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

Norwegian  University of Science and Technology (NTNU), Postdoc 1999-2001

UMass  Medical School, Assistant Professor of Medicine, Department of Medicine, Division of Infectious Diseases and Immunology, 2002-present

Research Interests:

Pathogen recognition by and evasion of innate immune signaling.
Toll-Like Receptors.

The last 8-10 years we have gained a lot of information on how the body defends itself against pathogenic microbes by its 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. Many of the advances in the knowledge on innate immune mechanisms have been achieved by studies of mammalian Toll-like receptors (TLRs). These sensors, originally described as homologues of the Drosophila Toll molecule, constitute a formidable line of first responders to infectious agents. Increased knowledge about recognition of pathogens will help in the design of future therapies and vaccines against infectious diseases.

My laboratory is focused on understanding the innate immune recognition of pathogens by TLRs. Initial studies were performed on basic functions of TLR2 and TLR4, and these two receptors were identified as signaling molecules recognizing bacterial lipoproteins and lipopolysaccharide (LPS), respectively. 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 – picogram per milliliter amounts are sufficient to induce a response. 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 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 mediates its activity by interaction with TLR4 and co-receptor MD-2, followed by subsequent triggering of intracellular signaling by adapter molecules MyD88, Mal, TRIF and TRAM. Downstream effects include nuclear translocation of transcription factors NF-kB and IRF-3, eventually inducing release of pro-inflammatory cytokines such as TNF, IL-6 and type I IFN.

One of the main projects in the lab is currently investigating the evasion of TLR4 signaling by the plague bacillus Yersinia pestis. This bacterium modifies its LPS at host temperature (37º C) to a structure that is a poor stimulator of TLR4, and we have found that this modification is necessary for Y. pestis to cause plague. An engineered Y. pestis strain producing a potent LPS was unable to cause serious infection in normal mice, thus, a sufficient stimulation of the innate immune response initiated anti-bacterial mechanisms to clear the bacteria at an early stage. This highlights the ability of TLR4 signaling to protect against life-threatening disease, and suggests that “stealth” from TLR4 is a critical strategy for bacterial virulence in Y. pestis. Furthermore, the engineered strain could serve as an effective vaccine against subsequent subcutaneous and intranasal infection with fully virulent Y. pestis. Hence, we have described a new method for producing vaccine strains containing enhanced TLR stimulatory activity.

Other projects in the lab includes signaling mechanisms by and regulation of TLR2, TLR4/MD-2 and TLR9. We have collaborative projects on TLR3 localization and function, and the role of TLRs in HIV, Borrelia and malaria infections and virus-induced diabetes.