Download The overarching research objective of the Sellati laboratory is to

The overarching research objective of the Sellati laboratory is to understand how host responses are
tailored to the specific pathogens they encounter, particularly pathogens that represent emerging and
re-emerging infectious agents whose arthropod vector are ticks. Studies in the laboratory focus on two
distinct, yet interrelated, aspects of bacterial pathogenesis (i.e., disease development and resolution).
In both instances, innate immunity, a pre-programmed first-line defense against invading pathogens,
plays a defining role in the disease process. A fundamental question we hope to answer is why some
individuals present with more severe and/or persistent inflammation during infection than others.
Current efforts span three research programs focused on combating Lyme disease, tularemia, and
antibiotic resistant bacterial infections.
Lyme disease, a multisystem chronic inflammatory disorder that affects the skin, joints, heart, and
nervous system, is caused by infection with the tick-borne spirochetal bacterium, Borrelia burgdorferi.
We have identified key players in the signal transduction pathway responsible for immune cell activation
that contributes to clinical manifestations. Cell surface receptors including CD14, a 55-kDa polypeptide
expressed on neutrophils and monocytes/macrophages, and Toll-like Receptor 2, whose engagement of
bacterial lipoproteins communicates a “danger signal” to the cell’s interior, regulate the secretion of
several pro- and anti-inflammatory immune modulators. Such regulation is thought to play a critical role
in Lyme pathogenesis and thus these signaling pathways provide rich targets for therapeutic
intervention.
With an infectious dose requiring as few as 10 individual bacteria Francisella tularensis, a Gram-negative
facultative intracellular pathogen, can cause a lethal vector-borne pulmonary disease in humans known
as tularemia. These features, coupled with its ability to contaminate food and water and the ease of
intentional dissemination via aerosol, have resulted in the pathogen being listed as a category “A”
biothreat agent by the U.S. Centers for Disease Control and Prevention. Current efforts are focused on
revealing the mechanism(s) whereby F. tularensis modulates host lipid mediator production as a means
to alter innate cell death programs and establish a principally anti-inflammatory or immunosuppressed
environment in which to replicate. Other studies focus on antigen presentation in the context of
vaccination and the role of TLR2 signaling in the development of protective immunity. Specifically,
ongoing efforts aim to develop a pan-bacterial, rapid vaccine-development platform that radically alters
the current approach to vaccination against highly infectious agents.
Coupled with the existence of biological threat agents engineered to be impervious to treatment, the
full range of antibiotic-resistant microbes found in hospitals and the broader environment represent a
“clear and present danger” to military personnel, first responders, and the general public. Current
efforts to combat the public health challenges associated with antibiotic resistance center around our
ability to engineer self-assembling antimicrobial nanofibers (SAANs) to be non-toxic and noninflammatory to human cells, resistant to degradation, and pan-bactericidal in effect. These properties
make SAANs the ideal substitute for traditional antibiotics and adding them to the clinical “arsenal” will
have a transformative impact on the field of anti-infective therapy. SAANs are being tested against
select biological threat agents (i.e., F. tularensis and Yersinia pestis) as well as highly antibiotic-resistant
Acinetobacter baumannii, which is responsible for nosocomial, community-acquired infections as well as
those acquired following war or natural disasters. The therapeutic potential of SAANs is being evaluated
using well-characterized and validated mouse models of respiratory tularemia and plague as well as
deep tissue wound and respiratory infections with A. baumannii.