Yersinia pestis, the bacterial agent of bubonic and pneumonic plague, is one of the most virulent human bacterial pathogens and is well known historically for its ability to cause devastating pandemics. Plague remains an international public health concern and periodically re-emerges in the form of sudden large outbreaks. The emergence of antibiotic-resistant strains of Y. pestis and the potential use of Y. pestis as a biological weapon exemplify the need for better medical countermeasures against plague.

Research in the group focuses on the genetic and molecular processes of plague transmission, infection, and immunity. Studies apply modern molecular biology, genomics, and immunology tools to established flea and rodent infection models. One goal is to identify and determine the function of Y. pestis genes that mediate transmission by fleas. Detailed understanding of this interaction may lead to novel strategies to interrupt the transmission cycle. For example, determining the antigens expressed on the Y. pestis surface as the bacteria exit the flea and enter the mammal may help in the design of new vaccines and diagnostics.

Plague is a highly fulminant disease that rapidly leads to life-threatening sepsis. In vivo gene expression and immunologic analyses by this group indicate that the severity of disease depends on several Y. pestis virulence factors that thwart the mammalian innate immune response. This group is interested in understanding the detailed function of these factors and determining their specific targets and mechanisms. The group uses the natural flea-borne transmission route and systems to examine the intradermal flea-bacteria-host transmission interface. This enables scientists to take into account the effects of vector saliva and other factors specific to the microenvironment of the flea-bite site. The group also uses its animal model systems to identify and evaluate new Y. pestis antigens for use in plague vaccines and diagnostics and to characterize the host response to naturally acquired infection.

The Flow Cytometry Section (FCS) provides DIR investigators with cutting-edge cytometric technologies and instrumentation for high dimensional cell analysis and sorting. In addition, the FCS provides training, consultation, method development, and support for experiments involving broad aspects of cytometry applications. Major goals within the FCS are to provide access to state-of-the-art technologies, to help design and run experiments, to facilitate data interpretation, and to provide results that are of consistent high quality. This mission is accomplished through the efforts of staff with extensive cytometry experience.

Philosophy - Advancing Human Health Through Immunological Research:

• Enhance understanding of immune system regulation in health and disease
• Provide mechanistic insights into disease pathology to inform therapeutic strategies
• Support translational research to develop targeted treatments for immune-related disorders

Secondary Lymphoid Organ Remodeling and Pathogen-Immune cell Interactions:

• Investigate structural remodeling of lymph nodes in immune responses
• Examine chemokine receptor sensitivity modulation by RGS proteins
• Characterize cellular networks facilitating virus envelope protein transfer

Extracellular Signaling, GPCR Signal Transduction and Immune Modulation:

• Investigate chemokine receptor-mediated signaling in immune cell regulation
• Examine heterotrimeric G-protein activation in lymphocyte function
• Study molecular mechanisms of G-protein-coupled receptor (GPCR) signaling
• Analyze how GPCR signaling orchestrates immune responses and cell dynamics

Experimental Approaches:

• Utilize genetically engineered murine models
• Employ intravital two-photon laser scanning microscopy (TP-LSM) and high-throughput flow cytometry

A range of methodologies is utilized in systems biology to simulate biological pathways, uncovering the intricate ways molecules function within living organisms and enabling hypotheses about potential interactions and reaction rate ranges without relying on traditional experimental measurements. Among these, rule-based modeling abstracts similar reactions into rules that summarize the characteristics and binding states of individual molecular components within large molecular complexes. This approach offers a distinct advantage by simplifying the representation of molecular reactions, organizing entities within hierarchical structures that align with biological formats at both the molecular and sub-molecular levels, such as domains and binding sites. Furthermore, the rule-based modeling approach can address the combinatorial complexity inherent in biological systems.

Simmune is a software suite that uses rule-based modeling to simulate biological pathways. It constructs models of biological reactions through its unique icon-based modeling language from single reactions and provides a flexible, high-level network view for model inspection. Simmune can simulate models in well-stirred environments, efficiently explore large parameter spaces, and help users identify the most relevant parameters, offering insights into the relationships between different parameters. Additionally, Simmune supports the simulation of spatially resolved models in discrete grid morphologies and 3D environments, with the ability to analyze and visualize results at fine-grained subcellular levels.

Simmune supports the Multistate, Multicomponent, and Multicompartment Species Package for SBML Level 3 (SBML-Multi) to exchange rule-based models. This standard is part of an initiative by the COmputational Modeling in BIology NEtwork (COMBINE) community standards and formats for computational models. Our group leads the effort for the SBML-Multi standard.

Simmune is built with technologies including C/C++, Qt, VTK, CMake, Python, SQL, MongoDB, Boost, version control, Sundials, and parallel computing, providing a powerful, flexible modeling tool that remains user-friendly for biological researchers with limited computing expertise. Our group collaborates with researchers in immunology, proteomics, computational modeling, and systems biology.

The Neurovirology Unit conducts research on the acute and long-term complications associated with human alphaherpesvirus infections and pulmonary infections caused by coronaviruses and influenza.

Using transgenic animal models and integrating approaches from molecular virology, neurobiology, and immunology, we investigate the mechanisms underlying viral pathogenesis in the central nervous system, which particularly involves analyzing roles of immunomodulatory host factors to understand their roles in pathogenesis, neuroprotection, and potentiating antiviral immunity. While studying different aspects of antiviral immunity, we also focus on understanding the neurological regulation of antiviral immunity, neuroinflammation, and the long-term manifestations of viral infection, such as neurodegeneration and cognitive decline using machine learning-based behavioral approaches.

Additionally, the Neurovirology Unit explores the interactions between viral proteins, host factors, and immune responses that drive differential disease severity observed in humans, paving the way for innovative therapeutic strategies. We are also committed to advancing human brain and lung organoid models to recapitulate disease phenotypes in humans and thereby enhance our understanding of viral disease mechanisms.