{"id":136,"date":"2010-04-21T11:41:17","date_gmt":"2010-04-21T16:41:17","guid":{"rendered":"http:\/\/new.sites.umaine.edu\/newbiomed\/?page_id=136"},"modified":"2022-03-11T09:04:00","modified_gmt":"2022-03-11T14:04:00","slug":"robert-wheeler","status":"publish","type":"page","link":"https:\/\/umaine.edu\/biomed\/home\/faculty\/robert-wheeler\/","title":{"rendered":"Robert Wheeler, Ph.D."},"content":{"rendered":"

\"Rob_Portrait_Dec2012\"<\/p>\n

Hitchner Hall Room 209
\nTwitter: Wheeler Lab@UMOWheelerLab
\nPhone: 207.581.2890<\/a>
\nEmail\/web: Send an Email<\/a>
\nNote that this page is not frequently updated.
\nPlease check out the Lab Webpage: http:\/\/umaine.edu\/wheelerlab\/<\/a><\/p>\n

Education<\/strong><\/p>\n

AB (1993) Harvard College
\nPhD (2000) Stanford University
\nPost-doctoral: Whitehead Institute<\/p>\n

Fungal host-pathogen interaction<\/h2>\n

There is an ongoing war between microbial pathogens and their hosts.For each mode of host immunity, the challenger has designed a defense, which in turn leads the host to devise a new avenue of attack.\u00a0Opportunistic pathogens such as the fungus\u00a0Candida<\/em>, a leading cause of hospital-acquired infection and an increasingly important killer, must be able to constantly evade the attacks of the host and exploit any break in host defense caused by a compromise of immunity.\u00a0The host, in turn, depends to a large part on innate immune responses to protect itself against this fungus.\u00a0Using high throughput cell biology and genetics, we are elucidating this ongoing battle between fungi and host from both sides of the conflict.<\/p>\n

Our work attacks fundamental biological questions that have clinical relevance.\u00a0In the near term, we expect to understand the normal host-pathogen interaction in disease and during drug treatment.\u00a0In the long term, we expect to identify new means to prevent and treat fungal infection through attacking the fungus and modulating immune response.<\/p>\n

Microbial strategies for resisting immune attack<\/strong><\/p>\n

Candida<\/em> is recognized by the innate arm of the immune system through evolutionarily conserved fungal surface molecules.\u00a0Although innate immune cells can recognize several different surface molecules, the fungus can cover some molecules to tailor the immune response.<\/p>\n

The sugar \u03b2-glucan is present throughout the cell wall of\u00a0Candida<\/em>, but as we discovered, the pathogen masks \u03b2-glucan from immune recognition to mute immune response.\u00a0We discovered that a potent antifungal drug has an unexpected side-effect and can cause increased exposure of\u00a0 \u03b2-glucan in addition to killing fungi.We are devising and exploiting novel methodology to look at the clinical consequences of treating fungal infection with this antifungal drug.<\/p>\n

\"\"<\/a>Host strategies for clearing fungal pathogens<\/strong><\/p>\n

We have recently begun using a transparent zebrafish model to probe host-pathogen interactions (Brothers et al. 2011, Tobin et al. 2012, Gratacap et al. 2013, Brothers et al. 2013). This model permits the real-time visualization of innate immune attack. Using this model, we have found that Candida<\/em>-innate immune interactions differ in vivo from our expectations based on in vitro experiments. We are currently using this model to probe the cellular effects of loss of phagocyte NADPH oxidase function. In the future, this model holds promise for understanding the molecular mechanisms that regulate Candida<\/em> interaction with innate immune cells, endothelial cells and epithelial cells.<\/p>\n

Host strategies for clearing fungal pathogens<\/strong><\/p>\n

We have recently begun using a transparent zebrafish model to probe host-pathogen interactions (see Publications Webpage). This model permits the real-time visualization of innate immune attack. Using this model, we have found that\u00a0Candida<\/em>-innate immune interactions differ in vivo from our expectations based on in vitro experiments. We are currently using this model to probe the cellular effects of loss of phagocyte NADPH oxidase function. In the future, this model holds promise for understanding the molecular mechanisms that regulate\u00a0Candida<\/em>\u00a0interaction with innate immune cells, endothelial cells and epithelial cells.<\/p>\n

Host and pathogen determinants of infection spread and dissemination<\/strong><\/p>\n

Work from two recent PhD graduates shed light on both how the growth shape of\u00a0Candida<\/em>\u00a0and host cells and processes combine to allow the non-motile fungus to move from tissue to tissue and spread the infection. Using transparent zebrafish, Brittany Seman discovered that only the yeast form of\u00a0Candida<\/em>\u00a0can disseminate; the filamentous form instead damages tissue and causes death. Allison Scherer found that\u00a0Candida<\/em>\u00a0can either use host macrophages as Trojan Horses to get to new areas of the host. \u00a0In the absence of macrophages and neutrophils to attack it and move it around,\u00a0Candida<\/em>\u00a0can also get through into the bloodstream and spread through the circulation. These complementary mechanisms of dissemination make\u00a0Candida<\/em>\u00a0a successful pathogen in different host conditions.<\/p>\n

Polymicrobial infections and their effect on antimicrobial drug action<\/strong><\/p>\n

Our recent published work has shown two surprising aspects of\u00a0Candida<\/em>\u00a0interaction with the bacterial pathogen\u00a0Pseudomonas aeruginosa<\/em>. Surprisingly, we found that the microbes have enhanced virulence during co-infection of the zebrafish. This suggests that they can promote each other\u2019s growth and virulence in the face of immune attack. But this enhanced virulence comes at a cost for the fungus,\u00a0Candida<\/em>, because it then becomes exquisitely sensitive to the antifungal drug fluconazole. In the presence of\u00a0P. aeruginosa<\/em>, fluconazole changes from a fungistatic to a fungicidal drug and kills the\u00a0Candida<\/em>\u00a0instead of just slowing its growth. In the future, we plan to discover how\u00a0P. aeruginosa<\/em>\u00a0causes this enhanced effect against\u00a0Candida<\/em>\u00a0and which pathways it affects in the fungus.<\/p>\n

 <\/p>\n

Publications (current as of March 2022)<\/p>\n

For most up-to-date information please check out our Google Scholar page:<\/p>\n

https:\/\/scholar.google.com\/citations?user=WfzFI3oAAAAJ&hl=en<\/a><\/p>\n