Criss, Alison K.

Alison K. Criss

Alison K. Criss

Primary Appointment

Assistant Professor, Microbiology, Immunology, and Cancer Biology

Education

  • BA, Biology and Chemistry, Williams College
  • PhD, Cell and Developmental Biology, Harvard University
  • Postdoc, Microbiology, Northwestern University

Contact Information


Email: akc2r@virginia.edu
Website: http://criss-lab.med.virginia.edu/

Research Interests

Cellular and molecular mechanisms of Neisserial pathogenesis

Research Description



Our laboratory studies N. gonorrhoeae, an obligate human bacterial pathogen that causes the sexually transmitted infection gonorrhea. Gonorrhea has existed within the human population for all of recorded history and remains the second-most commonly reported bacterial sexually transmitted infection in the world today. Gonorrhea continues to be a major public health problem because of rapid acquisition of antibiotic resistance (N. gonorrhoeae achieved superbug status in 2007), the failure of vaccines to stimulate a protective immune response, the fact that previously infected individuals remain susceptible to subsequent rounds of re-infection, and the predisposition of infected individuals to acquisition of HIV.

Since N. gonorrhoeae has no niche outside of humans, the biology of this organism is exquisitely tailored to life in the human urogenital tract. Not only is N. gonorrhoeae able to exploit the nutritional and environmental conditions at this site, but the bacterium also has an extraordinary ability to thwart challenges by the host immune response. N. gonorrhoeae evades humoral immune recognition by undergoing extensive variation of its surface structures, including high-frequency sequence changes in the N. gonorrhoeae pilin gene that lead to antigenic variation of the type IV pilus. N. gonorrhoeae is also highly adept at surviving confrontations with the innate immune system. Acute gonorrhea is a highly inflammatory disease characterized by the production of an exudate containing large numbers of neutrophils. Although neutrophils are the body's first defenders against bacterial and fungal challenge, neutrophils are ineffective at killing N. gonorrhoeae, and gonorrheal exudates contain viable, infectious bacteria.

Our research is currently centered on identifying how N. gonorrhoeae resists neutrophil clearance. Specifically, we are addressing which neutrophil antimicrobial factors are directed against N. gonorrhoeae and which bacterial gene products defend N. gonorrhoeae from neutrophil killing. We use a combination of cell biology, molecular biology, bacterial genetics and biochemistry to address these questions. The insights gleaned from these studies will help us to understand in general how the mucosal innate immune system defends against infection and how pathogens exploit mucosal defenses to aid in colonization and transmission. Specific areas of interest are outlined below.

Resistance of neutrophils to non-oxidative neutrophil killing: We have found that a significant proportion of N. gonorrhoeae presented to primary human neutrophils in vitro survive early infection and grow in association with them over time. Neutrophils generate reactive oxygen species (ROS) such as hydrogen peroxide and hypochlorous acid as part of their antimicrobial arsenal, but inhibition of neutrophil ROS production has no effect on N. gonorrhoeae survival. In the course of these studies, we identified bacterial mutants that are more sensitive to non-oxidative neutrophil killing. We plan to examine which non-oxidative neutrophil factors are active against N. gonorrhoeae and the reasons for the susceptibility of our bacterial mutants to non-oxidative neutrophil killing. We have also gained evidence that neutrophil phagosomes contain viable N. gonorrhoeae. We plan to characterize the neutrophil subcellular compartment(s) in which N. gonorrhoeae are found and examine their maturation over time.

N. gonorrhoeae suppression of neutrophil ROS production: In examining why neutrophil oxidative mechanisms are dispensable for killing of N. gonorrhoeae, we made the surprising observation that neutrophils generate little to no ROS after infection with exponentially-growing N. gonorrhoeae. Moreover, N. gonorrhoeae infection suppresses the ability of neutrophils to generate ROS in response to a variety of stimuli, including S. aureus and formylated peptides. We hypothesize that live N. gonorrhoeae produce factors that interfere with signaling pathways that normally lead to neutrophil ROS production. We are examining how N. gonorrhoeae impede neutrophil signal transduction and which bacterial gene products are responsible for this effect.



Thin-section transmission electron micrograph of N. gonorrhoeae-infected neutrophil.



Fluorescence/phase-contrast image of human neutrophils infected with strain FA1090 N. gonorrhoeae for 60 minutes. Green particles are intracellular bacteria; red/yellow particles are extracellular bacteria.

Selected Publications