Integrative studies for a mechanistic understanding of antiviral innate immunity and inflammation

Innate immune responses are the first line of defense against viral infection, but their inappropriate activation can cause autoinflammatory disease. The Best and Modis groups study how the host senses viruses, mounts sufficiently sensitive yet specific responses, and how this balance can be perturbed for example by disease mutations. Our work focuses largely on the roles of two key families of viral restriction factors, the TRIMs and RIG-I-like receptors (RLRs). We integrate an exceptionally broad spectrum of approaches, from in vivo work in high and maximum contain laboratories to state-of-the-art electron microscopy. This uniquely positions us to obtain a more complete understanding of virus-host interactions under physiological conditions with mechanistic insights in atomic-level detail.  

This PhD project will focus on unravelling important insights into how RNA viruses are detected and targeted by their hosts. The aims of this project will apply our full complement of approaches, including electron microscopy, biochemical and cell-based assays, and in vivo work as needed to obtain a detailed mechanistic understanding of the contributions of virus-host interactions to antiviral innate immunity and virus pathogenesis. Our long-term goal is to use contribute to the design of novel therapeutics, such as antivirals, vaccine adjuvants, or immunomodulatory therapeutics, with potential applications in the treatment of infection, autoinflammatory disorders and cancer.

Our teams at the NIAID Rocky Mountain Laboratories and University of Cambridge are strongly committed to fostering a supportive and inclusive work environment in which trainees can thrive and experience the thrill of scientific discovery.

References:
Chiramel AI, Meyerson NR, McNally KL, Broeckel RM, Montoya VR, Méndez-Solís O, Robertson SJ, Sturdevant GL, Lubick KJ, Nair V, Youseff BH, Ireland RM, Bosio CM, Kim K, Luban J, Hirsch VM, Taylor RT, Bouamr F, Sawyer SL, Best SM (2019) TRIM5α Restricts Flavivirus Replication by Targeting the Viral Protease for Proteasomal Degradation. Cell Rep 27:3269  PMC8666140

Yu Q, Herrero del Valle A, Singh R, Modis Y (2021) MDA5 autoimmune disease variant M854K prevents ATP-dependent structural discrimination of viral and cellular RNA. Nat Commun 12:6668  PMCID: PMC8602431

Stoll GA, Pandiloski N, Douse CH, Modis Y (2022) Structure and functional mapping of the KRAB-KAP1 repressor complex. EMBO J 41:e111179  PMC9753469

Shannon JG, Sturdevant GL, Rosenke R, Anzick SL, Forte E, Preuss C, Baker CN, Harder JM, Brunton C, Munger S, Bruno DP, Lack JB, Leung JM, Shamsaddini A, Gardina P, Sturdevant DE, Sun J, Martens C, Holland SM, Rosenthal NA, Best SM (2023) Genetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation in type I interferon and cytokine responses in COVID-19. Nat Commun 14:4481  PMC10368652