Faculty Profile


Leigh Knodler

Leigh Knodler

Assistant Professor

Departments

  • WSU Paul G. Allen School for Global Animal Health (primary appointment)
  • School of Molecular Biosciences, WSU (affiliate faculty)
  • Department of Veterinary Microbiology and Pathology, WSU (affiliate faculty)

Affiliated Organizations

  • American Society of Microbiology (ASM), member and Northwest branch president
  • American Association for the Advancement of Science, member

leigh.knodler@wsu.edu
Phone: 509-335-4046

 

Biography

Dr. Knodler obtained her PhD from the University of New South Wales in Australia in 1995. Her thesis focused on novel metabolic pathways in the protozoan parasite, Giardia intestinalis. From 1996 to 1999 she was a postdoctoral fellow at the University of California at San Diego studying gene regulation during the developmental cycle of Giardia. In 2000 she moved to Vancouver, Canada for a postdoctoral position in the laboratory of Dr. B. Brett Finlay where she studied the Salmonella enterica pathogenesis. She continued her studies on Salmonella-host cell interactions at the Rocky Mountain Laboratories, NIAID in Montana from 2002-2012, first as a Research Fellow and then as a Staff Scientist. Dr Knodler was recruited to the WSU Paul G. Allen School for Global Animal Health as an Assistant Professor in October 2012.

Personal Statement

I grew up on a cattle farm in Australia and always wanted to be outside, playing in the dirt. At a very young age I was given a magnifying glass and a microscope by my family because I was so interested in all the small bugs crawling around. Science was my favorite subject at school, even though it was not the easiest subject for me. I originally trained as a biochemist, studying metabolic pathways in parasites, so there has always been a link to microbes in my research. It was not until I moved to the US for a postdoc and saw Stanley Falkow speak at a regional ASM meeting that I was drawn to the bacterial pathogenesis field. He is such a captivating speaker, and essentially the “father” of bacterial pathogenesis as a field of study, and I ended up doing a second postdoc in Canada so I could work on Salmonella. Then I was hooked.

When I am not at work, I like to play in my garden, renovate houses, travel to exotic places and mountain bike with my husband.

Education and Training

  • BSc (First Class Honours) – University of New South Wales
  • PhD – University of New South Wales 

General Research / Expertise

Our lab studies host-pathogen interactions related to bacterial infections of the human gut. We are primarily focused on Salmonella enterica, the leading bacterial cause of food-borne illness in the USA. We use genetic, cell biological and microscopic approaches to tease apart how Salmonella enterica enters and colonizes intestinal epithelial cells, and then how it exits from these cells to be transmitted from one person or animal to another. We also study other enteric bacteria such as Shigella flexneri and Providencia alcalifaciens so we can determine whether the colonization mechanisms used by Salmonella enterica are unique to this bacterium, or shared by other bacteria that cause gastrointestinal disease.

Research Contributions

Our group has described a mechanism for escape of Salmonella enterica from intestinal epithelial cells, providing the first explanation for dissemination of this bacterium within a host and between hosts. Previously, Salmonella enterica had been shown to occupy a membrane-bound vacuole within host cells, but how it could could be shed and spread to other hosts from this intracellular location was an unanswered question. We found that a sub-population of internalized bacteria lyse their vacuole membrane, then rapidly replicate to eventually fill the entire cellular content. This initiates epithelial cell death and expulsion of infected cells, thereby releasing Salmonella. More recently, our laboratory has identified Salmonella genes that are required for cytosolic replication in, and subsequent bacterial egress from, epithelial cells. Collectively, these studies have changed the conventional wisdom about the intracellular pathogenesis of Salmonella enterica.

The inflammasome is an innate immune sensor that provides a protective role against bacterial and viral pathogens. Its actions were previously believed to be restricted to professional immune cells, such as macrophages. We have reported that intestinal epithelial cells also activate an inflammasome upon recognition of the subset of Salmonella enterica that live freely in the cytosol, which initiates cell death and expulsion of infected epithelial cells. In collaborative work, we further showed that inflammasome activation limits Salmonella replication in gut and gall bladder epithelial cells in vivo. Our studies were important because they were the first to define inflammasome activation as a mechanism controlling epithelial cell shedding in response to bacterial pathogens.

Research Details

The Knodler lab is focused on understanding the molecular interactions of enteric bacteria with the gut. We primarily use Salmonella enterica as a model enteric pathogen and tissue culture models of intestinal epithelium to define: (i) what bacterial factors drive lysis of bacteria-containing vacuoles and proliferation in the host cell cytosol, and (ii) what host cell mechanisms sense and respond to cytosolic bacteria in intestinal epithelial cells. To decipher these interactions, our research applies a multidisciplinary combination of cell biology, biochemistry, molecular biology and microscopy techniques. We also have active collaborations to study these host-microbial interactions in animal models of enteric infection.

Select Publications
  • Knodler LA, Vallance BA, Celli J, Winfree S, Hansen B, Montero M, Steele-Mortimer O. (2010) Dissemination of invasive Salmonella via bacterial-induced extrusion of mucosal epithelia. Proc Natl Acad Sci U S A. 107(41):17733-8. PMID: 20876119 PMCID: PMC2955089
  • Knodler LA, Crowley SM, Sham HP, Yang H, Wrande M, Ma C, Ernst RK, Steele-Mortimer O, Celli J, Vallance BA. (2014) Noncanonical inflammasome activation of caspase-4/caspase-11 mediates epithelial defenses against enteric bacterial pathogens. Cell Host Microbe. 16(2):249-256. PMID: 25121752 PMCID: PMC4157630
  • Du J, Reeves AZ, Klein JA, Twedt DJ, Knodler LA, Lesser CF. (2016) The type III secretion system apparatus determines the intracellular niche of bacterial pathogens. Proc Natl Acad Sci U S A. 113(17):4794-9. PMID: 27078095 PMCID: PMC4855615
  • Jessica A. Klein, Jesse R. Grenz, James M. Slauch, Leigh A. Knodler (2017) Controlled Activity of the Salmonella Invasion-Associated Injectisome Reveals Its Intracellular Role in the Cytosolic Population mBio vol. 8 no. 6 e01931-17 PMID: 29208746 PMCID: PMC5717391

PubMed List of Publications