NIH Scientists Show How Tularemia Bacteria Trick Cells to Cause Disease

May 30, 2018

Francisella tularensis is the bacterium that causes tularemia, a life-threatening disease spread to humans via contact with an infected animal or through mosquito, tick or deer fly bites. As few as 10 viable bacteria can cause the disease, which has a death rate of up to 60 percent. Scientists from the National Institute of Allergy and Infectious Diseases—part of the National Institutes of Health—have unraveled the process by which the bacteria cause disease. They found that F. tularensis tricks host cell mitochondria, which produce energy for the cell, in two different phases of infection. In the first eight hours of infection, the bacteria increase mitochondria function, which inhibits cell death and prevents the cell from mounting an inflammatory response to avoid an immune system attack. In the 24 hours after, the bacteria impair mitochondrial function, undergo explosive replication and spread. These basic science findings could play a role in developing effective treatment strategies, according to the researchers.

Previously, researchers discovered that F. tularensis could inhibit inflammation following infection of immune system cells called macrophages, but they did not understand how it occurred. The new study, published in Infection and Immunity, illuminates that process, confirming that the bacterium’s manipulation of the mitochondrial machinery in the host cell is required to block strong inflammatory responses. Also, the researchers show that the timing of the manipulation of the mitochondria machinery during infection is important to how the bacteria control host cell death. The researchers also said this could be the first study to show that a bacterium’s sugar-like protective outer capsule, or polysaccharide, can increase mitochondria function, in this case, during early infection.

The researchers believe that better antimicrobial treatment strategies—against F. tularensis and possibly other pathogens—could result from further study of the role the capsule polysaccharide plays in manipulating mitochondria. For example, learning how to block the increased mitochondrial function in phase one could limit infection, they say. In their study, they also treated F. tularensis-infected macrophages in the laboratory with two types of drugs that protect mitochondria. The treatment reduced cell death and limited bacterial replication. The group plans to extend that work to mice.

ARTICLE:
F Jessop et al. Temporal manipulation of mitochondrial function by virulent Francisella tularensis to limit inflammation and control cell death. Infection and Immunity DOI: 10.1128/IAI.00044-18 (2018).

WHO:
Catharine Bosio, Ph.D., chief of NIAID’s Immunity to Pulmonary Pathogens Section, is available to comment on this study.

This 25-second video shows macrophages derived from mice and infected with the bacterium Francisella tularensis. The white arrow indicates an infected cell that undergoes a sudden flash, indicating compromised host organelles, subsequent hyper-replication of the bacteria, and eventually cell death. The brown arrow indicates an uninfected “bystander” cell that also is being killed by a similar mechanism. Images were taken every 20 minutes over 30 hours.