“Our results demonstrate a previously unknown role of the pathway that recognizes these pathogens and stimulates the immune response,” said Masayuki Fukata, Ph.D., assistant professor of medicine in the Division of Gastroenterology, and the study’s senior author. “Our results provide an important way to activate the body’s innate immune response without causing systemic toxicity. We envision that targeting this pathway can be a new approach to treating patients within a window of infection.”
The study, “Host innate recognition of an intestinal bacterial pathogen induces TRIF-dependent protective immunity,” was published in a recent issue of the Journal of Experimental Medicine. The study used a well-established experimental model of oral Yersinia enterocolitica infection, which recapitulates many features of the human disease.
“The development of effective strategies to protect against multiple types of pathogens is challenging because innate immune responses are antigen nonspecific,” Fukata said. “We examined how the innate immune response in the intestine naturally protects against pathogens and whether strategies could be developed to enhance innate immunity against enteric pathogens.”
Fukata and his team focused on the process by which toll-like receptors (TLRs) in intestinal cells recognize the molecular patterns on the invading microorganisms, and how TLR4 activates two key signaling pathways – TRIF (toll/interleukin 1 receptor domain-containing adapter inducing IFN-) and MyD88 (myeloid differentiation factor 88) – that stimulate the release of inflammatory substances from the immune cells.
While TRIF has been known to be important in antiviral signaling related to TLR3, the Miller School study was the first to examine the role of TLR4-mediated TRIF signaling in protecting the host intestine against Gram-negative bacteria – which do not have detectable peptidoglycan components when stained with crystal violet dye (Gram-staining) in the GI tract.
“We found that the TRIF pathway applies to more than one Gram-negative pathogen,” said Fukata. “That’s particularly exciting because our team was able to manipulate the pathway to generate a more effective immune response.”
If these laboratory results can be replicated in clinical trials, physicians may gain a new weapon against dangerous GI bacterial infections, Fukata said. “Antibiotic treatment for an existing infection may trigger the multi-drug resistance of the bacteria. Instead, we can rapidly boost the TRIF pathway to allow the immune system to repel broad-spectrum bacterial invaders before they gain a foothold in the body.”
That could be an increasingly important approach, since most clinically significant enteric pathogens, such as Yersinia, Salmonella, Vibrio, or Shigella, are Gram-negative bacteria that have evolutionarily acquired an ability to evade host immune defenses. Although extensive studies have revealed the virulence factors of these pathogens, more studies need to be done to determine how the body’s immune cells formulate effective intestinal defenses to these pathogens, Fukata said.
“Serious public health problems can occur when sanitary systems are destroyed or disrupted,” he said. For example, Haiti faced a dangerous cholera epidemic after the devastating 2010 earthquake, and salmonella and E.coli outbreaks occur throughout the United States. “In situations where you can’t treat patients in a ‘normal’ way, providing them with TRIF-mediated protective immunity could be beneficial.”
These types of enteric pathogens raise additional health concerns because recent globalization of the food supply increases the chance of outbreaks and the potential for bioterrorism, Fukata added.
Summing up the findings, Fukata said the study demonstrates an unexpected role for the TRIF pathway in enteric infection by Gram-negative bacterial pathogens. “Our results highlight an immunological model in which TLR4-mediated TRIF activation promotes bactericidal activity,” he said.
Other Miller School co-authors included lead author and former research assistant John Sotolongo; Cecilia España, lab technician; Andrea Echeverry, Ph.D., post-doctoral associate in the Department of Microbiology and Immunology; David Siefker, Ph.D., student in the Department of Microbiology and Immunology; Norman Altman, V.M.D., professor and director of the Division of Comparative Pathology; Julia Zaias, D.V.M., Ph.D., director of the Division of Veterinary Resources; Rebeca Santaolalla, Ph.D., post-doctoral associate in the Division of Gastroenterology; Jose Ruiz, lab technician; Kurt Schesser, Ph.D., associate professor of microbiology and immunology; and Becky Adkins, Ph.D., professor of microbiology and immunology.