Higgins Lab Department of Microbiology and Immunobiology 
Harvard Medical School 
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Darren Higgins, Ph.D.
Principal Investigator

Dr. Higgins is a Professor of Microbiology and Immunobiology at Harvard Medical School. His laboratory at Harvard is currently focused on understanding fundamental host-pathogen interactions that lead to virulence and the development of protective immunity to intracellular bacterial pathogens. Dr. Higgins has served as an Editorial Board Member on several prominent journals in the field and has led research projects in collaboration with the New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases, Boston Children’s Hospital, and the Dana Farber Cancer Center. Dr. Higgins is also inventor on several patents and co-founded Genocea Biosciences, a company that aims to commercialize key breakthroughs in vaccine discovery and development with a focus on intracellular pathogens. Dr. Higgins holds a Ph.D. in Microbiology and Immunology from the University of Michigan Medical School and performed his postdoctoral studies at the University of Pennsylvania School of Medicine and University of California at Berkeley.

 

         
   

Daniel Grubaugh
BBS Graduate Student

Post-transcriptional control of Listeria monocytogenes virulence factor expression in response to serum

While mechanisms of L. monocytogenes infection of host cells have been well studied, how bacteria disseminate in the host from the gut to other organs such as the brain is relatively unknown. We hypothesize that survival and circulation within the bloodstream is critical for bacterial dissemination to distant organ sites. It has been observed that L. monocytogenes growth in the presence of blood or serum induces the expression of the principal virulence factors listeriolysin O (LLO) and ActA. LLO is required to lyse the phagocytic vacuole following invasion of host cells, while ActA mediates actin-based motility and intracellular spread during replication within the cytosol of host cells. To identify L. monocytogenes genes involved in serum induction of virulence factors, we performed a Himar1 transposon mutagenesis screen using a gfp reporter fused to the promoter region of actA. This screen identified multiple factors that appear to be involved in the expression of bacterial factors in response to serum. We found that these factors predominantly induce ActA and LLO expression post-transcriptionally. Using RNAseq, mass spectrometry, and analysis of defined genetic mutants, I am currently elucidating the mechanisms of post-transcriptional control of L. monocytogenes gene expression in response to serum and the contribution to virulence.

 

         
   

Pallab Ghosh, Ph.D.
Postdoctoral Fellow

Molecular basis of brain infection by intracellular bacterial pathogens

The primary focus of my research is to study the microbiology and immunology of intracellular bacterial pathogens. I am using Listeria monocytogenes as a model organism to understand complex host-pathogen interactions. One of the major concerns of L. monocytogenes infection is the ability of bacteria to invade the brain causing life-threatening meningitis and encephalitis. However, it is not well understood how L. monocytogenes breaches the blood-brain barrier to colonize the brain. Using a mouse model of systemic infection, combined with genetic and fluorescence microscopy approaches, I am elucidating the molecular basis of host cell tropism leading to lethal infection of the brain and immune evasion mechanisms that may establish a paradigm that could be applicable to other intracellular pathogens.

 

         
   

Yan Zhou, Ph.D.
Postdoctoral Fellow

Characterization of novel CD8+ T cell antigens of Listeria monocytogenes

My previous work focused on the mechanism of neonatal meningitis caused by E. coli K1. In 2015, I came to Harvard Medical School as a visiting scientist and studied the role of sensory neurons in pathogen infections. I found that pneumolysin contributed to neuronal activation by Streptococcus pneumoniae in vitro, including effects on the action potential, calcium flux, and neuropeptide release by sensory neurons. At present, my research work in the Higgins lab is focusing on the identification and characterization of pathogen-specific CD8+ T cell-stimulating antigens from Listeria monocytogenes. Of the thousands of potential T cell antigens that can be produced by a bacterial pathogen, cellular immune responses appear to focus on only a handful of proteins. Furthermore, for any given pathogen, T cells specific for only a few of these antigens will provide protection after immunization. The underlying biology for the immune hierarchy of pathogen-specific T cell antigens and their ability to stimulate protective immunity remains incompletely understood. L. monocytogenes has been used for decades as a model for studying CD8+ T cell responses. However, only a handful of listerial proteins have been shown to be protective CD8+ T cell antigens in a single mouse genetic background, making studies of immune hierarchy difficult. The goal of my project is to investigate the immune hierarchy of pathogen-specific T cell antigens in multiple genetic backgrounds using L. monocytogenes as a prototypic intracellular bacterial pathogen. 

 

         
   

Benjamin Gersten
Research Intern

Bacterial-mediated inhibition of viral infection

Benjamin was born in Seattle, Washington before moving to California where he now attends Robert Louis Stevenson High School. Currently, Benjamin is performing an internship in the Higgins lab where is learning how to conduct fundamental microbiology-based research and how these studies may be applied to the development of new treatments for the prevention of disease. During his internship, Benjamin is studying the use of non-pathogenic bacteria to deliver antibodies to host cells as a therapeutic strategy to block viral infections.