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Microbial Evolution and Co-Adaptation

June 8th, 2009

microbial A Tribute to the Life and Scientific Legacies of Joshua Lederberg

Institute of Medicine’s Forum on Microbial Threats convened a public workshop on May 20-21, 2008, to examine Dr. Lederberg’s - scientist, Nobel laureate who died on February 2, 2008 - scientific and policy contributions to the marketplace of ideas in the life sciences, medicine, and public policy. The resulting workshop summary, Microbial Evolution and Co-Adaptation, demonstrates the extent to which conceptual and technological developments have, within a few short years, advanced our collective understanding of the microbiome, microbial genetics, microbial communities, and microbe-host-environment interactions.

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Pathogen Evolution

As Lederberg (2000) observed, the host-microbe relationship is a dynamic equilibrium. Physiological or genetic changes in either partner may prompt commensal microbes to invade the tissue of their host, thereby triggering an immune response that destroys the invaders, but may also injure or kill the host. As they explored this process from the perspectives of pathogen and host, the workshop speakers featured in this chapter proposed a variety of possible evolutionary routes to the host-microbe relationships that underlie infectious diseases.

The chapter’s first paper, by Stanley Falkow of Stanford University, considers the nature of bacterial pathogenicity as it has been viewed historically, and as revealed by his research and that of his colleagues at Stanford University. He explains how key discoveries—beginning with Lederberg’s fundamental work on bacterial genetics—shaped the developing field of molecular biology, and more specifically, Falkow’s nearly 50 years of research on the genetic basis of bacterial pathogenicity.

Using the tools of molecular genetics to study Salmonella, Falkow and coworkers have observed how bacteria manipulate host cell functions, how horizontal gene transfer shapes pathogen specialization, and how inherited pathogenicity islands transform commensal bacteria into pathogens. Having screened the entire Salmonella genome for genes that are associated with different stages of infection with a microarray-based negative selection strategy, they have identified many pathogen genes expressed in the multistage process of host invasion. Using a mouse model, they have also identified host genes and gene pathways expressed in response to Salmonella infection.

Falkow also considers the importance of the microbes he refers to as “commensal pathogens”: bacterial species (e.g., Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae type b, Streptococcus pyogenes) that typically inhabit the human nasopharynx without symptom, but sometimes cause disease. Their existence raises a host of scientific questions regarding the relationship between microbial pathogenicity, infectious disease, and immune function—questions that, he argues, should be approached by studying microbial pathogenicity as a biological phenomenon, and not merely from the perspective of its role in causing disease.

Just as there is more to microbial pathogenicity than disease, there is more to infectious disease than the actions of pathogens on host cells and systems. The chapter’s second paper, coauthored by Elisa Margolis and workshop speaker Bruce Levin of Emory University, considers the host response to microbial virulence, which, the authors note, does not correspond to simple evolutionary models. They examine why bacteria harm the (mostly human) hosts they need for their survival, offering evidence that “much of the virulence of bacterial infections can be blamed on the seemingly misguided overresponse of the immune defenses.”

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