We apply systems immunology approaches to investigate human cutaneous leishmaniasis, a disfiguring chronic skin disease caused by the protozoan parasite Leishmania.

Cutaneous leishmaniasis (CL) is endemic and emerging in the southwestern United States and often also affects military personnel who have been deployed to Leishmania-endemic areas. Leishmania parasites are transmitted to humans via the bite of an infected sand fly. As the disease progresses, the immune response to the parasite in the skin can trigger pathologic inflammation that leads to chronic ulceration and permanent scarring. Current therapies for CL are variably effective with increasing reports of drug resistance. A major roadblock to the development of novel therapeutics for CL is our incomplete understanding of human immunity to Leishmania in the skin.

Our group seeks to define the cellular circuits that drive pathologic inflammation and damage to skin tissue in CL. To do this, we employ a variety of experimental and bioinformatic approaches, including single-cell transcriptomics, multiomic spatial profiling, and mechanistic multiscale tissue modeling to map the cell subsets and intercellular signals that drive CL immunopathology. Current efforts are focused on constructing a comprehensive single-cell and spatial atlas of human CL. This work is being performed in collaboration with the NIAID Leishmaniasis Clinic (Principal Investigator: Dr. Elise O’Connell, Laboratory of Parasitic Diseases). Our goal is to develop novel host-directed therapies for CL patients that 1) inhibit the critical signaling circuits driving pathologic inflammation in the skin and 2) enhance immune control of the parasite.

Another major focus of our group is investigating human immunity to vector bites and vector-borne pathogens via controlled human vector challenge studies. The immune response to vector bites profoundly affects the susceptibility of the host to vector-borne pathogens. In collaboration with Dr. Matthew Memoli (Laboratory of Infectious Diseases), we performed a human challenge study using mosquitos and sand flies, which revealed a conserved transcriptomic skin response against highly divergent vector species. We are now using single-cell and spatial profiling to map the cellular circuitry of the human skin response to vector bites. Our goal is to develop novel clinical therapies that co-opt these responses to enhance protection against vector-borne pathogens.

Inborn Errors of Immunity (IEIs) are genetic disorders of the immune system with clinical manifestations of infection and autoinflammatory syndrome. Neurological disorders are one of the common causes of irreversible morbidity and mortality in patients with IEIs. Neuroinflammatory, neuroinfectious and neurodegenerative diseases have been reported extensively in this patient population but the role of immune related gene defects on development, function and immunoregulation of nervous system is still unknown.

The NeuroImmunopathogenesis Unit performs an integrated bench to bedside research to better understand the role of immunodeficiencies in nervous system. Taking a comprehensive approach to evaluate profile and function of immune cells in both blood and cerebrospinal fluid, the most adjacent cells to nervous system, provides valuable understanding about dynamic of immune cells and responses in CNS immune-compartment paving the path to find more targeted therapeutics. By using induced pluripotent stem cell technology, the unit also investigates the role of immune related gene defects in development and function of human neurons and glia to find underlying cellular and molecular pathways in immunodeficient patients with neurological disorders.

Furthermore, rare neuroinfectious, neuroinflammatory and neurodegenerative diseases with atypical clinical features can be a manifestation of immune related gene defects. Our holistic clinical and basic immunology, neuroscience and genetic approach facilitates to better understand the underlying mechanisms of these presentations to clarify diagnosis and treatments of this patients’ complex and often refractory to treatment neurological diseases.

The Molecular Mycology and Immunity Section (MMIS) studies the molecular and cellular interactions between fungi and their hosts. Mammalian barrier tissues (gut, skin, lungs) are colonized by a plethora of microbial species that play important roles in shaping host immunity and physiology. While most research has thus far focused on bacteria, fungi are increasingly recognized as important components of our commensal flora. In addition to commensals, there are a number of fungal pathogens that cause a high human disease burden, leading to 300 million infections and up to 1.5 million deaths per year globally. These infections are difficult to treat, due to a lack of effective drugs and the increased emergence of drug-resistant pathogens.      

Our laboratory operates at the intersection of microbiology and immunology to understand the factors that dictate the outcome of fungal exposure at barrier tissues. We take an interdisciplinary approach leveraging fungal/mouse genetics, molecular biology, biochemistry, CRISPR, cellular immunology, and imaging approaches to address three major research topics:

1. Mechanisms and impact of host colonization by fungi: A major interest in our group is understanding how fungi colonize and impact host barrier tissues. We utilize yeast forward genetic screens to identify molecules that drive fungal evasion of the host immune system. We also aim to identify fungal secondary metabolites that act on host receptors/signaling pathways in order to understand how fungal colonization impacts mammalian tissue physiology.
2. Mechanisms and regulation of innate immune detection of fungi: Mammalian immune systems utilize germline-encoded pattern recognition receptors (PRRs) to 
3. detect invading microbes. Specific detection of fungal pathogens is largely mediated by extracellular sugar-sensing receptors of the C-type lectin receptor (CLR) family. While there has been major progress in identifying the ligands and downstream signaling pathways of these receptors, there is still much to learn about how CLR activation is regulated. We seek to understand the molecular pathways that activate/inhibit CLR signaling, and how these pathways are controlled by environmental cues sensed by myeloid cells in tissues. We are also focused on understanding mechanisms of cell-autonomous innate immunity to fungal pathogens, such as how intracellular fungi are detected and cleared by cytosolic surveillance pathways.
4. Myeloid cell responses to fungal infection in vivo: We seek to understand the cellular mechanisms underlying protective versus aberrant immunity to fungal infection. One major interest is understanding how alternatively activated macrophages induced by type 2 cytokine signaling influence fungal immunity and infection outcomes. We are also interested in how dendritic cells interact with fungi to shape discrete T cell differentiation states. Lastly, we seek to dissect the roles of other recruited myeloid cells (monocytes, eosinophils, neutrophils, basophils) during fungal infection.

• Parasites genetic diversity and associated phenotypes, such as antimalarial drug resistance and parasites virulence factors
• Epigenetic and epitranscriptomic modifications in parasite development and identification of novel targets for antimalaria drugs or transmission blocking
• Development of high-sensitivity assay for Plasmodium infection and others
• Multi-omic studies on disease vectors, with a focus on ticks and mosquitoes, aimed at identifying biomarkers and advancing vaccine development