Like bacterial zombies, microbes that cause an infection remain biochemically active after they die, continuing to trigger a host’s immune system while also making the immune response less effective.

In a new interdisciplinary study, Cornell researchers describe the results of a mathematical model developed to explore the generally overlooked role that dead pathogens play in the outcome of a potentially lethal infection. The study found that the difference between life and death for a host may be determined by already dead bacteria still circulating within it, since the host’s immune system continues to act upon those corpses much as if they were still alive.

The mathematical model developed in this study, published online in March in the American Naturalist, explains how these dead (but not gone) microbes can have a significant impact even beyond the outcome of ongoing infection. The model shows how their presence might also affect the evolutionary fine-tuning of host immune responses.

“We usually think that once something is dead, it no longer influences the immune process,” said Alex Vladimirsky, professor of mathematics in the College of Arts and Sciences and a co-author of the study. “It turns out, it can affect it in very significant ways.  This is true for each individual trying to handle an infection, and also for the species over evolutionary time scales, gradually changing how and why we respond to infections the way we do,” he said. 

“The study showed that the shielding by the dead could have enormous effects on the short time scale of an infection,” said Stephen Ellner, Ph.D. ’82, Horace White Professor of Ecology and Evolutionary Biology Emeritus affiliated with the College of Arts and Sciences, who is also a study co-author.

When a bacterial infection occurs, the host’s immune system senses the microbes and produces proteins that bind to bacterial cell membranes, collect there, and eventually create pores in the membrane that kill the microbe. While these immune system proteins, called antimicrobial peptides (AMPs), are a powerful weapon for defeating a pathogen, they can also damage the host, especially after an infection has already been controlled. Likewise, the presence of dead bacteria is also a double-edged sword. While the infection is ongoing, these corpses “sponge away” some of the host’s weapons: AMPs binding to them are sequestered and can no longer harm the living bacteria. To counter this, the host is forced to manufacture more AMPs, increasing the risk of autoimmune damage from AMPs to the host’s own body. On the other hand, once the infection is already defeated, the same dead bacteria could help reduce autotoxicity by mopping up lingering AMPs.

“On an evolutionary timescale, it could help the host get away with mounting an extremely intense immune response, since the dead bacteria would be around to absorb all of the immune effectors [AMPs] that otherwise are somewhat autotoxic to the host after the infection has been controlled,” Ellner said. 

The host that can deal with an infection better might have higher fitness and procreate more, and that creates a mechanism that allows evolution over multiple generations to fine-tune an immune response, Vladimirsky said. 

“Once it is fine-tuned, it turns out that this property allows the host to be more efficient, to defeat an infection while suffering less damage from bacteria and less damage from autotoxicity,” he said.

The study builds on prior modeling work and biological experiments conducted by the team, which also includes co-authors Nicolas Buchon, associate professor in the Department of Entomology in the College of Agriculture and Life Sciences (CALS); Tobias Dörr, associate professor in the Weill Institute of Cell and Molecular Biology and the Department of Microbiology in CALS;  Misha Kazi, a Fleming Postdoctoral Research Fellow in Dörr’s lab; and Brian Lazzaro, Liberty Hyde Bailey Professor of Entomology and of Ecology and Evolutionary Biology in CALS.