Purpose of the Center
Taken together, infectious diseases are the most powerful selective pressure with which our species must contend. This remains the case despite enormous progress in combating infection in many parts of the world by means of public health measures, immunization, and antibiotics. We imagine that infection was the dominant selective pressure operating on Homo sapiens for millions of years.
How do we know this? Global actuarial statistics indicate that about 26 percent of all human beings die of infections (Figure 1). A much higher rate of attrition applies in the developing world, and in the relatively recent past, all parts of the globe were “undeveloped.”
More important still is the fact that infections tend to claim victims during their early years, before or during reproductive age (Figure 2). Before the age of 44, more people die from infection than from all other causes combined. While cardiovascular disease kills more people worldwide than infection does, it is not equivalent as a selective pressure.
Because infection has been such a strong selective pressure, we know of many polymorphisms that protect us against infectious disease. Each was driven to high frequency in specific populations for this very reason. In the distant past, some mutations offering protection against disease were probably driven to fixation in Homo sapiens, and are no longer detectable as such. They may carry certain costs that are also invisible, having become part of the status quo. It may be assumed that infection has shaped the genome of most metazoans in a dramatic way.
Infection was the driving force for the development of both innate and adaptive immune systems, which draw upon thousands of genes. If not for the existence of these immune systems, we would have no autoimmune or autoinflammatory diseases, which themselves represent a major cause of morbidity and mortality in our species. Even diseases like atherosclerosis, cancer, and various forms of neurodegenerative disease have inflammatory components, and must in part be attributed to the same immune systems that keep us safe from microbes.
During the past 10 years, our understanding of host resistance has expanded on many fronts, but we see there is much that is still unknown. Immune responses occur more or less automatically when infections develop. A mechanistic viewpoint would hold that they are governed by basic principles of biochemistry and cell biology, some of them known and some yet to be learned.
Genetics has led the way to discovering the receptors that sense infection (Figure 3), the adaptor proteins and enzymes that transduce signals in immune cells, and the transcription factors that activate genes encoding cytokines, which mediate and generalize the innate immune response. Genetics has also led to the dissection of signaling in the adaptive immune system. And it has pointed to interactions between the two systems.
Some key discoveries about immunity came from studying human diseases, but some came from model organisms, including mice, fruit flies, plants, fish, and worms (Figure 4). In each instance, there was an attempt to relate discoveries made in one species to those made in another; to ask, “what is the equivalent response in my model organism?” Sometimes equivalent responses were found; sometimes not. But even when they were not, there was enhanced understanding of how an immune system might function, and how certain species fill gaps left by the lack a certain form of immunity.
The Center for the Genetics of Host Defense takes a broad view of immunity. Any process contributing to resistance to an infectious disease in any species is of interest to us. The Center supports the use of forward genetic techniques to find any and all genes that contribute to host resistance, and understand how their protein products cooperate to yield resistance.