Valerie Pavilonis

Researchers at the School of Medicine have discovered new proteins that help the Salmonella bacteria find new ways to replicate and thwart the human body’s immune responses.

Salmonella, which affects about 1.2 million people annually, has evolved for millions of years, in coordination with their vertebrate hosts. The Yale study, published in the journal Nature Microbiology on Sept. 17, has shed light on this coevolution process. The team’s findings highlight the unique balance between the host and pathogen, in which the pathogen-initiated response keeps the pathogen alive but also prevents it from expanding to deeper tissues.

“For us, the question has always been how does Salmonella pull this off?” said Jorge Galan, the chair of microbial pathogenesis at the School of Medicine and senior author of the paper.

Salmonella requires intestinal inflammation to secure necessary nutrients. The microbial infection, however, is often countered by the inflammatory responses of immune receptors that ultimately remove the pathogen.

Salmonella has coevolved with vertebrate hosts for millions of years, Galan said, allowing the pathogen to evade their hosts’ immune defense system.

“It has evolved absolutely amazing mechanisms to manipulate host cell functions, including a remarkable nanomachine known as ‘the type III protein secretion system,’ which literally works as a nanosyringe that injects bacterial proteins into host cells.”

The study found that Salmonella stimulates proinflammatory signaling, which provides necessary nutrients to the pathogen, through a unique mechanism started by specific proteins, called “effectors,” and delivered by its protein secretion system.

The effectors initiate two other proteins — Cdc42 and p21-activated kinase 1 — which leads to the desired inflammation.

In other words, Salmonella stimulates the inflammatory signalling in the intestinal tract necessary for the pathogen to survive by activating proteins downstream of the innate immune receptors.

The mechanism enables Salmonella to initiate intestinal inflammation without triggering innate immune receptors, thus avoiding the receptors’ negative regulatory mechanisms.

The research holds several medically important implications, according to Galan. By understanding how inflammatory signaling is initiated, researchers can develop therapeutic treatments that target these specific host-signalling pathways.

“We have showed that a small molecule inhibitor — in essence, a drug — of p21-activated kinases can effectively prevent Salmonella replication in the gut,” he said. “This is exciting as it would allow the targeting of Salmonella infections not by directly targeting the pathogen itself, like conventional antibiotics do, but rather by targeting host functions that are essential for infection.”

Daniel E. Salmon was credited with discovering the first strain of Salmonella in 1885.

Michelle Fang | michelle.fang@yale.edu