invading cultured human cells
Image courtesy of Rocky
Mountain Laboratories/NIAID
Preclinical research has shown how Salmonella infections that spread to the blood and organs can lead to life-threatening thrombosis.
Experiments in mice demonstrated that systemic infections prompt inflammation, which leads to thrombosis.
However, the sustained threat from thrombosis is independent of the continued presence of infection and instead parallels the regulation of inflammation within the host.
These findings, published in The Journal of Clinical Investigation, shed light on a poorly understood area of clinical medicine.
While some of the mechanisms that underpin the process of infection-driven thrombosis are known, particularly for Gram-positive organisms such as Staphylococci or Streptococci, they are not universally applicable.
Moreover, during sepsis, the causative pathogen is often never isolated or identified. The new study helps to explain why this is the case.
“For all of the advances we’ve made in this field, it is not always clear why people die from infection,” said study author Adam Cunningham, PhD, of the University of Birmingham in the UK.
“We think complications of thrombosis may be one reason. In Salmonella infections, severity is typically associated with the presence of bacteria in the blood, called bacteremia, even though the actual numbers of bacteria in the blood are very low. This suggested to us that the host response was crucial in determining the outcome.”
Dr Cunningham and his colleagues found that thrombi developed within the liver of murine models infected with Salmonella Typhimurium, and these thrombi persisted for many weeks.
The infection caused inflammation in the liver tissue, which then triggered thrombosis within vessels. This occurred via the ligation of C-type lectin-like receptor-2 (CLEC-2) on platelets by podoplanin, a molecule that is ordinarily absent in blood vessels but is expressed by macrophages responding to the infection.
The regulation and amplification of thrombosis was triggered by TLR4, a protein essential for the activation of the inflammatory cascade and the control of infection during its early stages.
Thrombosis remained at peak levels even when bacteria were absent from the blood and largely cleared from the infected organs.
“A little, controlled thrombosis is probably a good thing, as it helps to clear bacteria from the blood,” said study author Steve Watson, PhD, of the University of Birmingham.
“Therefore, any intervention would need to control, rather than deny, the host response. The problem only comes when it develops into a clot. Most of the current approaches to counter the development of these life-threatening thrombi do not account for the non-classical mechanism that we have shown to be at work.”
The researchers are now working to further understand how to manipulate and control this response, and how it can contribute to the complications of other infections and diseases.
