Many of the deadliest bacterial diseases that plague humanity in the modern age are caused by bacterial biofilms that produce chronic infections. However, most of our knowledge of the host immune response comes from the study of planktonic pathogens. While there are similarities in the host response to planktonic and biofilm bacteria, specific immune responses toward biofilms have not been well studied; the only apparent difference is the inability to clear the bacteria allowing the biofilm infection to become chronic. In some cases, the biofilms skew T-cell response toward a balance that allows a stalemate between the host and the pathogen, in which the infection can become persistent. In this minireview, we will summarize well-known examples of this phenomena as well as some emerging studies that may indicate that this situation is much more common than initially thought.

Within the species of Salmonella enterica, there is significant diversity represented among the numerous subspecies and serovars. Collectively, these account for microbes with variable host ranges, from common plant and animal colonizers to extremely pathogenic and human-specific serovars. Despite these differences, many Salmonella species find commonality in the ability to form biofilms and the ability to cause acute, latent, or chronic disease. The exact outcome of infection depends on many factors such as the growth state of Salmonella, the environmental conditions encountered at the time of infection, as well as the infected host and immune response elicited. Here, we review the numerous biofilm lifestyles of Salmonella (on biotic and abiotic surfaces) and how the production of extracellular polymeric substances not only enhances long-term persistence outside the host but also is an essential function in chronic human infections. Furthermore, careful consideration is made for the events during initial infection that allow for gut transcytosis which, in conjunction with host immune functions, often determine the progression of disease. Both typhoidal and non-typhoidal salmonellae can cause chronic and/or secondary infections, thus the adaptive immune responses to both types of bacteria are discussed with particular attention to the differences between Salmonella Typhi, Salmonella Typhimurium, and invasive non-typhoidal Salmonella that can result in differential immune responses. Finally, while strides have been made in our understanding of immunity to Salmonella in the lymphoid organs, fewer definitive studies exist for intestinal and hepatobiliary immunity. By examining our current knowledge and what remains to be determined, we provide insight into new directions in the field of Salmonella immunity, particularly as it relates to chronic infection.

Salmonella enterica serovar Typhi causes 14.3 million acute cases of typhoid fever that are responsible for 136,000 deaths each year. Chronic infections occur in 3%-5% of those infected and S. Typhi persists primarily in the gallbladder by forming biofilms on cholesterol gallstones, but how these bacterial communities evade host immunity is not known. Salmonella biofilms produce several extracellular polymeric substances (EPSs) during chronic infection, which are hypothesized to prevent pathogen clearance either by protecting biofilm-associated bacteria from direct humoral attack or by modulating innate phagocyte interaction with biofilms. Using wild-type and EPS-deficient planktonic and biofilm Salmonella, the direct attack hypothesis was tested by challenging biofilms with human serum and antimicrobial peptides. Biofilms were found to be tolerant to these molecules, but these phenotypes were independent of the tested EPSs. By examining macrophage and neutrophil responses, new roles for biofilm-associated capsular polysaccharides and slime polysaccharides were identified. The S. Typhi Vi antigen was found to modulate innate immunity by reducing macrophage nitric oxide production and neutrophil reactive oxygen species (ROS) production. The slime polysaccharides colanic acid and cellulose were found to be immune-stimulating and represent a key difference between non-typhoidal serovars and typhoidal serovars, which do not express colanic acid. Furthermore, biofilm tolerance to the exogenously-supplied ROS intermediates hydrogen peroxide (H 2 O 2 ) and hypochlorite (ClO − ) indicated an additional role of the capsular polysaccharides for both serovars in recalcitrance to H 2 O 2 but not ClO − , providing new understanding of the stalemate that arises during chronic infections and offering new directions for mechanistic and clinical studies.