Pradeep Uchil, PhD

Dr. Uchil has broad expertise in innate immunity, viral immunology, and in vivo modeling of retrovirus, flavivirus, and respiratory virus infections, including SARS-CoV-2. His research program centers on dissecting how host and viral factors govern antiviral immunity, viral dissemination, and disease progression. A major focus of his work on retroviral pathogenesis has been defining the cellular and molecular determinants of HIV/retrovirus spread in vivo. His studies revealed a pivotal role for Siglec-1/CD169-expressing sentinel macrophages in mediating retroviral capture and systemic dissemination across multiple routes of exposure. These data directly informed our mechanistic understanding of early retroviral infection and innate immune evasion. His research on respiratory virus infections has addressed fundamental questions in SARS-CoV-2 pathogenesis and immunity, including the mechanisms of action of neutralizing and non-neutralizing antibodies, convalescent plasma, antiviral drugs, and ACE2-based decoys across multiple in vivo models. This work spans both basic viral pathogenesis and translational evaluation of antiviral interventions. More recently, Dr. Uchil has expanded into flavivirus biology, focusing on early stages of replication, the role of the ubiquitin machinery in viral processes, and the identification of host proteases involved in NS1 protein maturation. Across these research areas, Dr. Uchil employs a bioluminescence imaging (BLI)-guided pipeline that enables real-time, noninvasive, longitudinal visualization of infection dynamics from whole-animal to ultrastructural scales. This visual approach-driven platform has not only been instrumental in accelerating mechanistic and preclinical studies, but also serves the broader scientific questions driving his program.

Structural "Glyco-Code" of viral entry: One focus of the laboratory is deciphering how the specific engagement of host lectins influences viral fate. We are defining how the supramolecular organization of the virus-receptor interface shapes downstream trafficking. Using Cryo-ET, we visualize the molecular architecture of the virus-lectin "synapse" to understand how structural geometry influences standard sorting signals. We examine how three sugar-binding lectins distinctly modulate viral fate: the C-type lectin Langerin directs viral cargo toward degradative pathways, DC-SIGN facilitates trans-cellular transmission to permissive targets, while CD169 (Siglec-1) promotes sequestration in stable, non-degradative Virus-Containing Compartments (VCCs). These structural principles highlight that lectins function as key modulators of viral fate. We are now extending this framework to interrogate how the tissue-specific expression of these lectins influences viral persistence or clearance during respiratory infection in vivo. By elucidating how myeloid lectins modulate the balance between effective antiviral control and collateral tissue damage, we aim to identify whether targeting lectin-mediated viral sorting represents a host-directed therapeutic axis to decouple protective immunity from immunopathology.

Antigen relay and adaptive immunity: We are also elucidating the immunological consequences of viral entry pathways. Our work established that VCCs in CD169⁺ macrophages function as "antigen depots," enabling a critical Macrophage-to-cDC1 antigen Relay that primes antiviral CD8⁺ T cell responses. We are currently using human organoid and humanized mouse models together with single cell genomics to test how relay shapes the outcome of HIV-1 specific CD8⁺ T cells responses in human lymphoid tissues.

Viral secretome and antibody immunity: We explore how viruses remodel the host environment through their secretome, specifically characterizing flavivirus NS1 and SARS-CoV-2 ORF8 as soluble toxins that drive disease severity. Simultaneously, we are defining the rules for effective humoral immunity by mapping the spatiotemporal determinants of Fc-mediated effector functions. By combining in vivo imaging with structural studies, we aim to resolve why certain antibody geometries trigger potent clearance while others induce Antibody-Dependent Enhancement (ADE), directly informing the design of next-generation monoclonal antibodies and CAR T-cell therapies.