Salmonella, a gram-negative bacterium notorious for causing foodborne illnesses, gained global attention in 1885 when Daniel Salmon’s laboratory first identified it as a pathogen. Today, it stands as a significant public health threat, annually causing 150 million cases of diarrheal illnesses and 60,000 deaths, making it the second-leading cause of foodborne illnesses in the United States. Its primary modes of transmission include contaminated food, water, and contact with infected animals. The escalating antimicrobial resistance, affecting approximately 16% of clinical isolates, underscores the need for judicious antibiotic use and alternative treatments. Moreover, the absence of FDA-approved vaccines for non-typhoidal Salmonella infections highlights the importance of research aimed at developing effective vaccines targeting various serotypes. This article explores the sophisticated cellular interplay between Salmonella and its host, revealing unexpected medical applications of this pathogen. 

Pathogenesis of Salmonella: A Cellular Interplay 

Salmonella embarks on a journey into the infected host, beginning with the activation of its acid tolerance response to withstand the harsh acidic conditions of the stomach. Its path takes a decisive turn with selective adherence to Peyer’s patches in the small intestine, setting in motion a series of events where Salmonella infiltrates various cell types, including epithelial cells and macrophages.  

Understanding Salmonella‘s pathogenesis unveils a cellular choreography where its virulence stems from metabolic traits and specific genetic elements, such as Salmonella pathogenicity islands (SPI), SPI-1 and SPI-2. These elements encode type 3 secretion system (TTSS), which functions as a remarkable mechanism, allowing Salmonella to inject virulence proteins directly into host cells. This strategic maneuver serves as a potent tool for evading the host’s defensive responses, manipulating host cellular processes, and providing Salmonella with a survival advantage. 

Salmonella‘s adaptability is particularly intriguing, as it can interact with different cell types, employing varied tactics based on encountered cells. For instance, invasion of epithelial cells involves cytoskeletal rearrangement, forming Salmonella–containing vacuoles (SCVs) through the injection of SPI-1 effector proteins. In contrast, macrophage invasion involves phagocytosis and does not necessarily require SPI-1 effectors. Additionally, Salmonella strategically uses Salmonella–induced filaments (SIFs) to convert host cell endosomes into interconnected tubular vesicles, promoting bacterial feeding and replication. 

To evade host immune responses, Salmonella employs sophisticated mechanisms using a wide range of bacterial effectors, which serve various functions depending on the stage of infection, contributing to such processes as evading lysosomal degradation, masking surface antigens, inhibiting innate immune signaling, reducing pro-inflammatory mediator production, and impeding efficient bacterial clearance by immune cells. 

Leveraging Salmonella as a Cancer Delivery System 

Remarkably, Salmonella has emerged as a valuable therapeutic agent, leveraging its unique properties. Salmonella can selectively target and colonize hypoxic tumor areas, exhibiting a tumor accumulation ratio exceeding 1000:1 compared to healthy tissues. This makes Salmonella an attractive candidate for developing anticancer agents. For example, a genetically engineered strain of Salmonella expressing TNF-alpha has shown promise as a melanoma-suppressing agent. Despite challenges associated with systemically administered cytokines, genetically modified Salmonella holds the potential for producing biological anticancer agents. 

Salmonella‘s utility extends to delivering anti-tumor agents for multidrug-resistant ovarian cancer. Attenuated Salmonella Typhi carrying small interfering RNA against the multidrug-resistance gene (MDR1) has demonstrated efficacy in cisplatin-resistant ovarian cancer cells, overcoming resistance and slowing tumor growth in mice.  

However, systemic administration of live Salmonella poses challenges, including inflammatory responses and side effects. Advances in biotechnology have facilitated the attenuation of Salmonella strains, enhanced safety, and enableding tailored engineering for specific tumor-targeting treatments.  

Using Salmonella for Treatment of Skin Conditions 

Engineered Salmonella also has therapeutic potential in a skin condition called atopic dermatitis. The researchers used a genetically modified Salmonella strain designed to express a specific microRNA targeting the macrophage-derived chemokine gene associated with atopic dermatitis severity. The engineered Salmonella strain demonstrated effectiveness in an atopic-like animal model, where it resulted in skin regeneration, hair regrowth, and reduced scratching behavior compared to control mice. Overall, these findings suggest the therapeutic potential of Salmonella-based gene therapy for atopic dermatitis, demonstrating positive effects on both immune responses and clinical symptoms in animal models. 

Salmonella as a Vaccine Vector 

Beyond its role in drug delivery, Salmonella is extensively studied as a live bacterial vector for delivering recombinant protective antigens and DNA vaccine vectors. The oral delivery capability of Salmonella eliminates the need for needles in immunization, presenting a practical advantage. Here, a strategy called recombinant attenuated Salmonella vaccines (RASVs) can be used, aiming for enhanced immunogenicity and attenuation and the ability to colonize internal lymphoid tissues. Regulated delayed in vivo attenuation of the bacterium, controlled protein synthesis, and Salmonella lysis are integral components of this RASV approach. The modulation of factors such as iron acquisition and acid resistance systems further enhances Salmonella‘s invasiveness and colonization of mucosa-associated lymphoid tissues. 

To deliver the vaccine to the cells for immune recognition, the Salmonella type 3 secretion system emerges as an effective approach facilitating direct antigen secretion from bacterial cells into the host cell cytosol, enhancing protective immune responses. This molecular needle precisely becomes activated when the host cell is present, delivering the antigen of choice directly to the cell that it targets, therefore acting as a molecular vaccine syringe. Mucosal administration of RASVs stimulates antibody production and cellular immunity. 

To fine-tune and optimize this bacterium-driven vaccination approach, the microbial structure can undergo additional modifications. This includes regulated delayed expression of attenuating phenotypes through controlled lysis, gene deletion-insertion mutations, and the utilization of sugar-regulated promoters. RASVs are engineered to withstand the challenges posed by the gastrointestinal tract, including low pH, through the regulated expression of acid tolerance response genes. 

These advancements in Salmonella-based vaccine design are aimed at enhancing safety, immunogenicity, and colonization efficiency, thereby paving the way for the development of effective live bacterial vaccines for diverse applications. 

Conclusions 

In summary, the pathogenic properties and survival strategies of Salmonella pose a substantial global health concern while concurrently offering avenues for groundbreaking applications in drug delivery systems and vaccine vectors. Research into the complex interactions between Salmonella and host cells is crucial, providing insights into combatting infections and revealing the potential for harnessing Salmonella‘s unique attributes for therapeutic advancements.  

References: 

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