Infection and disease
The development of new therapeutics for human pathogens requires a detailed analysis of their lifecycle to uncover vulnerabilities that can be exploited to kill these invaders. For bacterial or fungal infections, this involves understanding cellular behavior under conditions relevant to host colonization (e.g. biofilm formation). While for viral infections (such as HIV) it involves a detailed understanding of the mechanisms employed by the virus to subvert or circumvent host defense systems. Meticulous analysis of these systems reveals new potential targets for the creation of small molecules or biologics that can prevent colonization or eradicate an existing infection.
Several MCCB labs focus on studying aspects of viral, bacterial and fungal pathogens. These studies have identified new therapeutic targets and small molecules that exploit these discoveries. Click on the links below to see more details concerning work in this area.
HIV-1, the causative agent of the AIDS pandemic, is a complex retrovirus that thwarts innate antiviral immune mechanisms through auxiliary viral proteins. The Gottlinger laboratory has recently identified novel antiviral human cell surface proteins that are counteracted by the auxiliary HIV-1 protein Nef. In the absence of Nef, these antiviral membrane proteins are taken up into nascent HIV-1 virus particles and dramatically reduce their ability to infect new target cells. These findings suggest potential new strategies to combat HIV-1 that are currently being explored by the Gottlinger laboratory.
- Usami Y and Göttlinger, H. HIV-1 Nef responsiveness is determined by Env variable regions involved in trimer association and correlates with neutralization sensitivity. Cell Reports 5, 802-812, 2013.
Numerous pathogens perturb mitochondrial activity as part of their specific virulence programs. The Haynes Lab has found that one mechanism by which metazoans differentiate commensal and toxic bacteria such as Pseudomonas aeruginosa is by monitoring mitochondrial activity. Because nearly all mitochondrial toxins are produced by microbes, this mechanism allows cells to simply monitor an intra-cellular activity rather than evolve strategies to detect millions microbes simultaneously. Researchers in the Haynes Lab use C. elegans and mammalian models to examine mitochondria-pathogen interactions.
- Pellegrino MW, Nargund AN, Kirienko NV, Gillis R, Fiorese CJ, Haynes CM. (2014) Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection. Nature. Dec 18;516(7531): 414-417.
- Pellegrino MW, Haynes CM. (2015) Mitophagy and the UPRmt in neurodegeneration and bacterial infection. BMC Biology. April 3;13(1): 22. doi: 10.1186/s12915-015-0129-1.
- Reddy KC, Dunbar TL, Nargund AN, Haynes CM, Troemel ER. (2016) The C. elegans CCAAT-enhancer binding protein gamma is required for surveillance immunity. Cell Reports. Feb 23:14(7): 1581-1589.
Candida albicans is the most widespread fungal pathogen in humans and one of the most frequent hospital-acquired infections leading to an annual cost exceeding $1 billion per year. While it is responsible for common clinical problems (e.g. oral thrush), it can also cause life-threatening systemic infections. Surface adhesion, morphological switching, and biofilm formation are interrelated factors that contribute directly to C. albicans virulence. Therefore, compounds that impair these processes would have promising properties as first step towards new antifungal therapeutics. In collaboration with investigators at Worcester Polytechnic Institute, the Kaufman laboratory has identified compounds that prevent adhesion of Candida albicans to polystyrene surfaces. They are currently exploring how these compounds can be incorporated into medical plastics and medical device coatings to alter biofilm formation in that context.
- Fazly et al. (2013) Chemical screening identifies filastatin, a small molecule inhibitor of Candida albicans adhesion, morphogenesis, and pathogenesis. PNAS 110(33):13594-9
The discovery of successful treatment regimens that target the human immunodeficiency virus (HIV) have greatly improved the long-term prognosis of infected individuals and drastically reduced disease spread. However, the nature of the HIV life cycle, which involves integration of the viral DNA into the host genome, means that future production of new virus from endogenous sources can occur. In collaboration with the Luban Lab, the Wolfe Lab is developing new genome editing tools to inactivate or remove the HIV genome from infected cells. For more information on their collaboration go to www.umassmed.edu/GGR-project/hiv-latency/.