This article highlights the work of the Bahar lab in collaboration with the Arditi lab on the molecular origin of multisystem inflammatory syndrome in children (MIS-C) observed in Covid-19 patients. The article provides an extensive perspective, including interviews with Bahar, Arditi, and other scientists.
The Bahar lab discovered a superantigenic segment on the spike glycoprotein (Cheng et al., PNAS 2020), potentially implicated in triggering MIS-C as well as the cytokine storm and hyperinflammatory immune responses observed in severe Covid-19 cases (Rivas et al J Allergy & Clinical Immunol 2021). The TCR repertoire observed in in severely infected patients (Porritt et al, J Clinical Investigation, 2021) supported the occurrence of such a superantigenic reaction. The discovery of this superantigenic segment, which shares sequence and structure similarities with Staphyloccocal enterotoxin B led to the identification of a monoclonal antibody (6D3), which proved to reduce SARS-CoV-2 infection in experiments conducted at Cedars Sinai (UCLA) (Cheng et al., Structure 2021).
A myriad of inflammatory cytokines regulate signaling pathways to maintain cellular homeostasis. The IkB kinase (IKK) complex is an integration hub for cytokines that govern nuclear factor kB (NF-kB) signaling. In response to inflammation, IKK is activated through recruitment to receptor-associated protein assemblies. How and what information IKK complexes transmit about the milieu are open questions. In this paper, the Lee Lab track dynamics of IKK complexes and nuclear NF-kB to identify upstream signaling features that determine same-cell responses. Experiments and modeling of single complexes reveal their size, number, and timing relays cytokine-specific control over shared signaling mechanisms with feedback regulation that is independent of transcription. Their results provide evidence for variable-gain stochastic pooling, a noise-reducing motif that enables cytokine-specific regulation and parsimonious information transfer. They propose that emergent properties of stochastic pooling are general principles of receptor signaling that have evolved for constructive information transmission in noisy molecular environments.
Cruz JA*, Mokashi CS*, Kowalczyk GJ, Guo Y, Zhang Q, Gupta S, Schipper DL, Smeal SW, Lee REC. A variable-gain stochastic pooling motif mediates information transfer from receptor assemblies into NF-kB. Sci. Adv. 7, eabi9410 (2021)
Congratulations to Dr. Jianhua Xing for his promotion to Professor!
Congratulations to Dr. David Koes for his promotion to Associate Professor!