Research Interests:

Pathogen activation and evasion of innate immune signaling - Inflammasomes and Toll-like Receptors.

Over the last several years, 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 the innate immune recognition of pathogens by Toll-like receptors (TLRs) and inflammasomes. Lipopolysaccharide (LPS) from Gram-negative bacteria (also called endotoxin) is particularly interesting, it is a saccharide containing acyl chains (“fatty sugar”). LPS is a main component of the Gram-negative outer membrane, and one of the most potent activators of immune cells. LPS activation of host cells is a double-edged sword: An early sensing of LPS is important for clearance of an initial Gram-negative infection, but high amounts of LPS in circulation during overwhelming bacteremia and sepsis can lead to Gram-negative endotoxic shock and death. Thus, a well timed, balanced and measured host response to LPS is critical in determining outcome of an infection. LPS activates cells via TLR4 and MD-2, but recognition of other microbial components, such as those mediated by inflammasomes, also participates in an optimal host response. Inflammasomes formed in response to microbial compounds typically involve complex formation with NOD-like receptors (NLRs) such as NLRP3, NLRP12 or NLRC4, 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. A number of pathogens may attempt to minimize signaling via TLRs and NLRs, as this may be beneficial from a pathogen point of view. 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. Y. pestis, a master of immune evasion, normally produces tetra-acylated LPS with low ability to trigger TLR4 signaling. However, the activation potential can be restored upon the forced generation of a hexa-acylated LPS similar to that found in Y. pseudotuberculosis, and this markedly attenuates Y. pestis in vivo, suggesting a role for evasion of TLR4 signaling in the evolution of high virulence in plague. IL-1b and in particular IL-18 appear to be effective mediators of antibacterial defenses against Y. pestis, and NLR containing inflammasomes participate in optimal IL-18 and IL-1b production. We are also interested in innate immune responses to other pathogens such as Salmonella, Klebsiella, E. coli and cytomegalovirus, and in understanding mechanisms of adjuvant action for Yersinia, HIV-1 and malaria vaccines. Another topic we study is inflammation involved in the development of diabetes and obesity.

Biography:

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-present

NTNU; Associate Professor II, 2008-2011

NTNU; Professor II, 2011-present