Category Archives: Virology

El Niño and Possibly New World Primates Contributed to Zika Explosion

by Michelle Ziegler

The explosion of Zika-related birth defects this past year came out of the blue. Zika has been known since the 1940s but was seen as a mild dengue-like illness (Fauci & Morens, 2016). Leaving aside how and why microcephaly has appeared so dramatically, it is undeniable that Zika’s emergence and transmission in the Americas have been unusually rapid and extensive.

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Aedes aegypti from Tanzania (Source: Muhammad Mahdi Karim, 2009, GNU Free Documentation License)

Two papers published in December focusing on the Aedes mosquito vectors begin to shed light on how Zika was able to be established so quickly and pervasively. Zika utilizes the same tropical mosquito Aedes aegypti as dengue; it was once known as the yellow fever mosquito. It is also the vector of the chikungunya virus.

As first observed in West Africa many years ago, Zika epidemics followed a chikungunya epidemic by a couple years. Chikungunya was the emerging infectious disease of 2013, the year that Zika is believed to have arrived in South America (Fauci & Morens, 2016). Unrecognized by public health workers at the time, a Chikungunya epidemic was simultaneously chugging along under the radar in at least Salvador, the capital of the Bahai state of Brazil, during the peak of Zika epidemic of 2015 (Cardoso et al, 2017).

El Niño 2015-2016

In the first study by Cyril Caminade and colleagues at the University of Liverpool modeled Zika transmission in the two critical vector species in the Americas, the tropical Aedes aegypti found primarily in South America and the temperate Aedes albopictus found in the southern United States. It is thought that Zika transmits better from A. aegytpi but more research is needed to fully understand the differences. They developed a two vector, one host model where the climate is a variable to compare the effect of climate patterns on Zika transmission. They ran these simulations for each vector individually and together against historic climate data sets.

When they compared the worldwide distribution of the vectors and climate, they were able to show that all of the countries where Zika has been reported were predicted in their model. Ominously, South America was the most friendly region in the world for Zika (Caminade et al, 2016). The model for Zika produced a map that correlates extremely well with the global distribution of dengue. Due to the overlap of A. aegypti and A. albopictus territory, they found a high probability that Zika would transmit well in most of the southern United States.

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Risk of Zika transmission based on their models A. winter of 2015-2016 B. Risk over the last 50 years. (Caminade et al, 2016)

The global climate anomaly known as El Niño is known to impact mosquito-transmitted diseases, so they had a particular interest in comparing the 2015-2016 El Niño to historic data sets. The map shows the predicted Ro (reproduction number) for Zika around the world in 2015-2016  and in the bar graph compared to the last 50 years. The conditions for Zika were the best for the last 50 years. Other hot spots that did not experience a Zika epidemic, like India, did have a record year for dengue. They also note that the African hot spot for ideal transmission conditions corresponds and to Angola where there was a Yellow Fever outbreak. In short, it was a very good year for Andes aegypti! And now, as of January 2017, Yellow Fever had added to their misery in a Brazil.

A Sylvatic Reservoir? 

Understanding if Zika will establish a sylvatic reservoir in South America is of vital importance for projections and mitigation of future Zika epidemics in Brazil and elsewhere in South America. Zika was initially detected in a sentinel monkey in Uganda and has since been detected in a wide variety of smaller primates in Africa and Asia. Using a model originally proposed for dengue they were able to show that primates with rapid birth rates and short lifespans are ideal for establishing sylvatic Zika. In primates with short life span, five years or less, and rapid birth rates, the establishment of a sylvatic reservoir is “nearly assured” (Althouse et al, 2016). They predict that a primate population as small as 6,000 members with 10,000 mosquitoes could support a sylvatic reservoir (Althouse et al, 2016). Ironically, since infection rate is dependent upon bites per primate, a small primate population with a large mosquito population is better at maintaining the reservoir than a large primate population. Old World monkeys like the African Green Monkey, a known African host of Zika, are already established in free-living troops in South American forests.  While A. aegypti favors human environments, A. albopictus prefers forested environments and has been spreading in Brazil.  It could be a prime candidate for a bridging vector between a sylvatic and domestic Zika cycle. Studies on Zika vulnerability and incidence in all South American primates has to be a priority. Our ability to manage Zika in the future depends on it.


References

Caminade, C., Turner, J., Metelmann, S., Hesson, J. C., Blagrove, M. S. C., Solomon, T., et al. (2016). Global risk model for vector-borne transmission of Zika virus reveals the role of El Niño 2015. Proceedings of the National Academy of Sciences of the United States of America, 201614303–28. http://doi.org/10.1073/pnas.1614303114

Cardoso, C. W., Kikuti, M., Prates, A. P. P. B., Paploski, I. A. D., Tauro, L. B., Silva, M. M. O., et al. (2017). Unrecognized Emergence of Chikungunya Virus during a Zika Virus Outbreak in Salvador, Brazil. PLoS Neglected Tropical Diseases, 11(1), e0005334–8. http://doi.org/10.1371/journal.pntd.0005334

Althouse, B. M., Vasilakis, N., Sall, A. A., Diallo, M., Weaver, S. C., & Hanley, K. A. (2016). Potential for Zika Virus to Establish a Sylvatic Transmission Cycle in the Americas. PLoS Neglected Tropical Diseases, 10(12), e0005055–11. http://doi.org/10.1371/journal.pntd.0005055

Fauci, A. S., & Morens, D. M. (2016). Zika virus in the Americas—yet another arbovirus threat. New England Journal of Medicine, 374(7), 601–604. http://doi.org/10.1056/nejmp1600297

Ebola’s Chain of Infection

Chain of Infection A chain of infection is a method for organizing the basic information needed to respond to an epidemic.  I’ve gathered the best information I’ve been able to find. As the current epidemic is analyzed, there is no doubt some of the recommendations and basic knowledge will change.

The Ebola Virus (EBOV)

img8The Ebola virus is a Filovirus, an enveloped RNA virus containing only eight genes. Three of the five ebola virus species are highly pathogenic to humans: Zaire ebolavirus (Case fatality rate (CFR) 70-90%), Sudan ebolavirus (CFR ~50%) and Bundibugyo ebolavirus (CFR 25%). The 2014 epidemic is caused by the  Zaire ebolavirus.

Ebola attaches to the host cell via glycoproteins that trigger absorption of the virus. Once inside the cell it uncoats and begins replicating the eight negative sense RNA genes (seven structural genes and one non-structural gene). It initially targets immune cells that respond to the site of infection; monocytes/macrophages carry it to lymph nodes and then the liver and spleen. It then spreads throughout the body producing a cytotoxic effect in all infected cells. Death occurs an average of 6-16 days after the onset of symptoms from multi-organ failure and hypotensive shock.

Symptoms present 2-21 days after infection and the patient is contagious from the onset of symptoms.  Symptoms include a fever, fatigue, headache, nausea and vomiting, abdominal pain, diarrhea, coughing, focal hemorrhaging of the skin and mucus membranes, skin rashes and disseminated intravascular coagulation (DIC). In the 2014 epidemic, abnormal bleeding has only occurred in 18% of cases and late in the disease process.

The Reservoir

Fruit bats in Africa are believed to be the primary reservoir. Transmission between bats and other animals is poorly understood.

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Portal of Exit

Ebola leaves its reservoir by contact with body fluids of an infected animal, often by bushmeat hunters. The spill-over is usually very small with the vast majority of human cases being caused by human to human transmission.

Transmission 

Transmission between humans occurs by contact of skin or mucus membranes with the body fluids of an infected person. Viral particles are found in all body fluids: blood, tears, saliva, sputum, breast milk,  diarrhea, vomit, urine, sweat and oil glands of the skin, and semen. Ebola can be found in semen three months after recovery from an infection but transmission by this route is poorly understood. Viral particles are found in other body fluids for 15 days or less after the onset of symptoms. It lasts the longest in convalescent semen and breast milk. All fluids from dead bodies are highly infectious.

All materials touched by the infected person, body fluids, medical waste, and used PPE must be discarded and destroyed as infectious medical waste. Non-disposable items like rubber boots, furniture, and building structures must be professionally decontaminated.

Ebola virus is a Biosafety Level 4 pathogen and a category A bioterrorism agent along with other viral hemorrhagic fevers.

Portal of Entry

Ebola enters the human body through breaks in the skin, including micro-abrasions and splashes on mucus membranes. Personal protective equipment (PPE) includes full body coverage including hood, mask or face shield, a tight fitting respirator, boots or shoe coverings, and double gloving. A buddy system should be used for dressing and disrobing. Removing PPE is a point of frequent contamination and should be done with help from another robed person.

Vulnerable populations

The most vulnerable populations for ebola are defined by their occupation. Care givers in medical facilities are at the highest risk because the viral titers reach the highest levels in fatal cases shortly before death. Mortuary and burial workers are also at high risk. The infectiousness of the bodies means that the usual burial practices can not be done in any setting or country. Home caregivers and decontamination workers would also be at a higher risk.

Information is lacking on survival vulnerabilities such as age, gender, pregnancy, or pre-existing conditions. More information on these aspects should be available in the post-epidemic analysis of the current epidemic.

 

References and further reading:

Martines, R. B., Ng, D. L., Greer, P. W., Rollin, P. E., & Zaki, S. R. (2014). Tissue and cellular tropism, pathology and pathogenesis of Ebola and Marburg Viruses. The Journal of Pathology, n/a–n/a. doi:10.1002/path.4456 [in press]

Chowell, G., & Nishiura, H. (2014). Transmission dynamics and control of Ebola virus disease (EVD): a review. BMC Medicine, 12(1), 196. doi:10.1186/s12916-014-0196-0

Toner, E., Adalja, A., & Inglesby, T. (2014). A Primer on Ebola for Clinicians. Disaster Medicine and Public Health Preparedness, 1–5. doi:10.1017/dmp.2014.115

Bausch, D. G., Towner, J. S., Dowell, S. F., Kaducu, F., Lukwiya, M., Sanchez, A., et al. (2007). Assessment of the Risk of Ebola Virus Transmission from Bodily Fluids and Fomites. Journal of Infectious Diseases, 196(s2), S142–S147. doi:10.1086/520545

CDC: Ebola Virus Disease portal

The Spotty History of Chicken Pox

For its extreme antiquity, the virus that causes chicken pox has a surprising sparse documented history.  The earliest clear reference to the virus is actually to an emergence of its latent form as shingles, also called zoster. The ancient Greeks called it zoster after word for girdle, while shingles comes from the latin word cingulus (belt) both referring to the most common site of emergence along peripheral nerves of the back that wrap around the abdomen. There are many theories, but as far as I know, no one has successfully explained how it got the name chicken pox.

It was not until histological and immunological investigations in the early twentieth century that the relationship between the primary phase infection, chicken pox (varicella), and the emergence of the latent virus as shingles (zoster) was confirmed. Into the 18th century, chicken pox and smallpox were commonly confused as a severe and mild form of the same disease. There are subtle differences between the rashes than can distinguish them. Chicken pox produces watery pustules that concentrate on the head and trunk of the body, while smallpox lesions become hard and dimpled and are concentrated on the appendages.  Chicken pox lesions are sparse or absent from the palms of the hands and soles of the feet, while these areas are often heavily covered by smallpox lesions. But, both diseases can cause lesions anywhere in the body including internal cavities and both can leave deep scars. Chicken Pox 1 They are also, of course, distinguished by their mortality rates. Smallpox has a mortality rate of around 30%, while chicken pox  has a mortality rate of less than 1%. However, pregnant women and immune compromised patients are at high risk for life threatening complications from chicken pox. The blisters can also develop secondary bacterial infections that can become life threatening. Unlike chicken pox, smallpox requires a constant supply of non-immune hosts to persist in a community.

Viral Lifecycle

The lifecycle of the varicella virus is ideal to persist in small communities over many generations without outside introduction. It is primarily transmitted as a respiratory virus, but it can also be transmitted by contact with fluid from the blisters. Both routes are critical. Respiratory transmission allows it to spread rapidly while contact with blisters transmission allows it to persist in the community (more on this below).

As the virus enters the body it replicates for 10 to 21 days before the chicken pox rash of virus filled blisters appears. Meanwhile, some of the virons are infecting the peripheral nerves where the virus becomes dormant (latent). A couple days before the rash appears people feel unwell with fatigue, headache and potentially a fever, and they become contagious by coughing or sneezing. By spreading the virus before the rash appears, they spread the virus far and wide before the disease is recognized and isolated.

The blisters usually appear first on the scalp and on the trunk of the body with the number of blisters increasing with increasing age of the person. Young children can have as few as a dozen or less, while adults can have thousands of blisters. Over one to two weeks,  the immune system gains the upper hand and the pustules scab over. Once the rash is scabbed over, the person is no longer contagious.

The length of time it takes for the rash to stop depends completely on the strength of the immune system. The virus can remain dormant in the peripheral nerves for 50 years or more emerging when either the peripheral nerves become inflamed (often by injury) or immune suppression develops. It reemerges as shingles (zoster), a highly painful, high density group of blisters that break out along the line of the peripheral nerve they come from, usually spinal peripheral nerves. It will looks something like a whip mark of blisters wrapping around the body from the back to the front. Fluid from these blisters can cause chicken pox in non-immune people. This is a generational persistence strategy. In small communities, the virus persists by being transmitted from an elder’s shingles to children born after the last epidemic.

Life long immunity usually follows recovery from chicken pox.  Young children who only have a few lesions in their first infection can contract chicken pox a second time. It is also possible for vaccinated people to develop a usually mild case of chicken pox. In the United States vaccine acceptance is high enough that many people under age 25 have never seen a case of chicken pox. There is little doubt that if vaccination coverage wains, chicken pox will quickly become endemic again.

Origins and Evolution

The ancestral  Varicella-Zoster Virus (VZV), that causes chicken pox and shingles, co-evolved with apes, hominids and humans. Along with VZV, its closest alphaherpesvirus relatives herpes simplex 1 (HSV1, ‘cold sores’) and herpes simplex 2 (HSV2, genital herpes) have a common ancestor that is approximately 120 million years old. If the age estimates for the herpes phylogenetic tree are accurate, the evolution of the alphaherpesviruses  (VZV, HSV1, HSV2) coincides with the split of Africa from the supercontinent Godwanaland.

VZV has the ideal lifecycle to persist in small, isolated groups of humans, allowing it to easily survive through all three human epidemiological transitions. Latency and re-emergence in elders allowed the virus to survive in small hunter-gatherer groups, and continues to remain an advantage today. This process was observed in action on the small mid-Atlantic island of Tristan de Cunha where the population of about 200 people only experienced chicken pox outbreaks after an elder first exhibited shingles (Grose, 2012).

Phylogeny of VSV supports its origin in Africa before humans left the continent and subsequent spread through the world. Regionalism has likely occurred because VZV viruses undergo few replications per infection before they become latent so there is little chance for mutation or recombination between the clades (though it does occur).  Once many more sequences are available correlations between VZV evolution and human migration should become more clear. The history of the chicken pox virus still has a long way to go. As a DNA virus, it is possible that it may be found in ancient DNA but as a virus with a low mortality rate, it will be extremely difficult to find specimens with a high enough viral copy number to detect. Those rare mummies found with pox scars should be tested for both the smallpox virus and varicella-zoster virus. Regardless we must be careful distinguishing smallpox and chicken pox in the historic record.

References:

Grose, C. (2012). Pangaea and the Out-of-Africa Model of Varicella-Zoster Virus Evolution and Phylogeography. Journal of Virology, 86(18), 9558–9565. doi:10.1128/JVI.00357-12

Schmidt-Chanasit, J., & Sauerbrei, A. (2011). Evolution and world-wide distribution of varicella–zoster virus clades. Infection, Genetics and Evolution, 11(1), 1–10. doi:10.1016/j.meegid.2010.08.014

Wood, M. J. (2000). History of Varicella Zoster Virus. Herpes : the Journal of the IHMF, 7(3), 60–65.

Centers for Disease Control and Prevention (CDC): Chicken Pox (Varicella) Information portal. Last updated February 26, 2014.

CDC, Varicella: People at High Risk for complications. Nov. 16, 2011.

Conger, Cristen.  “How Chicken Pox Works”  11 March 2008.  HowStuffWorks.com. <http://health.howstuffworks.com/skin-care/problems/medical/chicken-pox.htm&gt;  24 May 2014.