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Category: Virology

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]

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]

Lurking beneath the ice

Scientists found dead tardigrades beneath the Antarctica based on their report published of recent.[1] It was a surprising discovery since tardigrades have acquired the mark as the tiny infinities. They are so resistant to extreme conditions that they are thought of as some sort of “immortals“. Nonetheless, scientists found remains of tardigrades, together with crustaceans in deep, frozen Antarctic lake.[1]

 

 

Antarctic Realm – The Cold Realm

 

Antarctic realm
The Antarctic biogeographic realm – the smallest of all realms.

 

The Antarctic is a region located in the southern-most tip of the Earth. The biogeographic realm that includes the Antarctic is called the Antarctic realm. A biogeographic realm refers to an area of land where similar organisms thrived and then evolved through periods of time in relative isolation.[2] It rouses extensive research with the paramount objective of understanding the extent of biodiversity, especially the distributional patterns of residing organisms and the biological evolutionary history incurred.

 

 

The Antarctic biogeographic realm is the smallest of all realms. It spans a total area of about 0.12 million square miles. Its components include the land area, the Antarctic tectonic plate, the ice in the waters, and the ocean itself. [2]  Because of the cold temperature, few floral species are able to persist and thrive. At present, around 250 lichens, 100 mosses, 25-30 livertworts, 700 algal species, and two flowering plant species (i.e. Antarctic hair grass and Antarctic pearlwort) inhabit the region. As for fauna, animal species include the penguinsseals, and whales.[2]

 

 

An Icy Surprise

 

tardigrade
Tardigrades . [Credit: Willow Gabriel, Goldstein Lab – https://www.flickr.com/photos/waterbears/1614095719/]
 

The discovery of the remains of tardigrades was unexpected, according to David Harnwood, a micropaleontologist. Late last year, Harnwood and his research team drilled a hole in the subglacial Lake Mercer. This frozen lake had been undisturbed for millennia.  Thus, their research project SALSA (Subglacial Antarctic Lakes Scientific Access) was the first to conduct direct sampling. They were absolutely surprised to find these water bears –frozen and dead.

 

Astounded, the animal ecologist, Byron Adams, conjectured that these tardigrades might have come from the Transantarctic Mountains, and then carried down to Lake Mercer. [1] Further, he said, “What was sort of stunning about the stuff from Lake Mercer is it’s not super, super-old. They’ve not been dead that long.”

 

 

Chilly Giants

mollivirus
“Mollivirus sibericum” found in Siberian permafrost.
[Credit: © IGS CNRS/AMU]
 

In September 2015, Jean-Michel Claverie and others reported two giant viruses (i.e. ”Pithovirus sibericum” and ”Mollivirus sibericum”) that they revived from a 30,000-year-old permafrost in Siberia.[3,5] Once revived, the viruses quickly became infectious to their natural hosts, the amoebae. [5] Luckily, these chilly giants do not prefer humans as hosts. Nonetheless, the melting of these frozen habitats could implicate danger to the public health when pathogens that can infect humans escape the icy trap.

 

 

A frozen Pandora’s Box

The frozen regions of the Earth hold so many astonishing surprises waiting to be “thawed”. In August 2016, a 12-year old boy from the Yamalo-Nenets region of Siberia died from anthrax. Reports included a few number of locals and thousands of grazing reindeer as well.[6] Prior to the anthrax outbreak, a summer heatwave caused the melting of the permafrost in the Yamal Peninsula in the Arctic Circle. The thawing of the frozen soil unleashed anthrax bacteria presumed to have come from the carcass of their reindeer host that died over 75 years ago. Their release apparently reached the nearby soil, water, the food supply, and eventually their new hosts.[5] The anthrax bacteria survived because they form spores that can protect them during their dormancy.

 

 

 

A Hotter Earth

Global warming supposedly increases the average temperature of the Earth’s surface enough to cause climate change. Accordingly, the global surface temperature increased 0.74 ± 0.18 °C (1.33 ± 0.32 °F) during the last century. The temperature rise brings threat as it could lead to environmental changes that could cause adverse effects of massive magnitude. One of which is the destruction of habitats due to the subsequent rise of water level from the melting of ice. Deadly pathogens could rise again from their cold slumber and plausibly cause another major mass extinction in no time. So, while we try to explore the deeper mysteries lurking beneath the ice, we should also make sure that we remain a step ahead. Claverie[5] excellently put it:

The possibility that we could catch a virus from a long-extinct Neanderthal suggests that the idea that a virus could be ‘eradicated’ from the planet is wrong, and gives us a false sense of security. This is why stocks of vaccine should be kept, just in case.

 

 

— written by Maria Victoria Gonzaga

 

 

References:

 

1  Berman, R. (2019, January 18). Dead – yes, dead – tardigrade found beneath Antarctica. Retrieved from [link]

2  Pariona, A. (2018, May 18). What Are The Eight Biogeographic Realms? Retrieved from [link]

3 CNRS. (2015, September 9). New giant virus discovered in Siberia’s permafrost. ScienceDaily. Retrieved from [link]

4  ‌ Wikipedia Contributors. (2018, November 10). Antarctic realm. Retrieved from [link]

5  Fox-Skelly, J. (2017, January 1). There are diseases hidden in ice, and they are waking up. Retrieved from [link]

6  Russia anthrax outbreak affects dozens in north Siberia. (2016, August 2). BBC News. Retrieved from [link]

7  Biology-Online Editors. (2014, May 12). Biology Online. Retrieved from [link]

“Do Big Viruses Really Make You Sick?”

Welcome to guest blogger, noted biologist Alan Cann

For most of my research career, I worked on viruses with small genomes, such as poliovirus and HIV. For me, the attraction of these viruses is that it is easier to understand all the interactions that go on within a small genome than with an unfeasibly large genome such as that of a cell.

(more…)