Major Areas of Research
- Inflammasome activation and the innate immune response
- Host factors controlling inflammasome-mediated events
- Role of the anthrax lethal and edema toxins in Bacillus anthracis pathogenesis
- Vaccines and therapeutics against Bacillus anthracis
Bacillus anthracis produces two toxins with a common receptor binding component. Edema toxin (ET) is an adenylate cyclase. Lethal toxin (LT) is a protease that cleaves several mitogen-activated protein kinase kinases (MEKs/MKKs) and the regulatory subunits of phosphoinositide 3-kinase (p85-alpha, p85-beta), impacting signaling pathways which are central to cell survival, proliferation, stress response, metabolism and other essential functions. LT also cleaves and activates rodent inflammasome sensor NLRP1, resulting in downstream caspase-1 cleavage, gasdermin cleavage a rapid cell death (pyroptosis).
Caspase-1 activation, which also occurs through activation of many other inflammasome sensors, including the NLRP3, NAIP/NLRC4, and AIM2 sensors, initiates an innate immune response through maturation and release of the pro-inflammatory cytokines IL-1β and IL-18. NLRP1 is also activated by Toxoplasma gondii, but the mechanism for activation is currently unknown.
My primary interests are understanding the signaling pathways targeted by anthrax toxins in cell and animal models. Our studies on anthrax toxin activation of NLRP1, shutdown of MEK signaling, modulation of PI3K/Akt signaling and dysregulation of cAMP signaling provide insight into disease pathogenesis, as well as aid in better understanding these important signaling pathways. Identification of novel toxin targets, new PAMPs and DAMPs which can activate the NLRP1 inflammasome, host genetic factors which control inflammasome-mediated responses and anti-inflammatory or anti-anthrax therapeutics are all areas of active study.
Mendenhall MA, Liu S, Portley MK, O'Mard D, Fattah R, Szabo R, Bugge TH, Khillan JS, Leppla SH, Moayeri M. Anthrax lethal factor cleaves regulatory subunits of phosphoinositide-3 kinase to contribute to toxin lethality. Nat Microbiol. 2020 Sep 7. doi: 10.1038/s41564-020-0782-1. Online ahead of print. PMID: 32895527
Greaney AJ, Portley MK, O'Mard D, Crown D, Maier NK, Mendenhall MA, Mayer-Barber KD, Leppla SH, Moayeri M. Frontline Science: Anthrax lethal toxin-induced, NLRP1-mediated IL-1β release is a neutrophil and PAD4-dependent event. J Leukoc Biol. 2020 May 18. doi: 10.1002/JLB.4HI0320-028R. Online ahead of print. PMID: 32421904
Greaney AJ, Maier NK, Leppla SH, Moayeri M. Sulforaphane inhibits multiple inflammasomes through an Nrf2-independent mechanism. J Leukoc Biol. 2016 Jan;99(1):189-99.
Vrentas CE, Moayeri M, Keefer AB, Greaney AJ, Tremblay J, O'Mard D, Leppla SH, Shoemaker CB. A Diverse Set of Single-domain Antibodies (VHHs) against the Anthrax Toxin Lethal and Edema Factors Provides a Basis for Construction of a Bispecific Agent That Protects against Anthrax Infection. J Biol Chem. 2016 Oct 7;291(41):21596-21606. doi: 10.1074/jbc.M116.749184. Epub 2016 Aug 18. PMID: 27539858
Moayeri M, Leppla SH, Vrentas C, Pomerantsev AP, Liu S. Anthrax pathogenesis. Annu Rev Microbiol. 2015;69:185-208.
Maier NK, Leppla SH, Moayeri M. The cyclopentenone prostaglandin 15d-PGJ2 inhibits the NLRP1 and NLRP3 inflammasomes. J Immunol. 2015 Mar 15;194(6):2776-85.
Moayeri M, Leysath CE, Tremblay JM, Vrentas C, Crown D, Leppla SH, Shoemaker CB. A heterodimer of a VHH (variable domains of camelid heavy chain-only) antibody that inhibits anthrax toxin cell binding linked to a VHH antibody that blocks oligomer formation is highly protective in an anthrax spore challenge model. J Biol Chem. 2015 Mar 6;290(10):6584-95.
Cirelli KM, Gorfu G, Hassan MA, Printz M, Crown D, Leppla SH, Grigg ME, Saeij JP, Moayeri M. Inflammasome sensor NLRP1 controls rat macrophage susceptibility to Toxoplasma gondii. PLoS Pathog. 2014 Mar 13;10(3):e1003927