The overall goal of the Singer laboratory is to understand mucosal immunity and apply that understanding to improve human and animal health. The main system we use for experimental studies is infections in mice with the protozoan parasite Giardia duodenalis. This species replicates in the small intestines of humans and many other species of mammals and is capable of causing severe diarrhea, cramps, nausea and fever. Giardia infects hundreds of millions of humans around the world and prevalence is highest in areas where proper sanitation is lacking. 

We have four main research topics focused on Giardia infections: the role of the innate immune response in recognition of the infection; the role of immune responses in contributing to pathogenesis of disease; the importance of interactions among the parasite, commensal bacteria and host in determining the outcomes of infection; and the development of a protective vaccine for human giardiasis. We are also pursuing the use of intestinal stem cells to develop in vitro models of infection and eventual use in regenerative medicine in the intestinal tract. 

Innate Immunity in Giardia Infections

A key tenet in immunology is that the innate immune response directs the development of adaptive responses.  The Singer laboratory is interested in how the innate immune system detects and responds to Giardia infection.  Our publications on regulation of dendritic cell responses by Giardia antigens were the first published studies on dendritic cells in giardiasis.  We are continuing to investigate mechanisms whereby the innate immune system senses the presence of the parasite and how these recognition events shape the outcome of infections.  The goal of these studies is to develop better adjuvants for stimulating immune responses, particularly in the intestinal tract as well as developing vaccines to prevent giardiasis in humans and animals.

Pathogenesis in Giardia

The outcome of Giardia infections in humans ranges from sub-clinical infections with nutrient malabsorption but no obvious clinical signs, to severe cramps, nausea, fevers, diarrhea and malnutrition with physical and cognitive developmental defects.  The variation observed is likely due to differences among the parasite strains able to infect humans as well as differences among the individuals being infected.  We have used inbred mouse models and clonal strains of Giardia in order to tease apart some of the mechanisms that contribute to pathology.  These studies implicate both parasite strain and host immunity in determining outcomes like sucrase deficiency and intestinal hypermotility which correlate to nutrient malabsorption and intestinal cramps in humans. Understanding these mechanisms may help develop therapeutics for intestinal syndromes such as celiac disease which are also characterized by nutrient malabsorption and food allergies which involve mast cell recruitment and activation against antigens in the intestinal lumen.

Giardia-Host-Microbiota Interactions

The role of commensal bacteria in shaping the development of the immune system has long been appreciated.  In 2000 we first published studies showing that commensal bacteria could prevent colonization of mice with Giardia and that antibiotic treatment could make mice more susceptible to infections.  In collaboration with Scott Dawson at the University of California, Davis we recently published studies investigating the specific effects that Giardia has on commensal bacteria, that commensal bacteria have on Giardia and how host immune responses mediate many of these effects.

Vaccine Development

There is still no vaccine approved for human use to protect against any parasitic infection, protozoan or helminth.  Much of the work in the laboratory over the years has examined mechanisms which contribute to elimination of parasites from the small intestine during primary infections. Antibodies, mast cells, anti-microbial peptides and nitric oxide production all have a potential role to play, but the parasite has evolved mechanisms to subvert and avoid these protective responses. We are now investigating the importance of these mechanisms during secondary infections in order to determine which are the best candidates for achieving a long-term protective immune response through vaccination.  

Giardia Co-infections

The majority of cases of giardiasis occur in the developing world and most of the individuals with Giardia are also concurrently infected with multiple other enteric pathogens. Indeed, some data from human studies suggests Giardia infection may actually protect against severe forms of diarrhea in children. We recently published work with Luther Bartelt on the results of co-infections of Giardia and enteroaggregative E. coli. We continue to be interested in mechanisms whereby Giardia infection can impact the outcome of infections with other pathogens and are using murine co-infection models to address this important question.