Streptococcus pyogenes interaction with the lymphatic hyaluronan receptor LYVE-1 as a mechanism for lymphatic dissemination and disease progression

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Streptococcus pyogenes, often known as 'group A strep' normally causes infections such as sore throat, tonsillitis and impetigo, commonly among children. However, it can also spread from person to person rapidly, to cause life-threatening infections such as necrotising fasciitis, maternal sepsis, and toxic shock, most commonly in those who were otherwise previously fit and healthy. The most virulent, or dangerous, types of group A strep often demonstrate a thick capsule, or outer coating, when grown from the blood stream. Heavily encapsulated strains of group A strep have also been associated with outbreaks of the immune disorder, rheumatic fever, the leading cause of valvular heart disease worldwide. Coupled with the relevance to lethal invasive strep infections, there is a major imperative to understand the interaction of group A strep with the immune system focussing in particular on the role of the capsule. The group A strep capsule is made from a substance known as hyaluronic acid or hyaluronan, a large sugar thought to facilitate wound healing, immune cell migration and cancer spread. Much of our own body is filled with hyaluronan, and group A strep may use this capsule to cloak itself from our immune system. Lymphatics are channels distributed throughout the body, through which fluid known as lymph flows to lymph glands, taking with it, the specialised white blood cells required for immune responses and also, hyaluronic acid - which is itself broken down in lymph nodes. The cells lining lymphatic channels actually have a receptor or 'hook' for hyaluronan to latch onto, presumably helping the hyaluronic acid to enter the channel although little is known about how the hyaluronan moves along the channels. We believe that group A strep exploits the very same hyaluronan 'hook' on the cells lining the lymphatic channel in order to enter lymphatics and reach lymph glands. The lymph glands are "depots" where microbes arising from infections elsewhere in the body are conveyed, so that they can be exhibited to the immune system to generate a protective immune response. We suspect that the group A strep hyaluronan capsule not only helps the microorganism to get to the lymph nodes but also protects it from being recognised and killed by the immune system. In this project we will find out whether group A strep does use this system to reach the lymph glands, and whether that has adverse consequences for people with infection, both those with tonsillitis and those with more dangerous infections such as necrotising fasciitis. In the work proposed, we will test strains that are currently causing disease in the UK for their ability to be trafficked in lymphatics, as well as strains that have been altered in the laboratory to express greater or lesser amounts of capsule. If we were able to show a deleterious effect of group A strep interacting with lymphatics, it might then be possible to block or prevent the interaction between the lymphatic cells and the streptococcus from occurring, and to develop treatments to prevent invasive infections from progressing, or to prevent triggering of inflammation.