"Ready or Not, Here I Come!" How Shigella flexneri Hides in our Bodies

            Dysentery is a GI disease with which not many in the industrialized world are familiar, but which posed a severe problem only a hundred years ago and still causes serious illness and death in the developing world. The bacterium that causes dysentery is called Shigella flexneri, which infects the mucosal surfaces of the colon and rectum. Shigella is a gram-negative, intracellular bacterium. This means that it has a cell membrane but no cell wall, and that when it infects a host it establishes itself and replicates inside the cell rather than in the spaces and fluid between cells. Intracellular bacteria can often be more difficult for the immune system to find, especially if they have ways to make a cell look healthy instead of showing the danger signs of infection.

            The innate immune system, or first responder to any infection of your body by a foreign pathogen, is not specific to particular pathogens and relies generally on compounds that are part of bacteria, viruses, or fungi, but are not present in humans¹. A distinguishing characteristic of gram-negative bacteria like Shigella is a compound called lipopolysaccharide, or LPS. LPS is a component of the bacterial cell membrane, and is highly toxic when separated from the membrane². LPS is strongly recognized by the innate immune system as a danger signal, also known as a pathogen-associated molecular pattern (PAMP)¹. LPS is made of a lipid called Lipid A, an oligosaccharide (a type of sugar polymer), and the O-polysaccharide, another sugar located on the bacterial surface³. Immune cells recognize the Lipid A part of bacterial LPS, and this causes the release of certain small molecules called cytokines. The specific cytokines released, particularly IL-1ß , TNF-alpha, IL-18, cause inflammation, which helps alert the rest of the immune system to start combating the infection, but also causes many of the symptoms associated with bacillary dysentery³.

1. Diagram of bacterial LPS

Prion Diseases: Are Researchers Finally Close to Uncovering a Cure?

Prion diseases are no laughing matter, although it might have seemed that way if you were a visitor on the island of Papua New Guinea in the 1950’s. It was here that members of the Fore tribe were suffering from what they had dubbed the “laughing sickness” due to the strange uncontrollable bursts of laughter that accompanied the debilitating shivering that struck it’s victims. The source of the disease, which came to be known as kuru, was found to be transmitted through ingestion of brain tissue during cannibalistic burial ceremonies. Ingestion of the diseased victims brain tissues exposed tribe members to a structurally altered form of the normally expressed cellular prion protein (PrP) which could react with healthy forms of the proteins in their brains, perpetuating further structural transformations.

There are a number of diseases spread in this manner, termed transmissible spongiform encephalopathies (TSE). All TSE's, which include the well-known mad cow disease (Creutzfeldt-Jakob disease), are inevitably fatal and lead to neurodegeneration, often mediated through pathologic neuroinflammation. The inflammation seems to be primarily due to the robust activation of microglial cells (Yang et al., 2008). Microglial cells are akin to the brain’s garbage trucks, constantly collecting cellular debris from the extracellular environment. This behavior coincidentally makes them especially fit for detecting the presence of extracellular pathogens as well.

Before a cure can be developed, researchers must first uncover the cellular mechanisms underlying the microglial-medated pathologic neuroinflammation observed in the victims of TSE. PrP106-126 is the region of the PrP protein that has been shown to mediate inflammatory and pathologic signaling following structural alteration. A recent study was able to use this peptide to identify many of the proteins and signaling molecules, thus potentially uncovering future targets for pharmaceutical therapies.