Pathogen activation and evasion of innate immune signaling - cell death pathways, inflammasomes and Toll-like Receptors.
Over the last three decades, we have gained a lot of information on how the body defends itself against pathogenic microbes by activation of the innate immune system. This part of the immune system provides the immediate defense against invading bacteria, virus or fungi, and is also able to fine-tune and optimize the subsequent more specialized adaptive immune response.
My laboratory is primarily focused on understanding how recognition of pathogens leads to activation of Toll-like receptors (TLRs), inflammasomes, and cell death pathways. Lipopolysaccharide (LPS) from Gram-negative bacteria (also called endotoxin) is particularly interesting, it is a saccharide containing acyl chains. LPS is a main component of the Gram-negative outer membrane, and one of the most potent activators of immune cells. LPS activates cells via TLR4 and MD-2, but recognition of other microbial components, such as secretion system apparatus interacting with inflammasomes and cell death pathways, also participates in the host response. Inflammasomes formed in response to microbial compounds typically involve complex formation with NOD-like receptors (NLRs), often an adapter called Asc and inflammatory caspases such as caspase-1. Activation leads to the generation of active caspase and subsequent cleavage of pro-IL-1b and pro-IL-18 into mature IL-1b/IL-18, key cytokines in many inflammatory responses, and cleavage of Gasdermin D, generating membrane pores during pyroptotic cell death. A number of pathogens may attempt to evade or minimize signaling via TLRs and NLRs, as this may be beneficial from a pathogen point of view.
Two methods Gram-negative pathogens may use for evasion are "stealth" by modifying their LPS, and active manipulation of host signaling by their type III secretion systems. However, this latter type of "pathological activity" can also be sensed by the host and lead to backup mechanisms. Increasingly, it is recognized that a great deal of cross-talk exists in innate immunity between different inflammatory and cell death pathways. One such example is from our work suggests that elements of extrinsic apoptosis, such as RIPK1 and caspase-8, can trigger mechanisms involving pyroptotic cell death and inflammasomes. A greater understanding of microbial activation and evasion of innate immunity can lead to new therapies and vaccines against infectious diseases.
One of the model systems we utilize involves bacteria of the genus Yersiniae, such as Yersinia pestis, the causative agents of plague, and the other human-pathogenic Yersinia, Y. pseudotuberculosis and Y. enterocolitica. We are also interested in innate immune responses to other pathogens such as Salmonella, Klebsiella, E. coli, SARS-CoV-2 and cytomegalovirus, and in understanding mechanisms of adjuvant action for vaccines. Other topics of interest are inflammation during IBD, obesity/diabetes and neurological diseases.
Norwegian Institute of Technology (NTH), M.Sc. 1992
Norwegian University of Science and Technology (NTNU); Ph.D. 1998
Boston University/Boston Medical Center; Postdoc 1997-99
NTNU; Postdoc 1999-2001
UMass Medical School; Assistant Professor of Medicine, Department of Medicine, Division of Infectious Diseases and Immunology, 2002-2007
UMass Medical School; Associate Professor of Medicine and Microbiology and Physiological Systems 2007-2016
UMass Medical School; Professor (tenured) of Medicine, and Microbiology and Physiological Systems 2016-present
NTNU; Associate Professor II, 2008-2011
NTNU; Professor II, 2011-present