The Microbiology & Molecular Pathogenesis Program affords students and post-docs a multi-disciplinary environment in which to explore their areas of research while benefiting from constant constructive collaboration with other researchers representing a wealth of different scientific backgrounds. Several examples of current collaborative projects focusing on various aspects of microbial pathogenesis are illustrated below.

A collaborative project between Randy Noelle's and Edward Usherwood's laboratories has shown an important role for retinoic acid in the defense against virus infection. There is an emerging understanding of the role played by retinoic acid in the immune response, however little is known about it's role in immunity to pathogens. Very early studies showed that vitamin A deficient patients were much more susceptible to a variety of infections, and more recent work has shown that all-trans retinoic acid (ATRA) is the vitamin A metabolite responsible. Studies from Randy Noelle's laboratory showed that ATRA is essential for potent CD4 and CD8 T cell responses to model antigens and tumors. Recently a collaboration between the Noelle and Usherwood laboratories has revealed that ATRA also has important functions in the T cell response to virus infection. The absence of retinoic acid resulted in a weaker CD8 T cell response to vaccinia virus, and surprisingly the differentiation of the response was altered to favor the generation of memory CD8 T cells. These cells provide long-term immunity to virus infection, so manipulation of retinoic acid biology may be a useful approach to develop better vaccines and immunotherapies to infectious disease.

Juliette Madan led a recent collaborative study with Jason Moore and George O'Toole studying the developing microbiome of infants with Cystic Fibrosis (CF). This multi-disciplinary team, with a neonatologist (Madan), bioinformatician (Moore) and microbiologist (O'Toole) explored the development of the microbial communities in the gut and upper respiratory tract of CF infants. Patients with CF develop a chronic bacterial infection of the lung later in life and also have persistent digestive issues due to the genetic mutation in the CFTR ion channel. However, little is know about how the microbes that eventually cause infection in this population begin the process of colonization. For the first time, this team addressed this question in a group of infants over the first ~2 years of life.

A collaboration between the Leib and Berwin labs in Microbiology and Immunology is using a variety of methodologies and approaches to examine the role of innate immunity in control of bacterial and viral pathogens. In a joint publication their labs used real-time bioluminescence imaging to study the spread and tropism of herpes simplex virus in mice lacking a variety of innate immune signaling molecules (Pasieka et al, 2011). Ongoing collaborative work in these labs is examining the role of autophagy in the genesis and regulation of the inflammasome during infection with Pseudomonas, herpes simplex, and during polymicrobial infections.

A collaboration between the Taylor and Skorupski labs in Microbiology and Immunology and the Kull and Mierke labs in Chemistry has led to the discovery of a class of small molecule inhibitors of bacterial virulence gene expression. Members of these laboratories have combined their expertise regarding the molecular mechanisms that cause some bacteria to be pathogens with sophisticated structural biology technology to deduce and understand the structure of bacterial proteins that induce virulence gene expression. The resolution of these structures is at the atomic level. A surprise finding was the identification of a small molecule bound within a molecular pocket of one of these regulators. These investigators went on to show that this small molecule is able to shut off virulence gene expression by preventing the regulatory protein from binding DNA. The regulator, ToxT of Vibrio cholerae, a bacterium that causes severe, lethal diarrhea, is a member of a broad class of regulators important for virulence gene expression in a wide variety of bacterial pathogens. This collaborative research team is now investigating the use of this class of small molecule inhibitors to treat various bacterial infections.

The Hogan Lab is collaborating with Dr. Ali Ashare and colleagues in the Pulmonology group at the Dartmouth-Hitchcock Medical Center to analyze clinical samples from the lungs of patients infected with the bacterium Pseudomonas aeruginosa or with various fungal pathogens.** This research will allow us to assess the similarities and differences between our in vitro models and human infections, and will provide insight into which microbial pathways may be the most effective targets for the development of future antimicrobial therapies.

The Hogan Lab is also collaborating with Dr. Robert Cramer studying bacterial fungal interactions. The Cramer and Hogan Labs are collaborating on the interactions between the human fungal pathogens Candida albicans and Aspergillus fumigatus and the bacterial pathogen Pseudomonas aeruginosa in the context of chronic lung infections where these organisms are associated with disease. Our studies use a variety of models to examine how mixed infections influence the behavior of the interacting microbes and the immune response that they elicit. A particular focus of our studies is on the impact of the fungal-microbe interactions on pathogen and host metabolism that can enhance immunopathogenesis. Consequently, these studies are expected to reveal the extent to which the presence of fungal-bacterial combinations worsen chronic pulmonary diseases such as Cystic Fibrosis, COPD, and asthma. A long-term goal and expected result of this collaboration is to provide insight into how to determine if treatment of fungi may be beneficial in these chronic disease settings.

The Cramer and Zegans laboratories are collaborating on the effects of antifungal drugs, which are utilized to treat increasingly common fungal cornea infections, on the host immune response in the eye. This collaboration is based on a recently published clinical trial in which Dr. Zegans and colleagues observed worsening of ocular disease in patients treated with the triazole voriconazole versus those on natamycin. This was unexpected since MIC were similar and led us to hypothesize that there might be off target effects of these antifungals on host tissues which might explain this difference in efficacy. Our studies are using ex vivo and in vitro models of fungal-phagocyte interactions to measure the impact of the different antifungal drugs on the host immune response. These studies are expected to provide new insights into the effects of different antifungal drug classes on host immune responses to fungi that could drive therapeutic decisions regarding the treatment of severe fungal infections of the eye.