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Simplified, the Red Queen hypothesis proposes a constant co-evolution between organisms in order to ensure survival of the involved parties in a competitive environment. When looking at the immune system this entails the constant evolution of pathogens to avoid the immune system, and in return the immune system evolving to continue to protect the body from pathogens. Researchers have now identified a new way bacteria inhibit the immune system using the host itself.
Immune responses are based on the recognition of pathogens via specific molecules (antigens) expressed on their surface. After the invasion is stopped, some immune cells develop into memory cells. These long-living cells can circulate the body, and in case of the reoccurring infection initiate a much faster response.
Arms race of evolution
Pathogens have learned to avoid immune responses. Take the influenza virus for example. It constantly mutates its genes. Thereby changing the antigens the immune system can recognises and allowing the survival of these newly mutated virus versions. The process, known as antigenic drift or antigenic variation, is also the reason why we have to vaccinate against the virus every year.
Trypanosoma brucei, an extracellular parasite causing sleeping sickness, took one step further. The parasite is covered with a dense, homogeneous layer of glycoproteins (VAGs). The density of this “coat” makes it hard for the immune system to identify antigens and when it does the parasite sheets its coat and express a new type VAG – making it invisible again. T. brucei encodes more than 1000 VAG genes. The back and forth between host and parasite can continue till the host is exhausted.
Another way pathogens hide from immunological detection is the production of immune-inhibitory modulators or toxins. A study now published in Nature Immunology identifies a new pathway by which bacteria hinder the immune system. Strikingly the bacteria do so using a host-made molecule.
Turing the body against itself
Heme is the ferrous part of hemoglobin in red blood cells. Oxidation of the chelated iron makes heme an oxygen carrier. Free heme, however, is potentially toxic for cells. Its degradation is therefore tightly regulated via heme-binding proteins such as haptoglobin and hemopexin. High levels of free heme during bacterial sepsis or malaria has long been associated with better growth of the attacker and poorer outcome for the patients. So far this has been attributed to bacteria using heme as a source for iron.
Martins et al. have now found that free heme can directly influence macrophage function, which leads to worse detection and clearance of bacteria. Using an E. coli based model of sepsis the researchers not only show that exogenous heme hinders clearance of bacteria, they also demonstrate that heme directly inhibits macrophage phagocytosis and migration rather than being simply a food source for the bacteria.
Heme interacts with the actin-cytoskeleton of the cells, rendering the cells less mobile. Hemes interfering with the actin remodelling (via DOCK8 and Cdc42) explains both the effects on cell migration and phagocytosis as for both processes formation of cell extremities (filo- or lamelli-podi) are necessary.
DOCK8 is an atypical guanine-nucleotide-exchange factor and activator of Cdc42, a key regulator of phagocytosis and migration. DOCK-8 deficient macrophages, while having lower basal phagocytosis levels, are protected from the inhibitory effects of heme – suggesting DOCK8 as binding partner for heme. Having identified the mechanism by which heme inhibits the immune system, the author screened potential molecules which can block hemes effect on phagocytosis. Quinine, an anti-malarial drug already used in clinics, could block hemes effect and restore phagocytosis in the macrophages.
This newly identified mechanism used by bacteria to block the immune system underlines the complex and interwoven interaction between pathogens and host. Understanding these mechanisms can help finding new therapeutic approaches, like the DOCK8-heme axis. It also demonstrates that we always only see a point in time – in case of heme the pathogens are one up as we as host have not developed a strategy to sufficiently prevent heme insult. Although it is to note that heme can only exert these effects when the body is coping with extreme hemolysis. Mild cases are counteracted by heme-binding molecules. Only once this pathway is overloaded can heme inhibit immune cells. Heme-binding proteins may have been the first evolutionary comeback to sepsis and bacteria trying to use heme against us.
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