Hello I am Peter Østrup Jensen and I run the Phagocyte Lab at Rigshospitalet in Copenhagen. In this lecture about the host response to biofilm infection I will go through the different types of host response to infections. Your body’s response to an infection consists of at least three components: The non-inflammatory defence, the immune response, and the inflammatory response. The non-inflammatory defence involves ongoing mechanisms that maintain the self-cleaning capacity of the body such as the skin and the respiratory tract. This defence system is ongoing by default, meaning that it is constitutively active, and it may be modulated by infectious microorganisms. Modulated means that it is enhanced or attenuated. The non-inflammatory defence is very important for the development of biofilm infections in the lungs of patients with cystic fibrosis. In cystic fibrosis patients thick layers of stiff dehydrated mucus compromise the mucociliary escalator system thereby disabling the ciliary movement, which results in poor self-cleaning capacity to remove invading microorganisms from the airways. And it is well accepted that this defective self-cleaning capacity of the mucociliary escalator is the main reason for the higher susceptibility to biofilm infections in the lungs of cystic fibrosis patients. The immune response is the body’s response to antigens. Antigens include pathogen associated molecular patterns such as extra-cellular DNA, various toxins, LPS and other microbial components. Traditionally, the immune response has been divided in the innate response and the adaptive response. The innate immune response provides the fastest response, but it has only little specificity. Approximately 300 receptors are involved in innate immunity. In principle the innate immune system has no memory - the innate immune system will respond the same way if infectious microorganisms infect the host several times. The humoral components of the innate immune system include the complement system, cytokines and bactericidal peptides. The cellular component mainly consists of polymorphonuclear leukocytes, also called the PMNs, the macrophages, Gamma Delta T cells and epithelial cells. The adaptive immunity provides a slower response that may take weeks to mature. Contrary to the innate immune response the adaptive immune response has high specificity and employs 1-10 million different receptors in the body. This allows the adaptive immune system to develop ‘memory’ of infections –This ability to remember previous infections is an integrated mechanism of all effective vaccines. The humoral components of adaptive immune system involve antibodies and cytokines. Lymphocytes and dendritic cells dominate the cellular components. So which part of the immune system is activated against biofilm infections? Some information may be obtained when considering the type of infection that predominates in patients with primary immunodeficiencies. That is patients born with particular deficient components of the immune response. We should also take into account that the infectious biofilm is mainly caused by bacteria and by fungi. If we take a closer look of this table, which shows the type of infection typically associated with the major categories of primary immune deficiencies, we see that against bacterial pathogens antibodies, phagocytes and the complement system are all important, but against mycobacteria and fungi it appears that the phagocytes provide the most important part of the host defence. In other words we could expect a response by the phagocytes against the biofilm formed by both bacteria, mycobacteria and as well as by fungi. The phagocytes of the immune response are dominated by PMNs and macrophages. The third component of the host response to infection is the inflammatory response. The inflammatory response is a reaction to tissue damage, and is not necessarily, as with the activation of the immune system, caused by antigens. Inflammation is characterized by pain, swelling, heat, redness and by loss of functionality. The tissue damage leading to the inflammatory response may be caused by physical insults such as pressure, temperature and radiation and by chemical insults such as acids, bases and oxidants. In addition antigens such as toxins may also cause the tissue damage. Within seconds of recognizing the injury, the generation of the inflammation is mediated by chemical signaling that loosens the vascular structure. This loosening allows migration of attracted inflammatory cells into the area of the stimulating insults. The early inflammatory cells primarily consist of PMNs and macrophages. The phagocytes immediately start to neutralize the initiating stimuli, which could be toxic chemicals or invading microorganisms. Successful destruction of the stimuli is followed by removal of debris and repair and restoration of tissue as part of inflammation. Sometimes the inflammatory response fails to destruct the stimuli. In these cases there will be a persistent inflammatory response. This persistent inflammatory response may eventually reinforce the inflammation by causing more tissue insults resulting in even more tissue deterioration. It should be noted that an immune response may also develop during inflammation and this immune response may be pro- or anti-inflammatory, meaning it may accelerate or dampen the inflammation. Before successful neutralization the inflammatory response is called an “acute-type inflammation”. After successful neutralization it is called a “chronic-type inflammation”. The acute-type inflammation is dominated by PMNs, while the chronic-type inflammation is dominated by macrophages, monocytes and lymphocytes. The high tolerance of biofilm against the host response prevents removal of the stimuli resulting in prolongation of the “acute-type inflammation”. Hence, biofilm may cause chronic infections with an acute-type inflammatory response, that leads to collateral tissue damage. Thank you!
