Interview with Resia Pretorius: how bacteria, viruses and their inflammatory products can impact blood clotting in chronic disease

August 6th, 2020 by Amy Proal

Resia Pretorius is both the Department Head and a Research Professor in the Physiological Sciences Department, Faculty of Science at Stellenbosch University in South Africa. Her team uses super-resolution and electron microscopy, together with flow cytometry and thromboelastic analysis of clot structure, to characterize inflammatory biomarkers (inflammagens) created by bacteria in human blood. She also studied how viruses like COVID-19 can drive similar clotting processes. Her team has published dozens of papers showing that bacterial inflammagens are increased in the blood of patients with a range of chronic inflammatory conditions, including Parkinson’s disease, Alzheimer’s disease and Type II diabetes. They have further detailed how such inflammagens interact with receptors on red blood cells, and bind or interact with the fibrinogen protein. This can impact the blood clotting cascade, resulting in hypercoagulation and chronic inflammation that negatively impacts surrounding blood vessels.

Here are some terms Resia mentions in the interview:

Platelets: component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby initiating a blood clot.

Coagulation: also known as clotting, coagulation the process by which blood changes from a liquid to a gel, forming a blood clot. Coagulation involves the activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.

Fibrin: an insoluble protein formed from fibrinogen during the clotting of blood. It forms a fibrous mesh that impedes the flow of blood.

Fibrinogen: a soluble protein in the plasma that is broken down to fibrin by the enzyme thrombin to form clots.

Inflammagens: Molecules, often tied to bacterial activity, that play a role in activating clotting cascades in blood. These inflammagens include:

  1. LPS: part of the bacterial cell wall that can act as an endotoxin
  2. gingipains: toxic proteins secreted by certain bacteria
  3. lipoteichoic acid: a major constituent of the cell wall of gram-positive bacteria
  4. cytokines: inflammatory molecules generated as part of the immune response to bacteria and other pathogens

At the beginning of the interview, Resia explains why her lab started studying bacteria in the blood of patients with Parkinson’s and Alzheimer’s disease. When she started the research, most of the scientific community did not think bacteria were capable of persisting in human blood. In fact, that’s what Resia and her students also believed. However, two of her students were trying to perform studies on Alzheimer’s and Parkinson’s blood and, to their surprise, kept finding bacteria in the blood samples. At first, they assumed that the bacteria must be contaminants (they assumed the bacteria in the samples were derived from the lab or the external environment as opposed to the human body). But, as they performed an increasing number of sterilizing approaches in an effort to prevent this bacterial “contamination,” nothing worked. Finally, they were forced to consider the possibility the bacteria in their samples might not be contaminants, but actual organisms present in Alzheimer’s and Parkinson’s blood.

In order to confirm that this might be possible, they began to talk to other research teams studying blood, all of whom were increasingly open to the possibility that the bacteria were indeed “real.” Resia also started to work more closely with Douglas Kell and team in the UK to better understand how bacteria can enter the blood via the gut and mouth. Her team also read this paper by the research team I worked with at Autoimmunity Research Foundation. Our paper put forth a model of how bacteria in tissue and blood may contribute to chronic inflammatory disease. Resia and team found the paper informative. All of the events jump-started dozens of research projects on the topic, and further work on how identified bacteria and their inflammatory product can impact the blood clotting cascade, blood iron levels, and even the shape (or deformability) of red blood cells.

In fact, since that time, Resia and team have found that minuscule concentrations of LPS and other bacterial inflammagens can produce a domino effect of soluble fibrinogen in the presence of thrombin in blood. This can further trigger the formation of extensive pockets of amyloid protein aggregates. They have performed hundreds of experiments on the topic, and found that a level of just 0.03ng/L of LPS can trigger such changes in fibrin and amyloid formation.

Key to Resia’s microscopy work is her ability to image bacteria in different states. Bacteria in the human body can persist in a dormant state, in which they are not active and replicating. However, under episodes of stress, or other inflammatory insults, the same bacteria can change their activity to drive a range of inflammatory processes, including clotting issues. One factor Resia and team have found can cause bacteria to shift from a dormant to active form is changes in blood iron levels.

Resia and team also study how bacteria and their inflammagens can cause red blood cells (RBCs) to change shape (red blood cell deformability). They have found that in the presence of bacterial inflammagens, RBCs can commit “eroptosis” – a type of programmed cell death. The figure to the right was photographed by Resia with a microscope. It shows bacteria and RBCs in Parkinson’s/ Alzheimer’s blood. The red blood cells display various abnormal shapes, likely due to the fact that inflammagens have interacted with their membranes, causing the membranes to lose their elasticity. The RBCs cannot reform to the correct disc shape, even when they travel through tiny capillaries. The team has also found that increased ferritin (iron) levels cause RBCs to stay elongated.   

Resia also explains how her team recently identified toxic gingipain proteins created by the bacterial pathogen P. gingivalis in Parkinson’s blood. In a series of experiments, they further showed how the gingipain proteins could increase hypercoagulation, the presence of amyloid formation in plasma, and profound ultrastructural changes to platelets. The findings are particularly exciting because P. gingivalis and its gingipain proteins were also recently identified in the Alzheimer’s brain by a different team. Taken together, the two studies suggest that P. gingivalis (which can enter the blood from the mouth/oral cavity) may play a much greater role in contributing to neurodegenerative/neuroinflammatory disease than previously believed.

Resia and team also recently published this amazing paper detailing how viruses can secrete products and proteins that also modulate platelet function and clotting in blood. They explain how, during infection, an onslaught of inflammatory and virus-derived stimuli can evoke and challenge platelets, leading to inappropriate activation, immunological destruction, and sequestration. They also just released this paper with data showing that the blood of patients with COVID-19 carries a massive load of pre-formed amyloid clots. These clots can be easily imaged in a clinical setting to provide a rapid, early detection test for clotting severity in COVID-19 patients.

Some other highlights from the interview include these comments from Resia:

  1. “I think that pathogens play a more prominent role [in contributing to chronic disease processes] than most clinicians and researchers can imagine .”
  2. “The focus of research on Parkinson’s disease has been very immunocentric. We think it should shift to focus on more prominently including the role of lifestyle and environmental factors. Because otherwise, to address the condition, where a mind-boggling number of people are suffering, we are missing something.”

  

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