UW Microbiology: Faculty

Tuesdays, 4:00 - 5:00pm T-639 UW Health Sciences Building
**Unless otherwise noted

Cammie Lesser, M.D., Ph.D.
Assistant Professor, Massachusetts General Hospital, Harvard Medical School

Tobias Hohl, Ph.D.
Assistant Member, Vaccine and Infectious Diseases Institute
Fred Hutchinson Cancer Research Center
Seattle, WA

"Initiation of Pulmonary Immune Responses to Aspergillus fumigatus."

Aspergillus fumigatus is a ubiquitous fungus that causes invasive disease in immunocompromised humans. Humans inhale Aspergillus spores (conidia) on a daily basis and, in immune competent hosts, the respiratory immune system prevents the process of spore germination into filamentous hyphae. This presentation will focus on the molecular and cellular events that underlie the generation of protective immune responses to Aspergillus. The induction of inflammatory responses to inhaled spores depends on Toll-like receptor (TLR) and lectin receptor signaling pathways, in part through recognition of a fungal polysaccharide, ?-D-1,3-glucan, by the signaling receptor dectin-1. Inflammatory responses to inhaled spores occur only if spores have begun the germination process, a process that may calibrate the inflammatory response to avoid host tissue injury. Although alveolar macrophages have long been regarded as central to the coordination of the innate immune response to inhaled spores, our recent work suggests that alveolar macrophage-independent mechanisms can compensate for loss of these cells. Neutrophils, however, are indispensable to murine survival and rapid airway influx is critical to host survival.

Although monocytes and antigen-specific CD4 T cells contribute to defense against inhaled fungal spores, how these cells interact during infection remains undefined. We investigated the role of CCR2+Ly6Chi monocytes and monocyte-derived dendritic cells during fungal infection. Using novel CCR2 reporter mice, we find that respiratory A. fumigatus infection induces influx of CCR2+Ly6Chi monocytes into lungs and draining lymph nodes. Depletion of CCR2+ cells reduced transport of A. fumigatus conidia from lungs to draining lymph nodes by >85% and abolished priming of CD4 T cells following respiratory challenge. In contrast, depletion of CCR2+Ly6Chi monocytes during systemic fungal infection did not prevent CD4 T cell priming in the spleen. Our findings demonstrate that CD4 T cell responses to inhaled spores require CCR2+Ly6Chi monocytes and their derivatives, revealing a compartmentally restricted function for these cells in adaptive respiratory immune responses.

October 20, 2009

Stanley Falkow, Ph.D.
Professor of Microbiology and Immunology
Stanford University

"Salmonella as an emerging infection - watching evolution in action."

Salmonella enterica cause important human and veterinary diseases. They invade and replicate within host cells, including epithelial cells and macrophages. Salmonella typhi only infects humans and is the causative agent of typhoid fever. Salmonella typhimurium causes gastroenteritis in humans but is a host-adapted systemic disease in mice resembling typhoid fever. Host-adapted Salmonella often causes an asymptomatic persistent infection that serves as a reservoir of infection
I will describe several molecular aspects of Salmonella pathogenesis, focusing in particular on the functions of bacterial genes required for survival and replication of Salmonella in host cells and in laboratory animals during systemic infection and particularly during persistent carriage. As a counterpoint, I will describe the features of Salmonella food poisoning. This has become an increasingly important public health problem because of changes in technology, animal husbandry and food distribution. While Salmonella food poisoning is self-limiting and not usually transmitted from human to human, susceptibility to infection by food-borne Salmonella and the likelihood of Salmonella carriage following systemic infection have some striking parallels.
Antibiotic resistance has become a major problem in the treatment of salmonellosis. The selective pressure of anti-microbial resistance appears to be responsible for the emergence of a new clone of S. typhimurium in parts of Africa that appears to be more host-adapted to humans and is the cause of serious systemic disease. The genomic analysis of these African strains in comparison to S. typhi and food-borne S. typhimurium reveals interesting insights into the evolution of Salmonella host adaptation.

Robert Palermo, Ph.D.
Principal Research Scientist
Department of Microbiology
School of Medicine
University of Washington

"Functional Genomics Studies in Non-Human Primate Models of AIDS Pathogenesis and Immunity"

Macaque/SIV models remain the benchmark system for preliminary evaluation of new strategies for HIV vaccines, yet functional genomics tools have found little application in this area. In light of the outstanding challenges in determining good correlates of immunity for such vaccines, we proposed using global transcriptional expression profiling of whole blood as a characterization technique in these non-human primate (NHP) trials. We present the results from one such project in a vaccine trial that employed replicating adenovirus vectors encoding SIV immunogens, with or without protein boosts. Pre-challenge, we see expression features that distinguish the most protected from the other analyzed treatment groups. We also describe the evolution of the expression patterns from peak viremia to set point, where the expression profiles suggest quite different immunological states to the vaccinated animals despite very similar levels of viral control.
We have also applied gene expression profiling to explore differences following lentiviral infection in natural vs non-natural NHP hosts. African Green Monkeys infected with SIVagm.sab support very high levels of viral replication, but have no evident long-term pathology. Pig-tail macaques infected with this same virus are subject to chronic inflammation and AIDS-like immune exhaustion. Gene expression profiling reveals quite distinct kinetics and compartmentalization to the immune and inflammatory responses for the two species, indicating unexpected complexity in how the natural host establishes a commensal infection.