Research Progress on Invasion-Related Virulence Genes in Salmonella Enteritidis
Research Progress on Invasion-Related Virulence Genes in Salmonella Enteritidis
Overview
Salmonella is a zoonotic Gram-negative bacterium belonging to the family Enterobacteriaceae and is a common pathogen of foodborne diseases. There are more than 2,500 serotypes of Salmonella, with Salmonella typhimurium and Salmonella enteritidis being the dominant serotypes. Salmonella enteritidis often causes intestinal diseases, manifested as acute fever, abdominal pain, diarrhea, nausea, vomiting and other symptoms, which generally do not require antibiotic treatment. However, in recent years, reports of extraintestinal infections have continued to increase, such as suppurative inflammation of the skin and subcutaneous tissue, endocarditis, arthritis, sepsis, meningitis and urinary tract infections. These invasive infections are related to their invasiveness and special ability to replicate continuously in cells. In its pathogenic process, it relies on the synergistic effect of multiple virulence factors. For example, phagocytes are an important line of defense for the human body against pathogen invasion, and participate in bactericidal effects through oxygen-dependent/non-oxygen-dependent pathways. Many pathogens have evolved mechanisms to evade phagocyte killing and survive in cells.
Figure 1. Pathogenesis model of Salmonella enterica serovar Typhimurium. (Sources: Fàbrega A, et al. 2013)
There are two ways for Salmonella enteritidis to enter macrophages: being phagocytosed by macrophages and actively invading macrophages. Studies have found that its type III secretion system can activate caspase-1, mediate the maturation and secretion of IL-1, and induce programmed apoptosis of macrophages. In addition, different virulence factors have different pathogenicity. For example, a report on carbuncle-causing Salmonella enteritidis pointed out that the pathogenic strain had three unique virulence genes, pef, spv, and rck. pef is related to its adhesion and biofilm formation, spv is related to invasiveness, and rck can enhance resistance to host immune response. Understanding these virulence factors is essential for understanding the pathogenic mechanism of Salmonella enteritidis and formulating control strategies.
Virulence Genes of Salmonella
Virulence genes located on mobile genetic elements such as Salmonella pathogenicity islands (SPIs), plasmids (pSTVs) and integrons are the main genetic determinants, involved in the adhesion and invasion of Salmonella to host cells and the spread of virulence and resistance between different strains. Among them, Salmonella pathogenicity islands play an important role in its pathogenicity. 17 SPIs have been found in Salmonella, and SPI-1, SPI-2, SPI-3, SPI-4, and SPI-5 exist in all Enteritidis Salmonella. SPI-1 and SPI-2 encode 2 different type III secretion systems (T3SS). After entering the intestine, Salmonella enteritidis attaches to intestinal epithelial cells and M cells. SPI-1 expresses T3SS-1. Some proteins act as "molecular syringes" in the form of channels, connecting the bacterial cytoplasm with the host cell membrane, and then "inject" more than 20 effector proteins into intestinal epithelial cells. One function of these effector proteins is to wrinkle the surface of the host cell, which is conducive to the entry of Salmonella enteritidis into the host cell. They also combine with the host cell membrane to form a vesicle structure (SCV) to provide a replication environment. In SCV, Salmonella enteritidis SPI-2 expresses T3SS-2. The secretion of these effector proteins is the key to systemic infection. SCV facilitates the survival and reproduction of Salmonella enteritidis in macrophages and intestinal epithelial cells. After Salmonella enteritidis passes through the intestinal epithelial cells, it enters the Peyer's patches, which present antigens as antigen-presenting cells, and then reaches the liver and spleen through the reticuloendothelial system and enters the bloodstream. After reaching the submucosal layer, it is engulfed by macrophages and rapidly spreads through the bloodstream accumulated in the mesenteric lymph nodes, eventually spreading to the spleen. Functional studies of SPI-3 focus on intestinal colonization and intracellular survival; SPI-4 is associated with intestinal diseases; SPI-5 is often regulated in coordination with SPI-1 or SPI-2 genes.
In addition to the above-mentioned secretion system, there are many virulence factors involved in the adhesion, invasion, immune escape, antibiotic resistance, nutrient uptake and other processes of Enteritidis Salmonella, such as pili, lipopolysaccharide, enterotoxin, etc. Invasion of phagocytes and non-phagocytes is a key step in causing invasive infection of Enteritidis Salmonella, which is achieved through the invasion protein encoded by its invasion gene. At present, the research on the invasion-related virulence genes of Enteritidis Salmonella is focused on SPI-1, such as inv, sip, hil and other genes. Flagella, as an important virulence factor, also plays a vital role in the invasion process. In addition, there are some virulence factors whose functions have yet to be clarified, such as yhbC, which need to be explored. The understanding and research of virulence genes that associate Enteritidis with invasiveness can provide new research ideas for the pathogenic mechanism of Enteritidis invasive infection and provide strong evidence for its prevention, early diagnosis and treatment.
Conclusion
In summary, the current research on the invasion-related virulence genes of Salmonella enteritidis focuses on SPI-1 and flagellar genes. Most of the studies use cells or mammals such as mice as models to explore the pathogenic mechanism of a single gene. However, the pathogenic process is often coordinated by many virulence genes. In addition, the regulatory mechanism of Salmonella enteritidis is complex, and its biological characteristics and pathogenic mechanism have not yet been accurately grasped. With the increasing drug resistance of Salmonella enteritidis and the widening of the drug resistance spectrum, the incidence and mortality of invasive infections are on the rise. Since invasive infections have the characteristics of hidden onset, unclear clinical manifestations, and high mortality, they have brought great challenges to clinical treatment and rational drug use. Early and accurate diagnosis is of great significance for the timely treatment of severe infections. Finding specific molecular diagnostic markers through the carriage of invasion-related virulence genes can provide a basis for early diagnosis and provide early warning for possible invasion-related diseases. In addition, the mechanism of invasive infection caused by Enteritidis Salmonella is still not thoroughly understood. Further exploration of related genes can provide basic data for mechanism elucidation and develop new anti-Salmonella targets for the current drug resistance phenomenon.
Reference
Ilyas B, et al. Evolution of Salmonella-Host Cell Interactions through a Dynamic Bacterial Genome. Front Cell Infect Microbiol. 2017, 7:428.
Fàbrega A, Vila J. Salmonella enterica serovar Typhimurium skills to succeed in the host: virulence and regulation. Clin Microbiol Rev. 2013, 26(2):308-41.
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Figure 1. Pathogenesis model of Salmonella enterica serovar Typhimurium. (Sources: Fàbrega A, et al. 2013)