Immunology taught by bacteria

We use the bacterium Legionella pneumophila (pictured) as a model organism for understanding the fundamental processes underlying infectious disease.

We are interested in the following questions:

• How is the presence of disease-causing (pathogenic) bacteria sensed by hosts? 

• Are pathogenic bacteria distinguished by the immune system from harmless bacteria, and if so, how? 

• What innate immune mechanisms protect cells from pathogens? 

• How do cells coordinate defenses that are appropriate for various categories of pathogens? 

• What mechanisms have pathogens evolved to evade host defenses?

Electron micrograph taken by Maria Ericsson (Harvard Medical School Electron Microscopy Facility). The bacterium shown is approximately 1 micron in length. The original electron micrograph was enhanced and colorized in Photoshop. The flagellum is the whip-like tail at one of the bacterium.

Legionella pneumophila: innate immunity and pathogenesis

L. pneumophila causes a severe pneumonia of humans called Legionnaires' Disease. We use L. pneumophila as a model organism to understand the processes underlying host defense against pathogens.

The tail of the bacterium, as seen in the picture above, is called its flagellum.  Many bacteria, including L. pneumophila, use flagella to move around in their environment.

Most healthy people are protected from L. pneumophila by their immune systems.  An important cell in the immune system that defends against bacteria is the macrophage. Macrophages are located throughout the body and have the ability to "eat" and kill bacteria.

Interestingly, L. pneumophila has the ability to evade the defenses of macrophages, and can actually grow to large numbers inside of macrophages.  In nature, L. pneumophila normally grows inside a variety of single-celled amoebae.  It appears that L. pneumophila's ability to grow in amoebe has, by chance, equipped it to grow in human macrophages as well.  For this reason, L. pneumophila has been called an "accidental pathogen".

One of our recent findings has been the discovery that macrophages appear to be able to sense the intracellular presence of L. pneumophila.  We showed that macrophages sense L. pneumophila by detecting the presence of a protein called flagellin, the main protein that makes up the flagellum (see image above).  The molecular mechanism by how this sensing of flagellin occurs is under investigation. We have also recently shown that macrophages have several other ways of detecting L. pneumophila, and we are interested in characterizing these pathways as well.

Macrophages that detect L. pneumophila respond by initiating a rapid cellular suicide.  By committing suicide, the macrophage prevents L. pneumophila from using itself as a home in which to replicate. It appears likely that the bacteria that are released from rapidly dying macrophages are then killed by other cells in the immune system called neutrophils.

Other areas of research

Inflammasomes. A major area of research in the lab is inflammasome biology. Inflammasomes are a family of recently described multiprotein complexes that assemble in the cytosol of mammalian cells in response to infectious or noxious stimuli. L. pneumophila flagellin activates a particular inflammasome called the Nlrc4 inflammasome. Once activated, inflammasomes recruit and activate a protease called Caspase-1. Caspase-1 is in turn required for processing certain cytokines (interleukins-1 and -18) and for induction of a specialized form of rapid cell death. In fact, it is the inflammasome pathway that is responsible for the rapid cellular suicide triggered by L. pneumophila. We are interested in the molecular mechanisms of how inflammasomes assemble and also in the question of how inflammasome activation initiates host defense.

Interferon response to bacteria. Most bacterial pathogens induce a host transcriptional response that is characterized by induction of genes encoding type I interferons. Type I interferons are cytokines that are very important in defense against viruses, but their role in bacterial infections is in general poorly understood. We are interested in the mechanisms by which bacteria induce type I interferons. L. pneumophila induces type I interferons by a mechanism that appears to involve translocation of bacterial nucleic acids, possibly RNA, into the host cell cytosol. We also found that another bacterial-specific nucleic acid, called cyclic-di-GMP, is able to induce a host interferon response. We are interested in determining the mechanism by which host cells sense cyclic-di-GMP.

Immune recognition of commensal bacteria. The mammalian intestinal tract contains trillions of bacteria which not only co-exist with us, but which also appear to be important for normal development of the immune system. In certain cases, the immune system can make inappropriate responses to these commensal bacteria, resulting in autoimmune diseases. But most of the time, the immune system somehow manages to co-exist peacefully with these bacteria. We are interested in understanding the molecular mechanisms that affect the homeostatic relationship between the immune system and commensal bacteria.

Forward Genetic Screens. We are interested in identifying novel bacterial and host genes that affect infection and immunity. To do so we have initiated several forward genetic screens, both in bacteria and in mice.

More information about our research can be found at the official UC Berkeley research page

Research Environment

The Vance Lab is located within a rich collaborative environment at the University of California, Berkeley. We benefit by being located on a floor with eight other immunology labs. We share ideas, techniques and, of course, equipment. There is a weekly Immunology floor meeting at which trainees have the opportunity to present their research in progress. We also benefit from being associated with the Cancer Research Labs, which runs a conveniently located flow cytometry facility. The Immunology Division is one of five divisions that comprise the large Molecular and Cell Biology Department. The Department houses researchers interested in the basic mechanisms underlying diverse areas of modern biology. One of the most unique and valuable aspects of the Immunology Division at UC Berkeley is that it is not isolated: we are enriched by our interactions with cutting-edge cell biologists, biochemists, and geneticists. New advances in these areas inevitably feed into cutting edge immunological research.

Our next door neighbor is the Barton Lab, which adjoins our lab in continuous lab space. The Barton Lab is also interested in innate immunity and thus we share many common interests. We hold a joint weekly lab meeting with the Barton Lab. Every spring we have a joint lab picnic and Bocce Tournament.

Our lab also works closely with the Portnoy Lab, with whom we hold joint monthly lab meetings. Dan Portnoy also coordinates a San Francisco Bay Area Program Project Grant that brings together a very collaborative group of labs working on intracellular bacterial pathogens.