The Zika Crisis

mosquitoIn 2015, the Zika virus outbreak began in the northeast region of Brazil. According to the World Health Organization, there has been 3174 suspected cases of microcephaly in Brazil since January 2, 2016, including 38 deaths (1). The northeastern region of Brazil continues to be the area most affected, with the highest number of suspected cases. On April 13, 2016, the US Centers for Disease Control and Prevention (CDC) published a paper in The New England Journal of Medicine which concluded that there is a direct causal relationship between prenatal exposure to Zika virus and the outcome of microcephaly and brain abnormalities in the exposed infants (2). While the common symptoms of Zika infection are fever, rash, joint pain, and conjunctivitis lasting from several days to a week after exposure from an infected mosquito’s bite, a recent study recounts two cases of patients who had contracted the Zika virus and later succumbed to acute disseminated encephalitis (ADEM) (3).  This is a condition in which the immune system attacks the body, producing swelling in the brain and spinal cord and damaging the myelin which serves to protectively encase nerve fibers. The same study also describes four patients who had Zika and then developed Guillain-Barré syndrome, a condition where the immune system attacks the body’s peripheral myelin.

Zika virus is quickly spread through the bite of the female Aedes aegypti mosquito, a mosquito that is usually associated with warmer climates. This species of mosquito bites during the day. The Pan American Health Organization (PAHO) sent out a warning of the first confirmed Zika virus infection in Brazil on May 2015, and on February 2016, the World Health Organization (WHO) declared Zika virus a public health emergency of international concern (PHEIC). The PAHO lists the following areas where local transmission of Zika virus is active (4): Aruba, Barbados, Belize, Bonaire, Brazil, Colombia, Costa Rica, Cuba, Curacao, Dominica, Dominican Republic, Ecuador, El Salvador, French Guiana, Guadeloupe, Guatemala, Guyana, Haiti, Hondruas, Jamaica, Martinique, Mexico, Nicaragua, Panama, Paraguay, Peurto Rico, Saint Vincent and the Grenadines, Saint Lucia, Saint Martin, Sint Maarten, Suriname, Trinidad and Tobago, US Virgin Islands, and Venezuela. Locally transmitted cases of Zika have been reported in the Commonwealth of Puerto Rico, the US Virgin Islands, and American Samoa. There is potential for Zika virus to continue to spread to other countries due to the expanding range of the Aedes aegypti mosquito. A population of this species not carrying Zika was found in Capitol Hill, Washington, DC. Genetic analysis revealed that this particular mosquito population survived five winters in the area (5). Although theAedes aegypti is the species most responsible for spreading the Zika virus, other mosquito species in the Aedes genus can also transmit it to humans. Once the virus enters the bloodstream of a human through the bite of a female mosquito (the male mosquitoes do not bite), another female mosquito can acquire Zika by feeding upon the same host, which can then go on to infect another human. In an area with many Aedes mosquitoes, the process will repeat itself exponentially, leading to widespread viral transmission. A possible solution can be to use genetically modified mosquitoes that are male which reproduce with local female mosquitoes to yield offspring which do not live past the pupae stage. Oxitec (6), a British biotechnology company, developed such a mosquito which has already been released and tested successfully in the Cayman Islands in 2010, leading to a drastic 80 percent reduction in population of Aedes aegypti. Release of the same strain of GMO mosquitoes in the suburb of Juazeiro, Brazil in 2011 resulted in a 81-95 percent reduction of Aedes aegypti in the test region. It is also possible to breed mosquitoes to be genetically resistant to diseases such as dengue, malaria, yellow fever and Zika. Gamma radiation is being used in Brazil to sterilize male mosquitoes. Moscamed, a non-profit organization based in Brazil, took to breeding 12 million male mosquitoes per week, sterilizing them with the cobalt-60 irradiator, and then releasing them into select high-risk areas (7). The released sterile males mosquitoes then meet wild female mosquitoes, but no offspring can be produced. As there is no vaccine available right now, the current method of battling Zika virus is to reduce the population of Aedes mosquitoes.

It has been found that the Zika virus can also be transmitted sexually from an infected human male to his sexual partners via vaginal or anal sex (8), and that the virus can remain for a longer duration in semen than in blood. As of now, it is not known whether a woman can sexually spread Zika virus, or if it can be transmitted through saliva or vaginal fluids. Couples who are pregnant, or men who have travelled to areas affected by Zika are advised by the CDC to abstain from sex or use condoms.

The Zika virus is in the Flavivirus genus of viruses, which also include the West Nile virus, dengue virus, tick-borne encephalitis virus, and yellow fever virus. As a flavivirus, the Zika virus is enveloped, has a capsid of icosahedral symmetry, and contains a single-stranded positive-sense RNA genome. The Zika genome is about 10.8 kilobase pairs long. The positive-sense RNA is significant because once the virus enters the host cell, this RNA viral genome can be directly translated into a viral polypeptide, which is then cleaved into structural proteins and proteins to aid in the replication process. The envelope (E) glycoprotein protruding from the membrane of the virus is used for attachment and entrance into human cells.  For the development of a potential vaccine for Zika virus, a segment of the E glycoprotein unique to the Zika virus can be used in the vaccine to mount an antibody-mediated immune response, possibly conferring immunity from future attacks of the virus.

The expanding range of travel of both humans and mosquitoes have allowed for rapidly widespread transmission of the Zika virus. The head and brain abnormalities caused by prenatal exposure from an infected mother are detrimental, and a direct casual link between the virus and microcephaly/brain defects has been determined by the CDC. For instance, the Zika virus genome was found in the brain of an aborted, infected infant (9) that had microcephaly, and Zika virus antigens were found in the brain of one newborn with microcephaly (10). Autopsies found the presence of Zika virus in the brains of infants with severe microcephaly who died. Pregnant women infected with Zika virus have consistently given birth to infants with microcephaly and other brain abnormalities (11). The CDC further found that women who deliver infants with microcephaly were infected with Zika virus during the first and second trimester of gestation, when the brain starts to form and develop (12). There are two hypotheses directed at explaining how the Zika virus causes birth defects such as microcephaly (13). The first hypothesis posits that the placenta transfers the virus directly from mother to the fetus. The second hypothesis refers to the possible reaction of the placenta in response to Zika, which may contribute to or result in birth defects. Pregnant women are advised not to travel to areas where Zika virus is occurring.

Sierra Delarosa

 

   References

 1) Microcephaly-Brazil. (2016, January 8). Retrieved April 15, 2016, from http://www.who.int/csr/don/8-january-2016-brazil-microcephaly/en/

2) Rasmussen, S. A., M.D., Jamieson, D. J., M.D., Honein, M. A., PhD, & Petersen, L. R., M.D. (n.d.). Zika Virus and Birth Defects — Reviewing the Evidence for Causality. The New England Journal of Medicine. doi:10.1056/NEJMsr1604338

3) American Academy of Neurology. (2016, April 11). Zika virus may now be tied to another brain disease. ScienceDaily. Retrieved April 16, 2016 from www.sciencedaily.com/releases/2016/04/160411082335.htm

4) Countries and territories with autochthonous transmission in the Americas reported in 2015-2016. (n.d.). Retrieved April 15, 2016, fromhttp://www.paho.org/hq/index.php?option=com_content&view=article&id=11603:countries-territories-zika-autochthonous-transmission-americas&catid=8424:contents&Itemid=41696&lang=en

5) Gustin, G. (2016, February 26). Zika Virus Mosquitos Have Been Found…on Capitol Hill. Retrieved April 15, 2016, fromhttp://www.washingtonian.com/2016/02/26/zika-virus-mosquitos-capitol-hill-aedes-aegypti/

6) More on the science: How does oxitec make genetically modified mosquitoes? (n.d.). Retrieved April 15, 2016, fromhttp://www.oxitec.com/oxitec-video/more-on-the-science-how-does-oxitec-make-genetically-modified-mosquitoes/

7) Boadle, A. (2016, February 22). Brazil to fight Zika by sterilizing mosquitoes with gamma rays. Reuters. Retrieved April 15, 2016, from http://www.reuters.com/article/us-health-zika-radiation-idUSKCN0VV2JK

8) Zika and Sexual Transmission. (2016, February 21). Retrieved April 15, 2016, from http://www.cdc.gov/zika/transmission/sexual-transmission.html

9) Mlakar, J., M.D. et al (March 10, 2016). Zika Virus Associated with Microcephaly. The New England Journal of Medicine, 374, 951-958. DOI: 10.1056/NEJMoa1600651

10) Martines RB, Bhatnagar J, Keating MK, et al. Notes from the Field: Evidence of Zika Virus Infection in Brain and Placental Tissues from Two Congenitally Infected Newborns and Two Fetal Losses — Brazil, 2015. MMWR Morb Mortal Wkly Rep 2016;65, 159–160. DOI:http://dx.doi.org/10.15585/mmwr.mm6506e1

11) Rasmussen, S. A., M.D., Jamieson, D. J., M.D., Honein, M. A., PhD, & Petersen, L. R., M.D. (n.d.). Zika Virus and Birth Defects — Reviewing the Evidence for Causality. The New England Journal of Medicine. doi:10.1056/NEJMsr1604338

12) Rasmussen, S. A., M.D., Jamieson, D. J., M.D., Honein, M. A., PhD, & Petersen, L. R., M.D. (n.d.). Zika Virus and Birth Defects — Reviewing the Evidence for Causality. The New England Journal of Medicine. doi:10.1056/NEJMsr1604338

13) Adibi, J. J., ScD. Et al (2016). Teratogenic effects of the Zika virus and the role of the placenta. The Lancet. http://dx.doi.org/10.1016/S0140-6736(16)00650-4

Of bats, flight and immunity to viruses

Flying batBats are the stealth bombers of the animal kingdom. Equipped with radar-like echolocation, the dark form of the bat allows this creature to stay in the shadows before launching into attack on its unsuspecting prey. Scientists are now increasingly interested in bats for the biological payloads they carry: these include highly pathogenic viruses such as Ebola, rabies, and SARS.

After rodents, bats are the second most numerous mammal species on earth. The increasing interaction between bats and humans might be due to mankind’s need for more land, bringing him closer and closer to the jungle. What allows bats to harbor viruses highly lethal to humans, with no overt signs of illnesses is an important question in public health. Surprisingly, the answer may lie with one of the most characteristic features of the bat: its ability to fly.

There are two major families of bats: the old world fruit bats and the echo-locating (predominantly-) insectivorous bats. In a paper published in Science on January 25th, Guojie Zhang and colleagues at the Beijing Genomics Institute, University of Copenhagen and Australian Animal Health Laboratory, describe a study where they compared the genomes of two wild bats: an Australian fruit bat (Black flying fox) and a Chinese insectivorous bat (David’s Myotis), with the genomes of a number of other mammals, including humans and rhesus macaques. Comparing genomes helps researchers identify how certain genes differ in bats and other mammals. These differences can help identify genes responsible for the evolution of certain features, for instance, flight in bats. Researchers now know that bat flight requires a lot of energy, which led to the selective evolution of genes involved in metabolism. This however raises another problem. Increased metabolism releases free radicals, which can cause DNA damage. To cope with this DNA damage, Zhang’s group found that bat genomes had selectively evolved a number of DNA repair genes.

DNA repair plays an important role in the immune system’s ability to fight pathogens. While looking for genes involved in the bat’s immune system, the researchers found one gene involved in both DNA repair and the immune system.

This discovery led the researchers to hypothesize that the consequence of bat’s evolution of flight may have led to changes in bat immunity.

More interestingly, Zhang and his colleagues identified major differences in genes of Natural Killer cells between bats and the other mammals. Natural Killer (NK) cells play hugely important roles in our immune system’s fight against viruses such as Ebola, SARS and HIV. Both bat genomes in this study lack the same NK cell genes that the other mammals had. This could mean that bat NK cells react to viruses differently. This is important, because most disease we see in humans after viral infections is due to our immune system’s battle against the microbes. Comparing how bat and our NK cells react to viruses could help us understand why bats don’t get sick from these highly dangerous viruses, but we do.

While Zhang’s work is thought provoking, there is still much left to be understood. Is there a causal relationship between bat flight and immunity, or are the links found just correlation? Rather, the differences in NK cells that these researchers found might be more interesting. Studying these differences between bats and humans could provide us with new drug targets that reduce the effects of an overzealous immune response. Tantalizingly, bats enjoy a longer life span than animals of similar size, and this may be due to their unique immunity. Only time will tell if the bat immune system holds the secret to our fountain of youth.

References:

1.         Zhang, G. et al. Comparative Analysis of Bat Genomes Provides Insight into the Evolution of Flight and Immunity. Science 339, 456–460 (2013).

Spreading the word, but not the virus

Don’t kiss me! Ever heard a girl say that to you? Well, I had to say that to a rather cute guy last weekend.

Medical school is coming to an end. As a matter of fact, I have five more weeks to go and I’m done. And boy do I have a bad case of the Senioritis Syndrome. According to Wikipedia, one of my favorite sources of information to the (rightful) dismay of my professional superiors, senioritis is a colloquial term used to describe the decreased motivation towards studies displayed by students who are nearing the end of their schooling careers. In other words, can you get me out of here already?

Therefore when a nice cute guy asks fed up girl out on a date, she gladly accepts. On we went to see Spiderman The  Musical.  To be honest, comics aren’t really my thing, and Spiderman had opened to rather unflattering critiques, but the public seemed to really love the action. Plus I’m always open to try something different, so why not?

Unlike in high school when you pay $5 to go to the movies to not watch the movie, we have now grown to be mature adults who can appreciate culture.  Unfortunately I side more with the critics than the crowd on this one. The music was pretty negligible, the dancing was subpar for Broadway standards, although I must admit that watching Spiderman and the Goblin flying all over the audience was quite thrilling and brought out the child in me.  However, it seemed like it wasn’t the only thing it brought out in me as I started feeling some itching on my lower lip all of the sudden. Did a bug bite me? Am I getting a pimple?

I slipped into the bathroom during intermission to find out what was going on. What I saw in the mirror was horrifying: Two or three tiny vesicles on an erythematous base right on the border of my lip. A cold sore! Otherwise known as a fever blister, or herpes labialis in the medical field. I remember I used to get them when I was a little girl, and it’s coming back to haunt me now?! Seriously?

Herpes labialis

Herpes labialis is caused by herpes simplex virus type 1 (HSV-1), and typically causes blisters or sores on or around the mouth area. On the other hand, herpes simplex virus type 2 (HSV-2) usually causes genital herpes, although it is possible for HSV-1 to affect the genitalia and HSV-2 to affect the oral region as well.

Herpes simplex virus is fairly common in the population, especially HSV-1.  As a matter of fact, most physicians won’t even bother testing for it. According to the College of Family Physicians of Canada, about 80% of people have been exposed to HSV-1 by adolescence, although some may never display any symptoms.  During an outbreak, the virus actively sheds from the blisters and the skin, and that’s when it is highly contagious. Once infected, the virus stays dormant in the nerve, usually retreating back to the trigeminal ganglion, and future outbreaks might be brought on by weather changes, stress, illness, or other unknown causes. Although annoying, it is a harmless condition in most healthy people, and the sores usually go away on its own in one to two weeks without intervention. There are treatment options that might speed up the healing process, though probably not by as much as one would like.

Docosanol 10% cream, or Abreva, is the only FDA-approved treatment for oral-facial herpes simplex infection. It is most effective if applied right at the prodromal phase, meaning at the first tingle or burning sensation before the blisters appear, and it needs to be applied five times a day. Docosanol works by inhibiting fusion between the human cell plasma membrane and the herpes simplex virus envelope, thereby preventing viral entry into cells and subsequent viral replication. Since the compound doesn’t act directly on the virus, it is less likely than antiviral drugs to produce resistance.

Other studies have shown that application of zinc oxide and glycine cream every two hours while awake shorten the duration of symptoms from 6.5 days to 5 days. Studies on antiviral creams such as acyclovir or penciclovir have mixed results, and the same goes for oral antiviral treatments.

The only significant improvement was seen in one old and very small study with 7 subjects published in the Lancet in 1989 showing that the anesthetic lidocaine and prilocaine creams (25 mg of each per 1 g) reduced the mean duration of subjective symptoms from 5.1 days to 2.1 days and the duration of eruption from 7.3 to 2.6 days.

Bottom line is, treatment is most effective if you start early; as soon as you feel something brewing underneath and even before the first sign of a blister, and it might accelerate the healing process by a bit.

As for my date, when he leaned in at the end of the night, I couldn’t help but shout: “Don’t kiss me! I think I have a cold sore.” Even though the vast majority of the population has been exposed to HSV-1, I still thought it was better to issue a warning. Well, no romantic Spiderman kiss for me! But I guess if he still calls me after that, I’ll know that he likes me for more than just my lips.

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