Donald Steiner, PhD

Dr. Steiner’s work has focused on respiratory pathogens and their interactions with host immunity. The bacterium Francisella tularensis, causative agent of the disease tularemia, has been a particular focus of interest. F. tularensis is a select agent which has been studied for use in biological warfare in the 20th century; it is also endemic in much of the Midwest and western United States. We still have no vaccine for F. tularensis and it remains a threat today, both from bioterrorism and from natural exposure.

Intracellular pathogens and host phagocytes

Francisella tularensis is a facultative intracellular parasite, able to replicate within the cytoplasm of host cells to evade immune defenses. In respiratory infections, which comprise the most lethal form of tularemia, the primary cells to become infected are alveolar macrophages in the lungs. However, while alveolar macrophages are the primary site of bacterial replication in such infections, they also play a necessary protective role in sublethal infection by facilitating neutrophil recruitment to the lungs. Depletion of alveolar macrophages failed to control infection since F. tularensis is not constitutively dependent on replication within this cell type. Deficiencies interferon γ signaling in alveolar macrophages increased sensitivity to infection by inhibiting neutrophil recruitment, and neutrophil depletion reduced survival in infected mice; however, IL-12 stimulation of macrophages conferred protection even following neutrophil depletion, through a mechanism dependent on NADPH oxidase and the oxidative burst.

Depletion of alveolar macrophages in combination with anti-F. tularensis serum opsonization was found to be protective against low lethal infectious doses of the highly pathogenic SchuS4 strain of F. tularensis. Survival was found to be linked to the prevention of disseminated infection beyond the lungs. The protection conferred by opsonization and macrophage depletion was found to be neutrophil dependent, suggesting that in the absence of alveolar macrophages, F. tularensis was engulfed and destroyed by neutrophils in a mechanism facilitated by opsonization.

Vaccine development

Antigen-pulsed antigen-presenting cells (APCs) have been investigated as a possible therapeutic intervention against certain cancers. The same treatment has potential against infectious disease, but culturing specific APC populations is a time-consuming and laborious task. It is possible to use peripheral blood mononuclear cells (PBMCs) isolated directly from the blood as a substitute for cultured APCs. Intranasal pulsed PBMC vaccination was as protective as intramuscular vaccination with an approved vaccine formulation (Prevnar-13) against Streptococcus pneumoniae, a commensal airway bacterium that can become an opportunistic pathogen in immunocompromised patients such as the elderly.