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.

Our research focuses on the complex interactions between the human immune system and insect-derived molecules, and how these interactions can influence the outcomes of vector-borne diseases such as dengue, Zika, Chikungunya, and leishmaniasis. When an insect bites, it injects hundreds of arthropod molecules into the host's skin, alerting our immune system to these foreign agents. If the insect is infected with a pathogen, the microorganism is delivered along with these insect-derived molecules. Our immune response to these molecules over time can either help or hinder pathogen establishment, ultimately affecting the disease outcome.

Our work is conducted at two primary locations: the Laboratory of Malaria and Vector Research (LMVR) in Rockville, which is equipped with cutting-edge technologies, and the NIAID International Center of Excellence in Research (ICER) in Cambodia, where we conduct field observations and studies.

At LMVR-Rockville, we use advanced technologies and methodologies to explore the molecular and immunological mechanisms underlying the human response to arthropod bites and the pathogens they transmit. In Cambodia, at the NIAID ICER, we engage in extensive fieldwork to gather critical data and observations directly from affected populations. By integrating field data with laboratory findings, we aim to develop robust hypotheses that can lead to effective strategies for disease mitigation and control.

Our multidisciplinary approach allows us to bridge the gap between laboratory research and field applications. By understanding how the human immune system responds to arthropod molecules, we can identify potential targets for vaccines, therapeutics, and diagnostic tools. Additionally, our research contributes to the development of innovative vector control strategies that can reduce the incidence of these debilitating diseases.

Through collaboration with local communities, healthcare providers, and international partners, we strive to translate our scientific discoveries into practical solutions that can improve public health outcomes. Our ultimate goal is to reduce the burden of vector-borne diseases and enhance the quality of life for people living in endemic regions.

Our research aims to improve dengue prevention and treatment strategies for U.S. travelers, personnel in endemic areas, and regions with reported dengue cases, such as Hawaii, Florida, Texas, Puerto Rico, the U.S. Virgin Islands, and Guam. Enhanced predictive, management, diagnostic, and preventive measures for dengue outbreaks are particularly crucial for these at-risk regions. The development and use of prophylactic therapeutics targeting specific immune responses to mosquito bites could reduce the transmission of arboviruses, including eastern equine encephalitis, Jamestown Canyon, La Crosse, Powassan, St. Louis encephalitis, and West Nile viruses. Improved diagnostic capabilities for vector-borne diseases and emerging infections will lead to better patient outcomes. 

The Opportunistic Bacterial Pathogenesis Unit is interested in Nocardia infections. Our bench-to-bedside research program incorporates immunology, microbiology, genetics, and bioinformatics to investigate the pathogenesis of nocardiosis. A major goal of our research is to identify the key immunological mechanisms that control Nocardia. Insights from this work will inform future efforts to develop host-directed therapies for nocardiosis. Another area of interest is host- and pathogen-specific factors that determine patterns of dissemination and patient outcomes.