Salmonella Biofilm Formation, Chronic Infection, and Immunity Within the Intestine and Hepatobiliary Tract

Abstract

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.

Keywords: Salmonella; biofilm; chronic infection; hepatobiliary; immunity.

Figure 1

Salmonella biofilms in the environment and humans. Non-typhoidal and typhoidal salmonellae are naturally acquired by humans through environmental or food sources. Salmonella Typhimurium colonizes and can form biofilms on various types of produce, while S. Enteritidis is often found within and on eggs. When within the intestines of various non-human animal species, salmonellae can cause either diarrheal disease or be a non-pathogenic inhabitant (e.g., in the chicken). This can lead to contaminated meat upon animal processing or shedding resulting in contaminated animal feces. Once ingested by the host, Salmonella spp. are capable of forming biofilms in the intestines and for S. Typhi, after systemically gaining access to the liver, can pass into the gallbladder and form biofilms on cholesterol gallstones. These biofilms within humans facilitate chronic Salmonella infection as well as continual shedding of Salmonella from the host. Images created with BioRender.com.

Figure 2

Overview of host immune response to Salmonella infection. Salmonella, infecting via the oral-fecal route, first passes through the stomach and into the lumen of the small intestine. There, Salmonella uses its SPI-1 type III secretion system to preferentially transcytose across M cells to gain access to the Peyer’s Patches. Immune cells in the Peyer’s Patches, such as macrophages and dendritic cells, sense Salmonella via toll-like receptors and begin to trigger an immune response. Macrophages and dendritic cells then migrate to the gut-draining mesenteric lymph nodes and the spleen (not shown) harboring Salmonella antigens as well as whole bacteria in Salmonella-containing vacuoles. In the lymph nodes and spleen, dendritic cells and macrophages present antigen on MHC class II to activate Salmonella-specific helper T cells which can then subsequently activate Salmonella-specific B cells. These adaptive immune cells then traffic back into the intestine to fight infection by releasing the antimicrobial cytokine interferon gamma or neutralizing antibodies. Any Salmonella that escape the immune response of the Peyer’s patches and mesenteric lymph nodes or spleen, can travel to, and invade, the liver and subsequently the gallbladder via the bile duct. In the liver, Kupffer cells phagocytose Salmonella and activate Salmonella-specific T cells to produce the anti-inflammatory cytokine interleukin-10, likely preventing bacterial clearance. The immune environment in the gallbladder is less clear, primarily because of the presence of Salmonella biofilms on gallstones, which can hinder/alter the immune response. The liver and gallbladder are both sites where the host can experience chronic infection with Salmonella. Images created with BioRender.com.