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Category: Pathobiology

Rabies pathobiology and its RNA virus agent – Lyssavirus

Having a dog as a pet presents myriad of benefits. One of them is having a companion reputed for being charismatic and loyal. Dogs, apparently, render a “cure” when melancholy “strikes“. However, there are repercussions to avoid or deal with when handling a dog. One of the most important concerns when domesticating a dog is preventing dog bites. Getting bitten by a dog is, in fact, how microbes could find their way through the skin.  Dogs, inopportunely, can be agents of medically-important diseases like rabies.

dog rabies
Dog infected with rabies

Rabies transmission

Rabies is a viral disease that is almost always deadly. It can be acquired chiefly through a single bite by an infective dog. One could also get it when a broken skin is exposed to infected saliva. Other potential routes include eyes, mouth, and nose. Nonetheless, not all dogs carry the virus causing the disease. Also, dogs are not the only ones that can transmit rabies virus. Most warm-blooded vertebrates (e.g. monkeys, raccoons, cattle, cats, bats, etc.) can carry the virus and transmit it to a human host. The virus has further adapted, and hence, could grow as well as in cold-blooded vertebrates.[1] However, because of the widespread domestication of dogs in human households dogs have consequently incited most rabies cases in humans.[2]  

Lyssavirus – the viral agent

The virus of rabies disease is a Lyssavirus, a type of RNA virus belonging to the family Rhabdoviridae, order Mononegavirales. It has a bullet shape. It carries a single negative-strand RNA as its genome, enough to code for proteins[3] — namely, nucleoprotein, phosphoprotein, matrix protein, glycoprotein, and RNA polymerase — to establish within the host cell.

Lyssavirus rabies virus
A coloured transmission electron micrograph of Australian bat lyssavirus (finger-like projections and the one that bud off from a host cell). Credit: Electron Microscopy Unit AAHL, CSIRO, CC 3.0 Unported license

In particular, the virus makes its way inside the host cell (e.g. muscle cell or nerve cell) through receptor binding and membrane fusion by way of endosome using its glycoprotein G. The virus transcribes its genome by its polymerase inside the endosome. Then, it fuses to the endosome to release its newly transcribed proteins and RNA into the cytosol.

The matrix protein regulates both transcription and replication of the virus. From transcribing, the polymerase shifts into replicating its genome. The nucleoprotein tightly binds to the newly replicated genome, thus, forming ribonucleoprotein complex. This, in turn, can now form new viruses.[4]

The virus performs transcription and replication processes via a specialized inclusion body referred to as the Negri body. In fact, the presence of Negri bodies in the cytoplasm of the host cell indicates histological proof of Lyssavirus infection.

Rabies – two types

Early symptoms of rabies disease include fever, discomfort, and paraesthesia (burning sensation at the bite site). Eventually, the symptoms progress to behavioral changes when the virus spreads to the central nervous system.

Lyssavirus enters and hijacks muscle cells to replicate. From the muscle tissue, it travels to the nervous system through the neuromuscular junctions.[5] The virus enters the peripheral nervous system directly and then spreads to the central nervous system where it can cause fatal inflammation in the brain and spinal cord.

Depending on the symptoms, the rabies may be described as “furious” or “paralytic“. The furious rabies — the more common form (80% [5]) — is characterized by hyperactivity, confusion, abnormal behavior, paranoia, terror, hallucinations, and hydrophobia (“fear of water“). The paralytic rabies, as the name implies, causes paralysis starting from the site of bite (or entry). Both of these types may lead to coma and eventually to death of the patient. However, patients with the furious type have higher risks, due to the likely cardio-respiratory arrest.[2]  Without an early and a proper medical intervention, death may ensue typically two to ten days after these symptoms manifest.

Rabies – pathobiology

How rabies causes behavioural changes baffles scientists. In 1980s and 1990s, researchers explicated how the virus caused paralysis. Accordingly, the glycoprotein at the cell surface of the Lyssavirus competes against acetylcholine in terms of binding affinities to specific muscle receptors (e.g. nicotinic acetylcholine receptors).[6] Lately, researchers conjectured that the virus could also be doing the same with the similar receptors found in the brain. Furthermore, they presumed that the interaction could have affected how the brain cells normally communicate, and thereby induced changes in the behavior of the host.[6] 

Further research

Recently, researchers from the Ohio State University College of Medicine and The Ohio State University Wexner Medical Center conducted a study aimed at identifying dog breeds and physical traits that pose high risk of biting with severe injury.[7] Their data could provide empirical basis when deciding which dogs to own. Still, further studies on rabies are necessary since the disease is marked as fatal as soon as the clinical symptoms set in.[2]  Although vaccine-preventable, rabies, especially via a dog bite, remains a significant cause of annual deaths in humans, both young and old. Novel treatments and vaccines that are effective and economical could preclude death. At present, the staggering cost of treatment remains a major health-care restraint. Without the proper and early treatment, death from rabies, unfortunately, is almost always certain.

— written by Maria Victoria Gonzaga

References:

1 Campbell, J. B. & Charlton, K.M. (1988). Developments in Veterinary Virology: Rabies. Springer. p. 48. ISBN 978-0-89838-390-4.

2 World Health Organization (WHO). (2019, May 21). Rabies. Retrieved from Who.int website: [Link]

3  Finke, S. & Conzelmann, K. K. (August 2005). “Replication strategies of rabies virus”. Virus Res111 (2): 120–131. doi:10.1016/j.virusres.2005.04.004  

4 Albertini, A. A., Schoehn, G., Weissenhorn, W., & Ruigrok, R. W. (January 2008). “Structural aspects of rabies virus replication”. Cell. Mol. Life Sci65 (2): 282–294. doi:10.1007/s00018-007-7298-1

5 Newman, T. (2017, November 15). Rabies: Symptoms, causes, treatment, and prevention. Retrieved May 23, 2019, from Medical News Today website: https://www.medicalnewstoday.com/articles/181980.php

6 University of Alaska Fairbanks. (2017, October 11). How rabies can induce frenzied behavior: Researchers better understand the disease that kills 59,000 people annually. ScienceDaily. Retrieved from website: [Link]

7 The Ohio State University Wexner Medical Center. (2019, May 22). Study identifies dog breeds, physical traits that pose highest risk of biting children. ScienceDaily. Retrieved from website: [Link]

RASER proteins selectively “hack” and “shut down” cancer cells

According to World Health Organization, cancer is the second leading cause of death worldwide. The record showed that it caused about 9.6 million deaths last year (2018). Accordingly, one in every six deaths is attributed to cancer.[1]

Cancer defined

Cancer refers to the disease that arises from the faulty uncontrolled proliferation of cell, usually at a rate faster than the normal, and spread to other parts of the body. Benign tumors are also a form of atypical cell proliferation. However, the latter does not spread.

Pathophysiology in cancer cells

Why cancer cells lead to a disease is largely due to the tendency of the cancerous cell to detach and leave its original location to set itself to another site in the body. It could spread locally or drift through the bloodstream and lymphatic system to reach distant parts of the body. As a result, the affected body part eventually cannot carry out its function as it normally would due to the obstructing cancer cells that ought not to be there in the first place. Under those circumstances, our immune system is fashioned to detect cells that have gone “rogue” and then respond by eliminating them accordingly. Nevertheless, cancer cells tend to undergo series of mutations until such time that the genes for tumor suppression have been significantly inactivated while the proto-oncogenes modify into oncogenes.

RASER proteins

A novel approach dubbed as RASER (Rewiring of Aberrant Signaling to Effector Release) showed promising results when it killed cancer cells grown in the lab while sparing non-cancerous healthy cells. Researchers from Stanford Medicine[2] designed RASER system, which, in essence, consists of two proteins fused together. Accordingly, the first protein responds to cancer-causing cell surface signals. It does so by binding to active ErbB receptors, which are always “on” (expressed) in cancer cells. The second protein redirects the cancer cell from cell growth and survival toward programmed cell death (by releasing a customizable “cargo” into the cell). When the first protein binds to an active ErbB receptor, the second protein component is cut off from the RASER moiety and then binds to the inner surface of the plasma membrane of the targeted cell. The researchers customized the “cargo” sequence that the second protein carries. Once inside the cell, the second protein releases the RASER “cargo” — in this case, one that triggers the cell to undergo cell death.[2]


Top:  Illustration of cancer growth where cell surface proteins signal the nucleus to proliferate uncontrollably and survive (see green pathway). Bottom: Illustration of how RASER works by redirecting the signal away from cell proliferation and survival toward programmed cell death (see orange pathway). Image credit: Michael Lin and Stuart Jantzen (Ref.2)

One of the researchers, Michael Lin, MD, PhD, said that with this new approach they could rewire cancer cells and bring about an outcome according to their choosing. Furthermore, he said, “We’ve always searched for a way to kill cancer cells but not normal cells. Cancer cells arise from faulty signals that allow them to grow inappropriately, so we’ve hacked into cancer cells to redirect these faulty signals to something useful.” [2]

Although it could take time, still, the conception and the future progress of RASER is an auspicious cancer treatment. In due course, cancer patients may reap from its stance of being more highly selective to cancer cells while sparing the healthy ones in which the current cancer treatments are failing at.

— written by Maria Victoria Gonzaga

References:

1 World Health Organization (WHO). (2018, September 12). Cancer. Retrieved from Who.int website: [Link]

 2 Conger, K. (2019). Synthetic biology used to target cancer cells while sparing healthy tissue. Retrieved from News Center website: [Link]

Measles vaccine hesitancy leads to outbreaks, deaths of unvaccinated

Many people are afraid of getting measles vaccine these days. The fear arises from the allegedly adverse effects of it, such as autism. However, this fear comes along with the resurgence of the dreaded measles outbreak. Consequently, measles once again takes many lives, especially of the children, who ought not die from such a preventable disease.

 

 

 

Measles vaccine being linked to autism

In 1998, a team of scientists headed by Andrew Wakefield published a paper in refutable science journals. Accordingly, MMR vaccine — a cocktail of vaccine that protects against measles, mumps, and rubella— seems to have a causal link to autism in children.[1] He and his colleagues reported twelve children that displayed delay in growth development; eight of them had autism a month following MMR vaccine. However, the paper was later retracted. Accordingly, “several elements” of a 1998 paper Lancet1998;351[9103]:637–41 “are incorrect, contrary to the findings of an earlier investigation”[2]. The retraction clearly indicated data misconception. However, that did not end there. Wakefield and his team published yet another study. Again, they implicated measles virus to autism.

 

 

 

Second study, still questionable

In 2002, Wakefield and his team biopsied samples from the intestines of two groups of children: with autism and control (without autism). They tested the presence of measles virus genome via reverse-transcriptase PCR and in situ hybridization. They reported 75 of 91 children with autism tested positive for measles virus genome. In the control group, only five of 70 were positive.[3]  Accordingly, their findings corresponded to their earlier conjecture linking measles virus to autism in children. However, critics still found critical flaws.[4] For instance, the authors failed to stipulate with proof the origin of the measles virus genome in the patients — whether from nature or from the vaccine.

 

 

 

Studies refuting the link

Two independent large-scale studies (one in California, USA and another in England, UK) denied the link between MMR vaccine and autism. Truly, the number of children with autism dramatically increased. However, the percentage of children receiving MMR vaccine remained constant. The empirical data on a larger scale of population indicated the absence of causal relationship between measles vaccine and autism.[4]

 

 

 

Impact

The side effects associated with MMR vaccine are mild symptoms of measles, mumps, and rubella. And not all children administered with it will show symptoms. As for measles, the common symptoms include swelling and redness at the site of injection, fever, and rash. Rare symptoms include anaphylaxis, bruise-like spots, and fits.[5] No categorical study has fully established that MMR vaccine causes autism in children. Nevertheless, many people remain hesitant despite the many years of proven efficacy of measles vaccine. Their worries were aggravated by the likes of Wakefield studies linking MMR vaccine to autism in children.

 

Dubbed as anti-vaxxers, these people utterly lost their confidence on vaccines so much that they secluded and kept their children from getting vaccinated. The main reason arises from their fear that vaccines would cause more harm than good. Some of them even took a legal step against vaccine manufacturers for allegedly having identified the culprit of their child’s developmental delay. And despite the disavowal of Wakefield’s paper and having been repudiated by ensuing studies dissociating autism from MMR vaccine, many people including autism advocacy groups have not abandoned their skepticism. Some of them even came up with a “conspiracy theory” that vaccine manufacturers may be conspired into hiding the “truth”, i.e. MMR vaccine causes autism.[2]

 

 

 

Pathobiology of measles

The genus Morbillivirus, a single-stranded, negative-sense RNA virus, is the causative agent of measles, the highly contagious airborne disease. Humans are the only known host of the virus. The video below describes how the measles virus infects the host cell.

 

[Video credit: Folks from Osmosis, Doc James; Source: Wikipedia, CC-BY-SA 4.0 ]

 

In summary,  the virus infects the epithelial cells lining the trachea or the bronchi upon reaching the mucosa. The virus gains entry into the host cell via its surface protein, hemagglutinin (H protein). The H-protein binds to the receptor (e.g. CD46, CD150, or nectin-4) on the surface of the target host cell. After binding, the virus fuses with the cell membrane to get inside the cell. Then, it makes use of the cell’s RNA polymerase to transcribe its RNA into mRNA strand. After which, the mRNA is translated into viral proteins in which the host cell’s lipid will envelope them for their subsequent release outside the cell. They spread to lymph nodes,  and then to other tissues (e.g. brain and intestines).[6] Soon, the disease manifests as fever, cough, runny nose, inflamed eyes, and rash. Common complications include pneumonia, seizures, encephalitis, and subacute sclerosing panencephalitis.

 

 

 

Measles vaccine

 

measles-vaccine
A child getting measles vaccine during the launch of a campaign to immunize children at the Beerta Muuri Camp for internally displaced persons in Baidoa, Somalia on April 24, 2017.

[Credit: UN Photo. Credit: UNSOM Somalia, Flickr]

 

The vaccine that prevented the disease was first made available in 1963. It may be administered solely or in combinations, like in MMR vaccine. MMR vaccine renders protection against measles, mumps, and rubella viruses. The World Health Organization (WHO) recommends that measles vaccine be administered to infants at nine or twelve months of age. A person needs only two doses during childhood for lifelong immunity.

 

 

 

How vaccines work

Measles vaccine contains live but weakened strain of measles virus. Vaccines work by triggering an immune response from the white blood cells. These cells recognize them through the surface proteins of the virus. White blood cells, such as B cells, produce multifarious antibodies. One of the antibodies can fit to the surface protein. This will trigger the B cell to produce clones, called memory B cells, which, in turn, will produce large amounts of antibodies specific to the identified pathogen.

 

A re-encounter with the virus having the same surface protein would enable the antibodies to respond quickly by binding with and disabling the virus. They can also make it “palatable” to macrophages and other phagocytic cells that engulf and kill pathogens. How come the measles vaccine remain effective for so many years? The surface proteins of the measles virus are not prone to changes as presumed, and any mutation on them may render them dysfunctional.[7] Thus,  the immune system will always recognize the measles virus. And the immune response would be so quick that most of the time the vaccinated individual would no longer be ill.

 

 

Herd immunity

One of the benefits of a rabid immunization program is that the immune protection extends to those who have not received the vaccine yet. Referred to as herd immunity, the community becomes protected from measles when a huge percentage of the population got the vaccine. In a study published in the journal Frontiers in Public Health, measles vaccination in a sequence recommended by WHO apparently helped reduce child mortality.[8] But in order to prevent and ultimately eliminate measles, WHO seeks global immunization coverage of at least 95%.[9]

 

 

 

Recent measles outbreak

 

measles
The Philippines, especially the NCR, currently experiences a large measles outbreak. CDC’s Jim Goodson took this photo of a child stricken with the disease during his visit in Manila to respond to the outbreak.

[Credit: CDC Global, Flicker, CC BY-SA 2.0]

 

Failure to reach the idyllic 95% global coverage leads to the inevitable measles outbreak. For several years, global coverage with the first dose of measles vaccine has stood at only 85% whereas the second dose, at 67%. Thus, measles outbreaks occurred in all regions with over a hundred thousands of fatalities mainly due to serious complications. In 2000, about 21 millions of lives have been saved due to measles vaccine. However, measles cases around the globe surged by more than 30% from 2016.[9]

 

Dr. Seth Berkley of Gavi, the Vaccine Alliance, elucidated the reasons of the alarming resurgence of measles of recent. He said, “Complacency about the disease and the spread of falsehoods about the vaccine in Europe, a collapsing health system in Venezuela and pockets of fragility and low immunization coverage in Africa are combining to bring about a global resurgence of measles after years of progress. Existing strategies need to change: more effort needs to go into increasing routine immunization coverage and strengthening health systems. Otherwise we will continue chasing one outbreak after another.”[9]

 

 

 

Concluding remarks

Measles vaccine has indubitably protected millions of lives. However, because of the escalating apprehensions and the reluctance towards measles vaccination, we fell short from achieving the goal of eliminating the disease. If only we could stick by the goal and support local immunization program efforts, we might have already won it over once and for all.  Measles is a preventable disease and measles vaccine has already been tried and tested for over so many years. I hope it would not reach to the point whereby an immunization mandate would be the inevitable recourse when in essence we can simply heed the call.

 

 

 

— written by Maria Victoria Gonzaga

 

 

References:

 

1 Wakefield, A.J., Murch, S.H., Anthony, A., et al. (1998). Ileal-lymphoid-nodular hyperplasia, nonspecific colitis, and pervasive developmental disorder in children. Lancet, 351: 637-641.

2  Eggertson, L. (2010). Lancet retracts 12-year-old article linking autism to MMR vaccines. Canadian Medical Association Journal182(4), E199–E200. [Link]

3 Uhlmann, V., et al. Potential viral pathogenic mechanism for new variant inflammatory bowel disease. Journal of Clinical Pathology: Molecular Pathology 55:1-6, 2002. [Link]

4 Offit, P.A. (n.d.). Vaccines and Autism. [PDF]

5 NHS Choices. (2019). Vaccinations. Retrieved from [Link]

6 Moss, W.J. & Griffin, D.E. (14 January 2012). “Measles”. Lancet379 (9811): 153–64. [doi:Link]

7 Cell Press. (2015, May 21). Why you need one vaccine for measles and many for the flu. ScienceDaily. Retrieved from [Link]

8 Frontiers. (2018, February 12). Measles vaccine increases child survival beyond protecting against measles: New study shows all-cause mortality is significantly lower when a child’s most recent immunization is a measles vaccine. ScienceDaily. Retrieved from [Link]

9 World Health Organization. (2018, November 29). Measles cases spike globally due to gaps in vaccination coverage. Retrieved from [Link]

Pathobiology of allergy and its most severe form, anaphylaxis

When allergy season looms, some people with serious hypersensitivity to allergens tend to be apprehensive of what may come. Some would rather stay indoors than risking the odds of sucking up triggers that could instigate severe allergic reactions. Apart from triggers from the environment, other common factors for allergy include food, medication, certain toxins, venom from insect stings or bites, stress, and heredity. How does an allergy manifest? Which cells are involved in forming an allergic reaction?

 

 

 

The immune system

allergy
How does an allergy occur? The pathobiological mechanism involves several white blood cells that play a role in mounting an allergic reaction.

 

The immune system protects the body from foreign substances (generally referred to as antigens) that could pose a threat to our well-being.  It prevents harmful bacteria, viruses, parasites, etc. from invading and causing harm. The white blood cells (also called leukocytes) constantly scout for antigens in order to destroy or disable them. The white blood cells include lymphocytes, neutrophils, basophils, eosinophils, monocytes, macrophages, mast cells, and dendritic cells.

 

 

 

Allergy – overview

 

allergy pathway
The allergy pathway.
Image (by Sari Sabban) distributed under the CC 3.0 Unported license.

 

An allergy is a state of hypersensitivity of the immune system in response to an allergen (i.e. a substance capable of inciting an allergic reaction). In this regard, several white blood cells play a role in mounting an allergic reaction.

In summary, the entry of an allergen into the body triggers an antigen-presenting cell, such as a dendritic cell. The dendritic cell takes up the allergen, process it, and then present its epitopes through its MHC II receptor on its cell surface. It, then, migrates to a nearby lymph node, waiting for a T lymphocyte to recognize it.

Upon recognition, the T lymphocyte may differentiate into a Th2 cell (type 2 helper T cells), which is capable of activating B lymphocyte. B lymphocyte, when activated, matures into a plasma cell that could synthesize and release IgE antibody in the bloodstream. Some of the circulating IgE may bind to mast cell and basophil. Thus, re-entry of such allergen could incite the IgE on mast cells and basophils to recognize its epitope. In effect, this activates the mast cell or basophil to release inflammatory substances (e.g. histamine, cytokines, proteases, chemotactic factors) into the bloodstream.

 

 

 

Anaphylaxis – a dreadful allergic reaction

The allergic reaction mounted by the immune system is supposed to protect the body. However, the allergens perceived by the body as a threat are generally harmless. The body tends to overly react to the allergens, and so leads to symptoms. Histamine, for instance, brings about the common symptoms of allergy: pain, heat, swelling, erythema, and itchiness.

 

Anaphylaxis is the most severe form of allergic reaction. It can occur rapidly and it affects more than one body system, such as respiratory, cardiovascular, cutaneous, and gastrointestinal systems. It occurs as a result of the release of inflammatory substances from mast cells and basophils upon exposure to an allergen. Within minutes to an hour, symptoms could manifest as a red rash, swelling, wheezing, lowered blood pressure, and in severe cases, anaphylactic shock.

 

In the presence of breathing difficulties, racing heart, weak pulse, and/or a change in voice, the situation is precarious. It calls for an immediate medical attention.

 

Why does anaphylaxis occur? IgE-mediated anaphylaxis is the common form of anaphylaxis. Initial exposure to an allergen leads to the release of IgE so that re-exposure to the allergen leads to its identification and the eventual activation of mast cells and basophils.  Apart from immunologic factors, though, other causes of anaphylaxis are non-immunologic. For example, temperature (hot or cold), exercise, and vibration may cause anaphylaxis. In this case, IgE is not involved. Rather, these agents directly cause the mast cells and the basophils to degranulate.

 

 

 

Novel mechanism identified

Recently, a team of researchers1,2 found a novel mechanism that could explicate the hasty allergic reaction during anaphylaxis. They were first to uncover a mechanism involving the dendritic cells. Accordingly, a set of dendritic cells seem to “fish” allergens from the blood vessel using their dendrites. The dendritic cell near the blood vessel takes up the blood-borne allergen. Rather than initially processing it, and then presenting the epitope on its surface, it hands over the allergen inside a micro-vesicle to the adjacent mast cells.

 

Mast cells, unlike basophils that are in the bloodstream, are located in tissues, such as connective tissue. Thus, the question as to how the mast cells detect blood-borne allergen could be answered by the recent findings.

 

Rather than being internalized by the dendritic cells for processing, the allergen was merely taken into a micro-vesicle that budded off from the surface of dendritic cells. This, thus, saves time. It cuts the process, leading to a much rapid allergic reaction.

 

However, these findings were observed in mouse models. Therefore, the researchers have yet to observe if this novel mechanism also holds true on humans. If so, this could lead to possible therapeutic regulation of allergies, especially the most dreadful form, anaphylaxis.

 

 

— written by Maria Victoria Gonzaga

 

 

References:

1 Choi, H.W., Suwanpradid, J. Il, Kim, H., Staats, H. F., Haniffa, M., MacLeod, A.S., & Abraham, S. N.. (2018). Perivascular dendritic cells elicit anaphylaxis by relaying allergens to mast cells via microvesiclesScience 362 (6415): eaao0666 DOI: 1126/science.aao0666
2 Duke University Medical Center. (2018, November 8). Using mice, researchers identify how allergic shock occurs so quickly: A newly identified immune cell mines the blood for allergens to directly trigger inflammation. ScienceDaily. Retrieved November 22, 2018 from www.sciencedaily.com/releases/2018/11/181108142440.htm

 

First Video Proof That Could Explain Antibiotic-Resistant Superbug Bacteria

Amidst the battle for supremacy, our army of immune cells relentlessly wages war against various pathogens, especially superbug bacteria. Despite the pool of ample winnings, our body still experiences defeat from time to time. We succumb to diseases as the war reels its favor towards the tenacious pathogens. Of course, we cannot allow our immune defense to be utterly defeated. Otherwise, we’d be dead. As bacteria advance by taking over much space and nutrients inside our body, we get external help through antimicrobial chemicals that scientists continue to contrive.  Unfortunately, antibiotic resistance has surfaced and turned certain strains of bacteria into a superbug – one that has become resistant to the effects of antibiotics.

 

 

 

Chemical warfare prior to the rise of a superbug

Antimicrobial chemicals, particularly antibiotics, came into existence as chemicals that were strategically designed and produced with the intent of killing pesky bacteria. In 1928, penicillin was discovered, which led to its use as the first natural antibiotic capable of undermining a spectrum of bacteria, if not by killing, by inhibiting their growth. Its role as a wonder drug against various bacteria caused Alexander Fleming to receive a duly recognition by winning a Nobel prize award for its discovery. Soon, more antibacterial agents came up to our defense. Antibiotics, such as penicillin and cephalosporin, destroy bacterial cell wall whereas polymyxins target bacterial cell membrane. Rifamycin, quinolones, sulfonamides, and the likes interfere with the enzymes essential to bacteria. Once again, we gained an upper hand.

 

 

 

Bacteria resisting: the rise of a superbug

A Scanning Electron Microscope (SEM) image of cells of the bacteria Vibrio tasmaniensis(Credit: Lewis Lab at Northeastern University. Image created by Anthony D’Onofrio, William H. Fowle, Eric J. Stewart and Kim Lewis)

 

While we thought we finally came up with a powerful weapon, the bacteria conjured up an amazing strategy to work in their favour — antibiotic resistance. Some of them started to morph. They evolved and mutated into new strains referred to as superbug. They became capable of resisting the drugs’ antimicrobial effects. One of their strategies is to produce β-lactamases that destroy the structure of β-lactam antibiotics (e.g. penicillin and cephalosporin). The bacteria that evolved into superbug organisms did not just live; they thrived. They multiplied and passed on to the next generation the features that could withstand a number of antibiotics.

 

 

 

DNA uptake by superbug bacteria

Apart from the vertical gene transfer of genes, antibiotic resistance could also be transferred through horizontal gene transfer. It is a mechanism whereby genes are taken up or transposed from one species to another, and one of the possible explanations for the rise of superbug bacteria. DNA uptake by a bacterial cell was captured for the first time in a video by a team of scientists from Indiana University. In the video1, it shows how a bacterial cell takes up DNA fragments from dead bacterial cells through its pilus. Like a harpoon, the pilus was used by the bacterium, Vibrio cholera, to catch and reel a stray DNA fragment, and then bring it inside the bacterial cell via the same pore on its cell wall. It, then, incorporates the DNA into its own genome. Accordingly, this is probably one of the mechanisms for a bacterium to turn into a superbug.

First video evidence of DNA uptake by Vibrio cholera.
(Video credit: Ankur Dalia, Indiana University, uploaded on YouTube by Group IU Biology News)

 

A researcher from the team, Courtney Ellison, recounted, “The size of the hole in the outer membrane is almost the exact width of a DNA helix bent in half… If there weren’t a pilus to guide it, the chance the DNA would hit the pore at just the right angle to pass into the cell is basically zero.” It appears that the pilus takes a crucial role in horizontal gene transfer. If left to chance the DNA fragment would not easily get inside the cell since the pore was too small for it to fit. Through horizontal gene transfer, those that were once sensitive to the antibiotic could later become superbug bacteria as well. As Ankur Dalia, another researcher from the same team, pointed out, “Horizontal gene transfer is an important way that antibiotic resistance moves between bacterial species….” The video that the research team captured for the first time could explain how antibiotic resistance can be acquired from one superbug bacterial species to another.

 

 

 

The battle is far from over. The antibiotic resistance already raised global concerns as it has rendered certain antibiotics ineffective. Pathogenic superbug bacteria have successfully armed themselves with genes that could neutralize antibiotic effects. Fortunately, scientists do not waver in determining the strategies that superbug bacteria exploit.  The recent discovery of the way by which bacteria employ to make them antibiotic-resistant superbug strains could lead to better therapeutic strikes that could counter them, hopefully, with ample success.

 

 

 

— written by Maria Victoria Gonzaga

 

 

 

References:
1 Indiana University. (2018). IU scientists watch bacteria ‘harpoon’ DNA to speed their evolution. Retrieved from https://news.iu.edu/stories/2018/06/iub/releases/11-scientists-watch-bacteria-harpoon-dna-to-speed-their-evolution.html

Pathobiology Of Broken Heart Syndrome

When someone says “I could die of a broken heart…”, chances are, that person may be truly risking life from a broken heart – a condition referred to as broken heart syndrome. The emotional agony can be likened to a physical pain. Apparently, it was only recently that it gained stalwart attention from researchers as they began to probe the pathobiology behind a broken heart syndrome.

 

 

 

Broken heart syndrome – overview

Hearing stories of a person in severe emotional distraught from a loved one’s death and then died not long after is not uncommon. How much of losing a loved one, a gut-wrenching rejection, or an austere betrayal could lead to death no longer surprise us. Deep sorrow certainly takes a toll. Death is inevitable but dying from a broken heart syndrome is something that is treatable and preventable, thus, is escapable. Inopportunely, the pathobiological aspect of a broken heart syndrome has not been fully unmasked. What is known about it so far is the fact that severe emotional stress is capable of triggering the transient weakening of the heart muscle, turning the latter fatally dysfunctional.

 

 

 

Pathology of Broken heart syndrome

An illustration of left ventriculogram in (A) broken heart syndrome (arrow) and (B) normal.

(Credit: JHeuser, WikiMedia Commons under GNU Free Documentation License)

 

The medical term for broken heart syndrome is takotsubo cardiomyopathy. The condition was first described in Japan in 19901 and the name is derived from”takotsubo“, which when translated means an “octopus trap“. It is so because the left ventricle of the heart of a person with broken heart syndrome is shaped like a contraption pot used for catching octopuses. Its apex balloons or bulges out while its base remains as is. As a result, the heart with temporarily enlarged apical ventricle cannot function as it should. Consequently, blood is not pumped properly and this leads to angina (chest pain) and shortness of breath, which are symptoms typical of a heart attack. Because of this, broken heart syndrome can be easily mistaken as a heart attack. The difference lies in the arteries. A true heart attack is due to an occlusion in the artery. In broken heart syndrome, arteries are not obstructed. Also, the ventricle is only temporary dysfunctional and therefore may normalize again if given enough time to rest and recuperate.

 

 

 

Biology of a broken heart syndrome

Unraveling the mysteries of broken heart syndrome is a recent biological pursuit. Consequently, the precise mechanism is not yet clear. Experts presume a surge in adrenaline and other stress hormones since the condition is often associated with emotional stressful events (n.b. it has also been reported to happen during euphoric events, e.g. winning a lottery). The overwhelming presence of these hormones might have stunned the heart and triggered structural changes in the myocytes and/or the coronary blood vessels.2 In a study published in Psychoneuroendocrinology, researchers found that bereaved individuals have higher levels of pro-inflammatory cytokines.3

 

 

 

A person who went through a broken heart syndrome and survived it could attest how the struggle had been real. Having to go through an intensely stressful event could plausibly cloud one’s drive and enthusiasm for life. Research on the pathobiology behind broken heart syndrome is understandably new, and as such inadequate for now.

 

 

 

— written by Maria Victoria Gonzaga

 

 

 

References:
1 Akashi, Y.J., Nef, H.M,, Möllmann, H., & Ueyama, T. (2010). “Stress cardiomyopathy”. Annu. Rev. Med. 61: 271–86. Doi:10.1146/annurev.med.041908.191750
2 Harvard Women’s Health Watch. (2018). Takotsubo cardiomyopathy (broken-heart syndrome). Retrieved from https://www.health.harvard.edu/heart-health/takotsubo-cardiomyopathy-broken-heart-syndrome.
3 Fagundes, C.P., Murdock, K.W., LeRoy, A., Baameur, F., Thayer, J.F., & Heijnen, C. (2018). Spousal bereavement is associated with more pronounced ex vivo cytokine production and lower heart rate variability: Mechanisms underlying cardiovascular risk? Psychoneuroendocrinology 93:65-71. doi: 10.1016/j.psyneuen.2018.04.010.

Epstein-Barr Virus – It’s More Than Just The Kiss

Epstein-Barr virus — the virus causing the kissing disease or mononucleosis — is eyed as a risk factor for contracting seven other major diseases. This is what the research team at Cincinnati Children’s Hospital Medical Center reported. The Epstein-Barr virus is contracted by kissing or by the oral transfer of saliva. Apparently, once the Epstein-Barr virus infects the body it stays there forever.

 

 

 

Epstein-Barr virus and mononucleosis

Epstein-Barr virus illustration. (Credit: Vix Maria, ©Biology-Online.org)

 

The Epstein-Barr virus belongs to the herpes family, Herpesviridae. It contains DNA that bears 85 genes and is surrounded by a nucleocapsid. Apart from the nucleocapsid, the virus is further bounded by a protein tegument and an outermost layer of a lipid envelope. The envelope has glycoprotein projections, which are crucial for the virus during its infection of the host cell.1 B cells, the immune cells producing antibodies, are ought to destroy them. However, the Epstein-Barr virus can outwit them by a slick mechanism. The virus invades the B cell, reprograms it, and makes it “follow” its “commands”. The virus is known for causing mononucleosis or the kissing disease. The common symptoms include fever, fatigue, sore throat, rash, and swollen lymph nodes, especially in the neck.

 

 

 

Epstein-Barr virus and the seven major diseases

According to the study led by three scientists, John Harley, Leah Kottyan, and Matthew Weirauch, the Epstein-Barr virus infection has been implicated to seven unrelated serious diseases.2 Previous studies by Dr. Harley and his team have already connected Epstein-Barr virus with the increased risk of developing systemic lupus erythematosus years ago. Recently, however, they found that the virus could also augment the risk of developing other serious diseases, such as multiple sclerosis, type 1 diabetes, inflammatory bowel disease, celiac disease, rheumatoid arthritis, and juvenile idiopathic arthritis.3 A person contracting the Epstein-Barr virus has a greater risk of developing them. This is because the virus produces a protein, Epstein–Barr virus nuclear antigen 2 (EBNA-2), that interacts with the human DNA, especially at genetic risk variants. 2 A genetic risk variant pertains to a variant in the DNA genome that has a potential to cause disease(s).

 

 

 

Epstein-Barr virus and future research

Epstein-Barr virus, known for causing kissing disease or mononucleosis, is linked to other serious diseases.

 

Dr. Harley and his team suspect that the EBNA2 protein from the Epstein-Barr affects a set of transcription factors. Accordingly, what the seven seemingly unrelated diseases share in common is a set of dysfunctional transcription factors, each affected by the EBNA2 protein.2 When the activity of transcription factors deviate from what they are supposed to do, the host cell (such as B cell) would not be able to carry out its normal function. This, in turn, could progress to certain diseases. With their recent finding, Dr. Harley and his team are optimistic that further intensive research could direct to finding better therapies and preventive methods such as vaccines against Epstein-Barr virus infection.

 

 

 

This recent finding suggests that contracting Epstein-Barr virus can lead to multiple diseases apart from mononucleosis. Therefore, this calls for more studies that aim at finding better cures and preventive measures. Currently, there is no vaccine against Epstein-Barr virus; being able to boost our immunity against the virus may help mitigate the risk to many other diseases, such as those mentioned above.

 

 

 

— written by Maria Victoria Gonzaga

 

 

 

References:
1Odumade, O.A., Hogquist, K.A., & Balfour Jr., H.H. (2011). “Progress and Problems in Understanding and Managing Primary Epstein–Barr Virus Infections”. American Society for Microbiology. 24 (1): 193–209. doi:10.1128/CMR.00044-10
2 Harley, J.B., Chen, X., Pujato, M., Miller, D., Maddox, A., Forney, C., Magnusen, A.F., Lynch, A., Chetal, K., Yukawa, M., Barski, A., Salomonis, N., Kaufman, K.M., Kottyan, L.C., & Weirauch, M.T. (2018). “Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity.” Nature Genetics. DOI: 10.1038/s41588-018-0102-3
3 Cincinnati Children’s Hospital Medical Center. (2018). ‘Mono’ Virus Linked to Seven Serious Diseases. Retrieved from https://www.cincinnatichildrens.org/news/release/2018/mono-virus.