Mycobacteria, Advanced Microscopy, & Cell Metabolism - The Rego Lab at Yale School of Medicine

Transcript

• 00:05Mycobacteria
• 00:06are a group of bacteria
• 00:07and there's lots of different
• 00:09types.
• 00:10Many of them are found
• 00:11in soil and water and
• 00:12are essentially harmless
• 00:14to most people. But there
• 00:16are a few mycobacteria
• 00:17that actually cause very devastating
• 00:19human diseases and one of
• 00:20the most famous is mycobacterium
• 00:22tuberculosis
• 00:23which causes tuberculosis.
• 00:25There's another mycobacteria called mycobacterium
• 00:27leprae that cause the disease
• 00:28leprosy.
• 00:35There are several unique features.
• 00:37First is that different from
• 00:38other bacteria it has a
• 00:40very unusual cell wall or
• 00:42cell envelope architecture.
• 00:44And the cell envelope is
• 00:46basically the thing that coats
• 00:47the bacterium and protects it
• 00:49and interfaces
• 00:50with the environment.
• 00:52Mycobacteria
• 00:52have a very unusual
• 00:54structure to its cell envelope.
• 00:56It's very thick, it's very
• 00:57waxy, and we think that
• 00:59that prevents a lot of
• 01:00antibiotics from actually getting into
• 01:01the bacterium
• 01:03to reach their target and
• 01:04to kill the bacterium. And
• 01:05then the second feature that
• 01:06we think is really unusual
• 01:08to mycobacteria
• 01:08is that even
• 01:10in a genetically identical population,
• 01:13mycobacteria seem very good at
• 01:14generating a lot of diversity
• 01:17in different physiological
• 01:18properties.
• 01:20We think that differences in
• 01:21in these mycobacterial
• 01:23populations at the single cell
• 01:24level can be really important
• 01:26for the bacteria
• 01:28to tolerate antibiotics, meaning that
• 01:30there are some bacteria
• 01:32that can survive antibiotic pressure
• 01:35simply because they phenotypically
• 01:36look a little different than
• 01:38others.
• 01:39How are individual mycobacteria
• 01:41different? How do they differ
• 01:43in the responses to antibiotics?
• 01:44What are the underlying causes
• 01:46of those differences?
• 01:47We think a lot of
• 01:48it traces down to metabolism
• 01:50and so my lab is
• 01:50really trying to understand the
• 01:52metabolism
• 01:53of individual mycobacteria.
• 02:00We use microscopes to answer
• 02:02those questions.
• 02:04That can range from simple
• 02:05time lapse videos where we
• 02:07look at individual cells over
• 02:09time. And because some of
• 02:11them can grow and divide
• 02:12really slowly, we have to
• 02:13run our microscopes for up
• 02:14to five days in order
• 02:15to,
• 02:16capture the cell growth and
• 02:17and division of these of
• 02:19these organisms. But we also
• 02:20use, super resolution microscopy to
• 02:22understand the spatial organization
• 02:25of proteins within the cell.
• 02:27We also started using these
• 02:29fluorescent reporters or sensors
• 02:31for different metabolic properties of
• 02:33the cell.
• 02:35For example, we have used
• 02:36a fluorescent reporter for, ATP,
• 02:38which is the energy currency
• 02:40of the cell. And so
• 02:41now we can measure ATP
• 02:42levels
• 02:43in individual cells, and understand
• 02:46how differences in in,
• 02:48say, ATP or other metabolites
• 02:50are generated in a clonal
• 02:52population and what are the
• 02:53consequences for having different levels
• 02:55of of these metabolites.
• 03:03Our goals are treating some
• 03:05of these mycobacterial
• 03:06infections.
• 03:07Tuberculosis
• 03:08kills more people each year
• 03:09than any other single infectious
• 03:11disease, and in history has
• 03:12actually killed more people than
• 03:14any single infectious disease. So
• 03:16it's an incredible global health
• 03:18problem.
• 03:19If someone gets TB,
• 03:21they have to go on
• 03:22a course of antibiotic therapy
• 03:24that can last anywhere from
• 03:25four to six months with
• 03:26a combination
• 03:27of four antibiotics,
• 03:29which as you can imagine
• 03:30is a very long time
• 03:31to be on antibiotic therapy.
• 03:34We think that if there
• 03:35are all these differences
• 03:37in metabolism
• 03:38and physiology
• 03:40of that bacterial population,
• 03:42then we think that if
• 03:43we can transition
• 03:45cells or force cells into
• 03:47a more antibiotic favorable state
• 03:49that we might be able
• 03:50to treat an infection more
• 03:51rapidly.