Solving the Puzzle of the Super Bug

Solving the Puzzle of the Super Bug

"We have applied the latest genome sequencing technology to show that Staph can readily become vancomycin (antibiotic) resistant by acquiring a single mutation in its DNA. When the bacteria mutate, they are reprogramming themselves, changing their cell walls to resist the action of our antibiotics"-Dr. Stinear.

 

                The treatment of mild to serious infections from Staphylococcus aureus (Golden Staph) is severely hindered by the development of antibiotic resistance. This antimicrobial resistance is a major public health threat which is further worsened by the development of strains of Staph bacteria with resistance to strong antibiotics such as vancomycin and daptomycin, which are considered last line antimicrobials. Patients in hospitals are more susceptible to staph infections because their immune systems are already compromised.  In hospitals around the world, infections with methicillin-resistant Staph aureus (MRSA) continue to cause a significant number of unnecessary deaths.  Therefore developing treatments to fight staph resistant strains as well as reduce the number of cases in hospitals is a major topic of study.  Recently research has added a new piece to the puzzle of elucidating the mechanism by which Staph evades the immune response to develop resistance to these last-line antibiotics.  

Frighteningly so, a small number of clones of staph account for the large number of hospital acquired infections.  In Australia, multi-locus sequence type (MLST) 239 termed ST239 comprises the major clone MRSA and has been infecting patients for over 30 years.  Unfortunately this clone is resistant to almost all antibiotic types therefore the current treatment for such an infection is the strong antibiotic vancomycin. Generally speaking, vancomycin is only prescribed after treatment with other antibiotics has failed; therefore it is administered as a last resort. However, recently strains have evolved to develop a low resistance to this antibiotic as well.  These strains partially resistant to vancomycin are named vancomycin-intermediate S. aureus (VISA).  The genetics of these strains that enable them to resist vancomycin antibiotics are the topic of a recently published study in the journal PLoS Pathogens titled Evolution of Multidrug Resistance during Staphylococcus aureus Infection Involves Mutation of the Essential Two Component Regulator WalkR.

LAG3 Gene and Early Onset of Type 1 Diabetes

The lymphocyte activation gene-3, LAG3, is a significant regulator of the immune system and recently has been concretely attributed to development in Type 1 Diabetes in diabetes prone mice. Type 1 Diabetes is an autoimmune disease in which cells of the body are mistaken as pathogens and destroyed by the immune system. In Type 1 Diabetes, the cells that are destroyed are the insulin-producing beta cells. This disease is generally characterized by insulitis and beta-cell autoantibodies (Van den Driessche et. al, 2009).

LAG3 may be responsible for the malfunctioning of the immune system and the onset of Type 1 Diabetes. LAG3 plays a large part in regulating T cells, which are critical to fighting infections and diseases. LAG3 both regulates the numbers of T cells in the body and is required for the proper functioning of T cells and Natural Killer cells (Workman et. al, 2009). Moreover, many critical cell types in the immune system express LAG3, including CD4⁺ and CD8⁺ T cells, natural killer cells, and plasmacytoid dendritic cells (Workman et. al, 2009). These cells each play important functions in detecting pathogens throughout the body and carrying out the removal of harmful entities.

Lag3 deletion in normal mice has been documented to have minor noticeable changes, with little to no effect on the prevalence of diabetes development (Miyazaki et. al, 1996). However, it has been recently demonstrated that in autoimmune-prone conditions, LAG3 plays a critical role in an early onset of Type 1 Diabetes (Bettini et. al, 2011).

Bettini et. al used non-obese diabetic mice, or NOD mice, to test the control of LAG3 on three important types of cells in the immune system: T cells, natural killer cells and plasmacytoid dendritic cells (2011). NOD mice were the subjects of choice, for they are often used as a mouse model of Type 1 Diabetes (Crawford et al., 2011). Bettini et. al bred NOD mice with a Lag3 mutation, rendering the gene non-functional. The mice were then tested for diabetes onset at various points of development by analysis of urine samples and blood glucose levels.

IRF-1 is Essential for Immunity Against West Nile Virus Infection in Mice

The West Nile Virus (WNV) is spread via mosquitoes and has been affecting humans in the United States since 1999 (1). Current research by immunologist further dissects antiviral immunity, in hopes of understanding WNV infectivity and how it can be combated or prevented. Previous research in mice has identified several immune mechanisms of control against WNV including cytokines, chemokines, complement, B CD4+ and CD8+ T cells (reviewed in [1]). These are all various aspects of the innate and adaptive immune system that aid in fighting against pathogens. More specifically, type 1 IFN (IFN-αβ) has been given special attention, as mice deficient in it, rapidly succumb to WNV infection (2). Further, it was determined that IFN induction is dependent on certain transcriptional signals. Past research pointed Brien et al. (2011) in the direction of IRF-1, as it has been reported to contribute to IFN-β induction. For example, it was found that IRF-1 transcription factor activated IFN-β gene transcription and regulated genes that directly impeded replication of several viruses. Further roles of IRF-1 have been found in controlling herpes virus, even though mice lacking IRF-1 did not have defects in their type I IFN response. This would suggest that IRF-1 regulates IFN genes “in a pathogen and cell type-dependent manner” (1). Further research has also identified IRF-1 as a tumor suppressing gene and a regulator of the adaptive immune response (3).
To understand the role of IRF-1, Brien et al. (2011) assessed WNF infectivity in IRF-1 normal and IRF-1 deficient mice (1). As previously mentioned, they chose to manipulate IRF-1 because mice lacking it (IRF-1-/- ) were vulnerable to WNV infection. First, it was confirmed that IRF-1 is required for control of lethal WNV infection. After infection with WNV, Wild-type (WT) mice had a 65% survival rate and a mean time to death of 11 days, whereas IRF-1-/- mice had a 0% survival rate and a mean time to death of 9.5 days.
To better understand how IRF-1 deficiency is a disadvantage for mice with WNV infection, the ‘viral burden’ was measured at various points post infection in serum, several peripheral organs, and the central nervous system (CNS). Indeed, increased levels of viral RNA were found in the serum and lymph nodes in IRF-1-/- mice compared to the WT. Therefore, IRF-1 controls the early stages of WNV infection. Additionally, WNV infected the spleen more rapidly and clearance was delayed in IRF-1-/- mice. WNV was also detected sooner in the kidneys of IRF-1-/- mice, further suggesting that IRF-1 normally functions to control infection in peripheral tissues.

Bye-Bye B Cells, Hello MS Treatment

Multiple sclerosis is a chronic inflammatory disease that affects the brain and spinal cord, or central nervous system (CNS), leading to sensory and motor impairments. MS is more common in women than in men and is typically diagnosed between the ages of 20 and 40. Approximately 400,000 individuals in the United States currently have MS and more than 2.1 million people worldwide live with the disease. MS is diagnosed as one of two forms, either relapsing-remitting (RRMS) or primary progressive (PPMS). The vast majority of patients are initially diagnosed with RRMS, which is characterized by periods of exacerbation, or flare-ups, followed by periods of remission. Patients with PPMS do not experience remissive phases. Most of the medications approved for MS treatment are aimed toward ameliorating the relapsing-remitting disease course. Currently, MS is commonly treated with an interferon beta (IFN beta) drug, which reduces disease activity, in combination with other medications that target the various symptoms experienced by patients (2).

The clinical presentation of MS varies from person to person; however, pathologically, the disease results from an autoimmune attack on myelin sheath (a protective covering around nerve fibers). Immune cells (lymphocytes) become self-reactive against certain proteins that make up myelin and subsequently destroy it. This process is called demyelination. When the myelin sheath is damaged, signaling between nerve cells becomes slowed or prevented altogether. As a result, simple tasks like walking become quite difficult, and patients may experience vision impairments, episodes of numbness and tingling, loss of balance and coordination, as well as other symptoms. Unfortunately, the mechanism through which an individual develops MS is not entirely understood, and therefore, the repertoire of treatment targets is limited. In order to gain a better understanding of the cause and progression of MS, researchers use various animal models of the disease. The most commonly used MS model is experimental autoimmune encephalomyelitis (EAE), which can be induced in a variety of animal species including certain rodents and non-human primates. In the upcoming November issue of the Journal of Neuropathology and Experimental Neurology, a study by Kap and colleagues investigates whether or not B cell depletion (an experimental treatment for MS) is a valid therapeutic target (1). The authors employed an EAE study in the common marmoset (monkey species). Marmosets were first utilized to examine the clinical and pathological features of MS in 1996, and have been found to exhibit a disease course more closely related to human MS than that observed in rodent models. The marmoset EAE model demonstrates widespread demyelination in both white matter and grey matter of the CNS, strongly resembling the conditions of MS in humans. Furthermore, marmosets have similar immune and nervous system genes to humans, establishing another advantage of using this model (3).

A Mechanism for Low Zone Tolerance and Implications for Allergies

Allergic reactions occur when the immune system reacts to an allergen found in the environment, promoting hypersensitivity towards the substance. These reactions are normally quite docile but can become very severe. These allergens can be quite common (such as peanuts, shellfish, gluten, etc.), raising the question: why do some people initiate an immune response to them and others don't? One answer is low zone tolerance (LZT), which involves the repeated exposure to small doses of an antigen. At the other end of the spectrum is high zone tolerance, occurring when individuals are exposed to a high dose of an antigen. LZT is believed to be one of the main routes by which tolerance to an antigen is developed. Failure to install LZT may be due to a high dose exposure during the first initial contact, leading to contact allergies (Luckey et al. 2011). Contact allergies are fairly prevalent in the population, affecting approximately 10% (Cavani et al. 2007). Therefore, allergies are just another example that bolsters the importance of immune tolerance. Autoimmunity is an additional example of when tolerance goes wrong, specifically when the immune system initiates an attack against itself.

Lucky et al. (2011) decided to examine the mechanism by which LZT is initiated, a process which is largely unknown. Previous research by Lucky's group determined that LZT is maintained by CD8+ suppressive T cells, a certain subset of T cells. These cells are induced to develop after stimulation by IL-10, a chemical messenger, which is secreted by helper T cells. The authors connected this information with another chemical messenger hypothesized to regulate the LZT response, Tumor Necrosis Factor (TNF). TNF is a cytokine messenger which is secreted as part of the immune response and has a myriad of functions from promoting inflammation and apoptosis to exerting immunosuppressive effects. TNF binds to two receptors TNFR1(p55) and TNFR2 (p75) (Locksley et al. 2001). These two different receptors are what give TNF such dual-sided functions.

Wandering between Two Worlds: A Closer Look at the Neuroimmune Communication

Do you pass out when you see blood? Have you ever been so emotionally shocked that the next thing you know, you are lying on the floor surrounded by people asking if you are all right? Fainting is a consequence of direct stimulation of the vagus nerve. This nerve is often termed, the “wandering” nerve, because as it leaves the brainstem, it “wanders” through organs in the neck, thorax, and abdomen. This means that the vagus nerve regulates various tasks such as heart rate, swallowing, speech, and breathing – tasks that are vital for our existence. Most of us likely know someone suffering from hypertension and the cardiac diseases associated with high blood pressure. However, low blood pressure can be as equally dangerous because it can lead to stimulation of the vagus nerve, which causes the blood flow to be redirected from the brain to the heart and the rest of the body. Such a temporary lack of blood flow and oxygen to the brain triggers vasovagal syncope, a fancy term for what we call fainting. During emotional shock, there is an increased stimulation of the vagus nerve, which in turn leads to slowing of the heart thereby causing a blood pressure drop and hence, fainting. Stimulation of the vagus nerve does not only result in fainting, but it also triggers vomiting. If you are an EMT, this is the reason why an oropharyngeal airway (OPA) must only be used on unconscious patients without a gag reflex. Insertion of the OPA in the back of the pharynx may stimulate the vagus nerve and result in vomiting, thereby presenting an airway obstruction.

This wandering nerve is not only involved in the physiological tasks that are vital for us, but it has also been implicated as an immunomediator thereby presenting a linkage between the nervous and the immune system. Research aimed towards understanding the mechanisms behind neuroimmune communication has been gaining popularity in recent years. For instance, receptors for the neurohormone, melatonin, a regulator of the circadian rhythm, has been found on human T cells, hence giving melatonin regulatory functions in the immune system as well (Lardone et al. 2011). Likewise, cytokines secreted by immune cells also control neural and glial activity in the brain such as neuroplasticity, a phenomenon that takes place during learning and memory where new neural synapses are formed or reorganized (Huh et al. 2000). Furthermore, major histocompatibility complex (MHC) proteins, which allow antigen presentation in the immune system, are also found in neurons (Trakhtenberg and Goldberg, 2011). If cytokines released by immune cells can regulate neuronal function, can other neurotransmitters released by neurons also regulate immune function?