Novel innate immune functions of saliva

Abstract: The innate immune system in humans has succeeded in developing numerous mechanisms against the injurious effects of bacteria, along with their toxins as a result of several thousand years of co-evolution. The oral mucosal surface represents such a unique environment, where despite being constantly exposed to microbes and their products, overt infection and damage is a rarity. An important component of the human oral cavity is saliva that is known to aid a wide variety of functions, which not only includes basic physiological activities like swallowing, but also preservation of the overall health of the oral cavity. Saliva flow that is diminished in either quantity or quality is often linked to development of numerous oral maladies. The oral cavity harbors a diverse and abundant microflora interacting with saliva. Saliva has innate immune functions and many direct interactions between saliva and bacteria have been described previously. We therefore chose to study the interaction between saliva and other components of the innate immune system in the oral cavity. Salivary lipids were found to improve antimicrobial peptide (AMP) synthesis and promote clearance of intracellular bacteria in keratinocytes. We also observed how saliva modulates the functions of the prime guardian leucocyte, the neutrophil. Saliva triggers a response via salival mucins, which stimulates neutrophils to undergo a rapid mode of cell death called NETosis, wherein the neutrophils extrude a web to catch microbes in the form of a DNA framework decorated with AMPs known as neutrophil extracellular traps (NETs). These saliva-induced NETs had great capacity for entrapment and killing of bacteria. Lastly, we explored the effect of saliva on plasma, in presence of pathogenic streptococci. Streptococcal pharyngitis is defined by plasma exudation into a saliva rich environment. We found that upon intermixing with plasma, saliva triggers several proteolytic cascades within plasma that include the complement system and both arms of the coagulation systems. This results in clot formation that entraps bacteria of the oral flora. Using a well-characterized virulence factor, streptokinase, the important human pathogen Streptococcus pyogenes subsequently sequester and activate host plasminogen, enabling them to escape the clots. This thesis describes how saliva boost the function of other important components of the innate immune system in the oral cavity, namely keratinocytes, neutrophils and plasma and thereby shed light on some of the molecular mechanisms involved in health and disease.