , responded differently to peroxide and UV stresses, suggesting a role for this gene as a determinant of downstream prenyl phosphate metabolism. Together, these findings suggest that MEV may serve as an anaplerotic pathway to make isoprenoids under stress conditions. IMPORTANCE Organisms from all domains of life utilize isoprenoids to carry out thousands of critical and auxiliary cellular processes, including signaling, maintaining membrane integrity, stress response, and host-pathogen interactions. The common precursor of all isoprenoids is synthesized via one of two biosynthetic pathways. Importantly, some bacteria encode both pathways, including M. marinum . We found that only one pathway is essential in M. marinum , while the nonessential pathway may confer metabolic flexibility to help the bacterium better adapt to various environmental conditions. We also found that the polyprenyl synthetase IdsB2 plays an important role in driving such phenotypes. Further, we demonstrate metabolic interplay between both functional pathways. These insights represent the first characterization of isoprenoid biosynthesis in dual pathway-encoding mycobacteria.

  PublisherDOI

• Transient vascular occlusions in a zebrafish model of mycobacterial brain infection

  PLoS ONE · 2025-09-12

  articleOpen accessSenior authorCorresponding

  Mycobacterial brain infection, for example tuberculous meningitis (TBM), caused by Mycobacterium tuberculosis, is a severe manifestation of tuberculosis that occurs when the bacteria invade the brain. In addition to extensive inflammation, vascular complications such as stroke frequently arise, significantly increasing the risk of disability and death. However, the mechanisms underlying these vascular complications remain poorly understood, as current knowledge is derived exclusively from human studies. To date, no animal model has been established to investigate the onset and progression of vascular pathology in TBM. Here, we use transparent zebrafish larvae to investigate vascular pathology during the early stages of TBM, establishing a model for studying vascular complications from mycobacterial brain infection. We find that mycobacteria preferentially attach to the lumen of vessel bifurcations and induce vessel enlargement. These attached microcolonies are sufficient to occlude brain blood vessels in the absence of an organized thrombus. The majority of microcolony-associated occlusions are transient and contribute to global hypoperfusion of the brain. These vascular disruptions lead to accumulation of oxidative stress and cell death in both the vasculature and neurons. Taken together, these findings demonstrate the occurrence of ischemic events during the early stages of mycobacterial brain infection and establish an animal model for studying vascular complications in TBM.

  PublisherDOI

• Transient Vascular Occlusions in a Zebrafish Model of Tuberculous Meningitis

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-11

  preprintOpen accessSenior authorCorresponding

  Abstract Tuberculous meningitis (TBM), caused by Mycobacterium tuberculosis, is a severe manifestation of tuberculosis that occurs when the bacteria invade the brain. In addition to extensive inflammation, vascular complications such as stroke frequently arise, significantly increasing the risk of disability and death. However, the mechanisms underlying these vascular complications remain poorly understood, as current knowledge is derived exclusively from human studies. To date, no animal model has been established to investigate the onset and progression of vascular pathology in TBM. Here, we use transparent zebrafish larvae to investigate vascular pathology during the early stages of mycobacterial brain infection, establishing a model for studying TBM-associated vascular complications. We find that mycobacteria preferentially attach to the lumen of vessel bifurcations and induce vessel enlargement. These attached microcolonies are sufficient to occlude brain blood vessels in the absence of an organized thrombus. The majority of microcolony-associated occlusions are transient and contribute to global hypoperfusion of the brain. These vascular disruptions lead to accumulation of oxidative stress and cell death in both the vasculature and neurons. Taken together, these findings demonstrate the occurrence of ischemic events during the early stages of mycobacterial brain infection and establish an animal model for studying vascular complications in TBM.

  PublisherOA PDFDOI

• The mevalonate pathway of isoprenoid biosynthesis supports metabolic flexibility in <i>Mycobacterium marinum</i>

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-14

  preprintOpen access

  Abstract Isoprenoids are a diverse class of natural products that are essential in all domains of life. Most bacteria synthesize isoprenoids through either the methylerythritol phosphate (MEP) pathway or the mevalonate (MEV) pathway, while a small subset encodes both pathways, including the pathogen Mycobacterium marinum (Mm). It is unclear whether the MEV pathway is functional in Mm, or why Mm encodes seemingly redundant metabolic pathways. Here we show that the MEP pathway is essential in Mm while the MEV pathway is dispensable in culture, with the ΔMEV mutant having no growth defect in axenic culture but a competitive growth defect compared to WT Mm. We found that the MEV pathway does not play a role in ex vivo or in vivo infection but does play a role in survival of peroxide stress. Metabolite profiling revealed that modulation of the MEV pathway causes compensatory changes in the concentration of MEP intermediates DOXP and CDP-ME, suggesting that the MEV pathway is functional and that the pathways interact at the metabolic level. Finally, the MEV pathway is upregulated early in the shift down to hypoxia, suggesting that it may provide metabolic flexibility to this bacterium. Interestingly, we found that our complemented strains, which vary in copy number of the polyprenyl synthetase idsB2 , responded differently to peroxide and UV stresses, suggesting a role for this gene as a determinant of downstream prenyl phosphate metabolism. Together, these findings suggest that MEV may serve as an anaplerotic pathway to make isoprenoids under stress conditions. Importance Organisms from all domains of life utilize isoprenoids to carry out thousands of critical and auxiliary cellular processes, including signaling, membrane integrity, stress response, and host-pathogen interactions. The common precursor of all isoprenoids is synthesized via one of two biosynthetic pathways and importantly, some bacteria encode both pathways, including M. marinum . We found that only one pathway is essential in M. marinum , while the nonessential pathway may confer metabolic flexibility to help the bacterium better adapt to various environmental conditions. We also found that the polyprenyl synthetase IdsB2 plays an important role in driving such phenotypes. Further, we demonstrate metabolic interplay between both functional pathways. These insights represent the first characterization of isoprenoid biosynthesis in dual pathway-encoding mycobacteria.

  PublisherOA PDFDOI

• Group B Streptococci lyse endothelial cells to infect the brain in a zebrafish meningitis model

  PLoS Biology · 2025-07-03 · 5 citations

  articleOpen accessSenior author

  To cause meningitis, bacteria move from the bloodstream to the brain, crossing the endothelial cells of the blood-brain barrier. Most studies on how bacteria cross the blood-brain barrier have been performed in vitro using cultured endothelial cells, due to a paucity of animal models. Group B Streptococcus (GBS) is the leading cause of bacterial meningitis in neonates and is primarily thought to cross the blood-brain barrier by transcytosis through endothelial cells. To test this hypothesis in vivo, we used optically transparent zebrafish larvae. Time-lapse confocal microscopy revealed that GBS forms extracellular microcolonies in brain blood vessels and causes perforation and lysis of blood-brain barrier endothelial cells, which promotes bacterial entry into the brain. Vessels infected with GBS microcolonies were distorted and contained thrombi. Inhibition of clotting worsened brain invasion, suggesting a host-protective role for thrombi. The GBS lysin cylE, implicated in brain invasion in vitro, was found dispensable in vivo. Instead, pro-inflammatory mediators associated with endothelial cell damage and blood-brain barrier breakdown were specifically upregulated in the zebrafish head upon GBS entry into the brain. Therefore, GBS crosses the blood-brain barrier in vivo not by transcytosis, but by endothelial cell lysis and death. Given that we observe the same invasion route for a meningitis-associated strain of Streptococcus pneumoniae, our findings suggest that streptococcal infection of brain blood vessels triggers endothelial cell inflammation and lysis, thereby facilitating brain invasion.

  PublisherDOI

• Group B streptococci lyse endothelial cells to infect the brain in a zebrafish meningitis model

  bioRxiv (Cold Spring Harbor Laboratory) · 2024 · 1 citations

  Senior authorCorresponding
  • Microbiology
  • Biology
  • Virology

  Abstract To cause meningitis, bacteria move from the bloodstream to the brain, crossing the endothelial cells of the blood-brain barrier. Most studies on how bacteria cross the blood-brain barrier have been performed in vitro using cultured endothelial cells, due to a paucity of animal models. Group B Streptococcus (GBS) is the leading cause of bacterial meningitis in neonates and is primarily thought to cross the blood-brain barrier by transcytosis through endothelial cells. To test this hypothesis in vivo , we used optically transparent zebrafish larvae. Timelapse confocal microscopy revealed that GBS forms extracellular microcolonies in brain blood vessels and causes perforation and lysis of blood-brain barrier endothelial cells, which promotes bacterial entry into the brain. Vessels infected with GBS microcolonies were distorted and contained thrombi. Inhibition of clotting worsened brain invasion, suggesting a host-protective role for thrombi. The GBS lysin cylE , implicated in brain invasion in vitro, was found dispensable in vivo . Instead, pro-inflammatory mediators associated with endothelial cell damage and blood-brain barrier breakdown were specifically upregulated in the zebrafish head upon GBS entry into the brain. Therefore, GBS crosses the blood-brain barrier in vivo not by transcytosis, but by endothelial cell lysis and death. Given that we observe the same invasion route for a meningitis-associated strain of Streptococcus pneumoniae, our findings suggest that streptococcal infection of brain blood vessels triggers endothelial cell inflammation and lysis, thereby facilitating brain invasion.

  PublisherDOI

• Zebrafish: an underutilized tool for discovery in host–microbe interactions

  Trends in Immunology · 2022 · 27 citations

  Senior authorCorresponding
  • Biology
  • Computational biology
  • Genetics
  PublisherOA PDFDOI

Recent grants

• NIH Grant F32AI104240

  NIH · $102k · 2015

Frequent coauthors

• Tan‐Yun Cheng

  Brigham and Women's Hospital

  23 shared

• D. Branch Moody

  Brigham and Women's Hospital

  22 shared

• Lalita Ramakrishnan

  University of Cambridge

  19 shared

• Emilie Layre

  Centre National de la Recherche Scientifique

  15 shared

• David C. Young

  University of Utah

  15 shared

• Matthew McConnell

  University of Calgary

  9 shared

• Vincenzo Cerundolo

  University of Oxford

  9 shared

• C. Anthony Debono

  Massachusetts Institute of Technology

  8 shared

Labs

• The Madigan LabPI