Assistant Professor of Microbiology and Immunology
Virology, Innate Immunity, Gene Delivery, Restriction Factors
To defend against infection, our innate immune system needs to “sense” the invading pathogen, sound the alarm signals, and then engage a protective response to fight the threat. My lab studies innate immunity at these three levels: 1) at the level of detection, to understand how viruses such as HIV-1 can be sensed by pattern recognition receptors under the right conditions, 2) at the level of signaling, to understand the transcriptional controls that underpin our defense systems, and 3) at the level of the response, to determine how antiviral cytokines and restriction factors can block infection and protect the host. We use a combination of systems biology tools (harnessing functional -omics data) and targeted molecular approaches (gene editing technologies and fundamental virology/cell biology assays) to answer questions such as:
How is HIV-1 detected?
Innate immune responses during acute HIV‑1 infection are protective and exert strong selective pressure on the virus. However, dysregulated innate responses can exacerbate non-specific inflammation, increase target cell susceptibility, and contribute to HIV pathogenesis. Since we don’t fully understand how the innate immune response can shift from being protective to pathogenic over the course of infection, it’s critical that we gain a mechanistic understanding of how HIV‑1 is sensed by the innate immune system and how downstream responses are regulated. My lab uses forward genetic screens to identify cellular factors that are important for steps in the virus life cycle, innate immune sensing, signal transduction, and virus restriction. We also test pathways of “collateral damage” that are activated during virus infection and impact innate immunity. Although we incorporate functional genomics and systems biology approaches into our work, our goal is to gain mechanistic insight into how cellular components direct and regulate innate sensing of HIV‑1 and other viruses.
How do cells “tune” innate immune responses?
Transcriptional regulation of innate immunity requires tight control. The system must maintain a sensitive response to infectious threats while avoiding unwanted inflammation and autoimmunity. When control is lost, health is often compromised, as errors in innate immune pathways accompany many disorders including cancer, arthritis, neurodegeneration, diabetes, autoimmune disease, and chronic virus infections. However, the mechanisms that “tune” innate immune signaling (i.e. those that increase or decrease responses, or control expression of gene subsets) remain poorly understood. My lab studies how innate immune responses are regulated in several model systems, including primary human myeloid cells. We are uniquely positioned to perform high-efficiency genetic modifications in monocytes, monocyte-derived DCs, and macrophages using CRISPR-Cas9 and lentivirus technology. We also perform experiments in myeloid cell lines (such as THP-1 and U937 cells), which express a battery of pattern recognition receptors, are competent for sensing viral nucleic acids, and are tractable model systems. Currently, we are focused on understanding transcriptional control of the interferon response, which is perhaps the most potent antiviral weapon in our cells’ arsenal. We hope that our studies will illuminate new strategies to treat inflammatory disorders and combat infectious disease.
- Nazitto R, Amon LM, Mast FD, Aitchison JD, Aderem A, Johnson JS, and Diercks A. ILF3 is a negative transcriptional regulator of innate immune responses and myeloid dendritic cell maturation. J Immunol. 2021 May 24;ji2001235. PMID: 34031149
- ChristensenDE1, Ganser-Pornillos BK1, Johnson JS, Pornillos O, Sundquist WI. Reconstitution and visualization of HIV-1 capsid-dependent replication and integration in vitro. Science. 2020 Oct 9;370(6513):eabc8420. doi: 10.1126/science.abc8420. PMID: 33033190. PMCID: PMC8022914
- Johnson JS, De Veaux N, Rives AW, Lahaye X, Lucas SY, Perot BP, Luka M, Garcia-Paredes V, Amon LM, Watters A, Abdessalem G, Aderem A, Manel N, Littman DR, Bonneau R, Ménager MM. A Comprehensive Map of the Monocyte-Derived Dendritic Cell Transcriptional Network Engaged upon Innate Sensing of HIV. Cell Rep.2020 Jan 21;30(3):914-931.e9. doi: 10.1016/j.celrep.2019.12.054. PMID: 31968263; PMCID: PMC7039998
- Johnson JS, Lucas SY, Amon LM, Skelton S, Nazitto R, Carbonetti S, Sather DN, Littman DR, Aderem A. Reshaping of the Dendritic Cell Chromatin Landscape and Interferon Pathways During HIV Infection. Cell Host Microbe. 2018 Mar 14;23(3):366-381. PMID: 29544097. PMCID: PMC 6176724