Cutting-Edge Technologies and Animal Models Advancing Life Science Research on Shigella Infection Mechanisms in Humans

Shigella infection can cause severe discomfort in humans, emphasizing the need for mechanisms to understand it. With new technologies and animal models, you can see how far life science researchers have come. These tools have paved the way for healthcare providers to treat Shigella-related diseases.

What Are Shigella Infections?

A Shigella infection — otherwise known as shigellosis — attacks your intestines. These germs work together to cause diarrhea, fever, stomach pain, and other discomfort. The Centers for Disease Control says about 450,000 infections happen annually in the United States. However, areas with fewer resources are more prone to Shigella’s various infections.¹

The Shigella family includes four types of infections: sonnei, flexneri, boydii, and dysenteriae. Sonnei is the most common in the U.S., whereas the other three are rarer.¹ While Shigella infections don’t typically threaten lives, type 1 of the dysenteriae species can be fatal. In the past, it has caused outbreaks and fatalities due to its exotoxin production.²

Children are the most likely age group to get a Shigella infection, especially those under 5 years old.³ However, adults can still contract the illness. Shigellosis spreads through germs infecting a person’s stool. The bacteria can then spread into a person’s food, water, and other daily essentials.

The Technologies Advancing Shigella Infection Mechanisms in Humans

Scientists have recently developed new mechanisms to treat the Shigella infection in humans. What technologies are on the horizon? These four innovations demonstrate the power of research.

1. Organ-On-Chip Models

With organ-on-chip models, scientists can mimic human organs in a controlled environment. Some experts believe it could be an alternative to human or animal testing when developing drugs. When you place a miniature organ on a chip, you can observe and manipulate it as needed, especially when researching shigellosis.

Organ-on-chip research has revealed critical insights into what you know about Shigella infections. A 2024 Trends in Microbiology study examined how biomechanical forces affect pathogen interaction. With organ-on-chip technology, researchers revealed critical insights that could change how other industry professionals view Shigella forces.⁴

‘Work using the Intestine-Chip model challenged the long-standing hypothesis that Shigella invades poorly from the apical cell side, revealing instead that when mechanical forces mimicking natural intestinal processes are applied, S. flexneri can achieve significant invasion of enterocytes directly from the lumen,’ the researchers said.⁴

2. Bacterial Genome Sequencing

Identifying and typing Shigella is critical due to its highly contagious nature and mass spreading. How can genome sequencing help? This process identifies mutations and is often helpful in food safety and agriculture. Considering Shigella variations can pass through food, genome sequencing is essential. New surveillance and methods have advanced Shigella research.

The Pasteur Institute in France has advanced the surveillance process by sequencing the bacterial genome. With over 4,000 reference strains and clinical isolates, the researchers developed a new standardized technique. The approach led to accurate classification and high-resolution typing, thus removing the liability of frequent gene transfer.⁵

The findings could have ramifications for other known dangerous diseases. For instance, the researchers found that the core-genome multilocus sequence type scheme (cgMLST) is a practical genome method covering the diversity of Shigella. With this information, researchers can determine natural populations for the pathovar of E.coli.⁵

3. High-Resolution Microscopy

Imaging technologies are vital for evolving Shigella infection mechanisms in humans. With improving lab equipment, scientists can follow shigellosis as it navigates host cells and triggers immune responses. Increasing the resolution of microscopes is a significant step in research, as it paints clearer pictures and improves analyses.

Experts have used high-resolution microscopy to examine Shigella flexneri further, considering its closeness to E. coli. The primary difference is the Shigella strand requires a type III secretion system for the bacteria to invade the host cell. In a 2024 London School of Hygiene and Tropical Medicine study, the researchers used a high-resolution microscope to monitor the infection process.⁶

With advanced microscopy, the U.K. researchers found less DNA and protein synthesis and concluded Shigella flexneri can cause cell-cycle arrest. Artificial intelligence (AI) also factored into the image analysis through convolutional neural networks. With AI and deep learning measures, the study was able to distinguish the intracellular microenvironment influencing Shigella flexneri infections.⁶

4. GMMA Platform for Vaccines

The Generalized Modules for Membrane Antigens (GMMA) platform has been critical for affordable vaccines. Researchers can genetically modify GMMA to control the risk of system reactogenicity, considering their particulate size.⁷ While relatively new in life sciences, it provides a crucial path forward for helping people fight diseases and illnesses.

How can GMMA help fight shigellosis? Researchers have developed potentially lifesaving technologies to treat the infection. Among the most effective vaccines is the Shigella sonnei 1790GAHB, which studies have demonstrated to be effective.⁸ Treating the sonnei variant is critical, as it can cause bloody or prolonged diarrhea for over three days.⁹

A 2021 Frontiers in Immunology study demonstrated promising results with the GMMA platform, as the vaccine increased levels of anti-Shigella lipopolysaccharides (LPS). Another promising vaccine for combating Shigella is the HOPS-G meningococcal vaccine enhanced with aluminum hydroxide. Human trials have shown promise through safety and increased bacterial activity against Shigella.⁷

What Do Animal Models Reveal About Shigella Infections?

Before understanding Shigella infection mechanisms in humans, scientists have used animal models to understand the causes and progression. What have recent studies revealed for researchers? Here are four critical examples for the future.

1. Zebrafish

Zebrafish are a common test subject because of their genetic manipulability and swift development. These fish are genetically similar to humans, making them a key factor in shigellosis testing. In a 2023 Science Advances study, the scientists found introducing zebrafish larvae with Shigella protection improved their bacterial clearance efficiency.¹⁰ 

One of the study’s most vital revelations centered around the neutrophils. While their bacterial clearance stood out, the researchers also noted the shift in their epigenetic landscape. After inducing the protection, Shigella left the H3K4me3 antibody on the 1612 genes. Therefore, there was more microbial recognition and mitochondrial reactive oxygen species (ROS) production.¹⁰

Another critical factor was introducing new neutrophils instead of naive white blood cells. With the novel neutrophils, the Shigella infection enhanced protection and could kill unwanted molecules more efficiently. The researchers attributed this infection control to the host affecting the inflammatory state. Despite another infectious challenge, there was increased survival.¹⁰

2. Mice

Mice are another standard animal for modeling, considering their genetic makeup and rapid reproduction. In laboratory settings, they can help discover more about Shigella and other infections. Since mice are naturally less vulnerable to shigellosis, researchers must be more creative when genetically modifying and creating models.

Experts have learned about Shigella through mice by examining epithelial inflammasomes. In a 2023 Seminars in Immunology study, the researchers activated the NAIP and NLRC4 inflammasomes to kick-start removing infected intestinal epithelial cells. A critical finding was that NAIP and NLRC4 removal could happen without gasdermin proteins present.¹¹

Overall, the study discovered how the inflammasome responses safeguarded the mice against enteropathogenic bacteria. The researchers found that the NAIP and NLRC4 defense might be enough to protect the rodent subjects from any Shigella enteropathy. However, more examinations are necessary to determine the effectiveness of Shigella flexneri infections, especially after six days.¹¹

3. Guinea Pigs

In addition to mice, guinea pigs have evolved to be critical elements of Shigella research. These rodents can exhibit similar symptoms of the infection, thus lending more value in trials. Past studies have found colon infections and other potent responses to a Shigella infection. Building on this research, a 2023 Gut Microbes study examined shigellosis progression in guinea pigs.¹²

The France-based scientists assigned the animals a low-ascorbate diet to lower their vitamin C levels. By reducing this nutrient, the researchers wanted to see how it would affect the progression of a Shigella infection. The results demonstrated increased severity in the shigellosis infection with each strand, thus providing insight into immune responses.¹²

Late time points were integral to this animal model, as they demonstrated late arrivals of neutrophils within the colonic mucosa. However, the Shigella infection had already penetrated the bloodstream and the organ. The vitamin C deficiency caused the Shigella to penetrate deeper. Now, scientists have more information about the development of Shigella infection mechanisms in humans.¹²

4. Mice, Guinea Pig, and Rabbit Vaccines

Sometimes, researchers use mice, guinea pigs, and rabbits to increase confidence in their findings and understand critical differences. If a vaccine is successful for each animal, these scientists can consider a human trial to examine the effectiveness further. A 2023 Vaccines study introduced a multivalent vaccine with positive results in their animal models.¹³

The Russia-based study focused on tri-acylated S. flexneri 2a lipopolysaccharide (Ac3-S-LPS) and its clinical effectiveness. After molecular and antigenic characterizations, the researchers found no adverse effects in the rabbits after subcutaneous administration. There were no pyrogenic or toxicity issues after extra PLVF administration, and the study concluded the safety and efficacy of the combined vaccine.¹³ 

This study challenged the Shigella flexneri serotypes in the guinea pigs and mice. For the mice, the administered antibody killed between 35% and 66% of the bacteria. The guinea pig model was even more effective, as the efficacy increased to a range of 50% and 75%. With these promising results, the next step could be expanding vaccine construction to other serotypes of gram-negative bacteria.¹³

Developing Shigella Infection Mechanisms in Humans

A Shigella infection typically doesn’t threaten your life. However, experts are increasingly concerned about the bacteria’s ability to resist drugs.¹⁴

Therefore, researchers must develop technologies and vaccines to aid human health. So far, scientists have used bacterial genome sequencing, organ-on-chip models, and other solutions to advance research. Animal models have demonstrated promise through safe and effective vaccination results. 

Sources:

1. Centers for Disease Control. About Shigella Infection.
2. Government of Canada. Shigella spp.: Infectious substances pathogen safety data sheet.
3. Mayo Clinic. Shigella infection.
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5. Yassine I, Lefèvre S, Hansen EE, et al. Population structure analysis and laboratory monitoring of Shigella by core-genome multilocus sequence typing. Nat Commun. 2022;13:551. https://doi.org/10.1038/s41467-022-28121-1
6. López-Jiménez A, et al. High-content high-resolution microscopy and deep learning assisted analysis reveals host and bacterial heterogeneity during Shigella infection. bioRvix. https://doi.org/10.1101/2024.03.06.583762
7. Mancini F, et al. GMMA-Based Vaccines: The Known and The Unknown. Front Immunol. 2021;12:715393. doi: 10.3389/fimmu.2021.715393
8. Frenck Jr R, et al. Efficacy, safety, and immunogenicity of the Shigella sonnei 1790GAHB GMMA candidate vaccine: Results from a phase 2b randomized, placebo-controlled challenge study in adults. eClinicalMedicine. 2021. 13;39:101076. doi: 10.1016
9. Applied BioCode. Common Gastrointestinal Infections.
10.  Gomes M, et al. Shigella induces epigenetic reprogramming of zebrafish neutrophils. Science Advances. 2023;9(36). doi: 10.1126/sciadv.adf9706
11. Gül E, et al. Epithelial inflammasomes, gasdermins, and mucosal inflammation – Lessons from Salmonella and Shigella infected mice. Seminars in Immunology. 2023;70:101812. https://doi.org/10.1016/j.smim.2023.101812
12. Skerniskyte, et al. Ascorbate deficiency increases progression of shigellosis in guinea pigs and mice infection models. Gut Microbes. 2023;15(2). https://doi.org/10.1080/19490976.2023.2271597
13. Ledov V, et al. A Pentavalent Shigella flexneri LPS-Based Vaccine Candidate Is Safe and Immunogenic in Animal Models. Vaccines. 2023;11(2):345. https://doi.org/10.3390/vaccines11020345
14. University of Florida Emerging Pathogens Institute. Extensively drug-resistant Shigella infections are increasing. Here’s what you need to know.