Platelet aggregation responses to <i>Salmonella</i> Typhimurium are determined by host anti-<i>Salmonella</i> antibody levels

Invasive non-typhoidal <i>Salmonella</i> infections are responsible for &gt;75 000 deaths/year and &gt;500 000 cases/year globally. Seventy-five percent of these cases occur in Sub-Saharan Africa, an increasing number of which are from multi-drug resistant strains. Interactions between bacteria and platelets can lead to thrombus formation, which can be beneficial for control of infection (immunothrombosis), or harmful through uncontrolled inflammation and organ damage (thromboinflammation). It is unknown whether <i>Salmonella</i> Typhimurium can activate human platelets. To assess this, light transmission aggregometry was used to measure platelet activation by two different <i>Salmonella</i> Typhimurium strains in 26 healthy donors in platelet-rich plasma and washed platelets. In platelet-rich plasma, but not in washed platelets, <i>Salmonella</i> Typhimurium activated platelets in a donor- and strain-dependent manner mediated through the low affinity immune receptor FcγRIIA and the feedback agonists, ADP and thromboxane A₂. Plasma swap studies between strong and weak responders demonstrated a plasma component was responsible for the variation between donors. Depletion of anti-<i>Salmonella</i> antibodies from plasma abolished <i>Salmonella-</i>induced platelet aggregation responses, and addition of polyclonal anti-<i>Salmonella</i> antibody allowed aggregation in washed platelets. Correlating levels of anti-<i>Salmonella</i> total IgG or the IgG1, IgG2, IgG3 and IgG4 subclasses to platelet responses revealed total IgG levels, rather than levels of individual subclasses, positively correlated with maximum platelet aggregation results, and negatively with lag times. Overall, we show that anti-<i>Salmonella</i> IgG antibodies are responsible for donor variation in platelet aggregation responses to <i>Salmonella</i> and mediate this activity through FcγRIIA. <i>Salmonella</i> is widely known as a bacterial pathogen that causes diarrhea, with recovery occurring after about a week. However, there exists another, less well known and more severe form of <i>Salmonella</i>, called invasive non-typhoidal <i>Salmonella</i>. This type of <i>Salmonella</i> infection gets across the gut barrier, enters the bloodstream and spreads through the body. There are over half a million of these kinds of invasive <i>Salmonella</i> infections globally every year, leading to over 75 000 deaths. The majority of these are in sub-Saharan Africa but also are significant causes of harm in the elderly or those with compromised immune systems. When the bacteria are in the bloodstream, they can come into contact with various different types of cells, including platelets, the cells that cause blood to clot. Sometimes the presence of bacteria in the blood can cause platelets to clump together, leading to blood clots, which can block the blood vessels and cause organ damage, and death. The ability of <i>Salmonella</i> bacteria to cause clots has not been investigated in depth. <i>Salmonella</i> is widely known as a bacterial pathogen that causes diarrhea, with recovery occurring after about a week. However, there exists another, less well known and more severe form of <i>Salmonella</i>, called invasive non-typhoidal <i>Salmonella</i>. This type of <i>Salmonella</i> infection gets across the gut barrier, enters the bloodstream and spreads through the body. There are over half a million of these kinds of invasive <i>Salmonella</i> infections globally every year, leading to over 75 000 deaths. The majority of these are in sub-Saharan Africa but also are significant causes of harm in the elderly or those with compromised immune systems. When the bacteria are in the bloodstream, they can come into contact with various different types of cells, including platelets, the cells that cause blood to clot. Sometimes the presence of bacteria in the blood can cause platelets to clump together, leading to blood clots, which can block the blood vessels and cause organ damage, and death. The ability of <i>Salmonella</i> bacteria to cause clots has not been investigated in depth. <b>What is new?</b>We show that the bacteria that cause invasive <i>Salmonella</i> infections are able to trigger platelets to clump together and form a blood clot. However, the response of platelets in blood plasma from donors varies widely - some people’s platelets do not clump together much, whilst others form large clots. We show that the amount people’s platelets clot is linked to the level of antibodies that bind to <i>Salmonella.</i> We show that the bacteria that cause invasive <i>Salmonella</i> infections are able to trigger platelets to clump together and form a blood clot. However, the response of platelets in blood plasma from donors varies widely - some people’s platelets do not clump together much, whilst others form large clots. We show that the amount people’s platelets clot is linked to the level of antibodies that bind to <i>Salmonella.</i> <b>What is the impact?</b>There are limited treatment options for invasive non-typhoidal <i>Salmonella</i> infections due to increasing antimicrobial resistance. Therefore, understanding the mechanisms behind how <i>Salmonella</i> interacts with blood cells such as platelets could help direct further research to identify new treatment options for these infections. There are limited treatment options for invasive non-typhoidal <i>Salmonella</i> infections due to increasing antimicrobial resistance. Therefore, understanding the mechanisms behind how <i>Salmonella</i> interacts with blood cells such as platelets could help direct further research to identify new treatment options for these infections.