Ötzi’s Lyme Disease in Context

One of the ancient DNA finds that continues to intrigue me is the discovery of Borrelia burgdorferi, the agent of Lyme disease, in Ötzi the 5300-year-old ice mummy from the Italian Alps. As far as I know, this is the only finding of B. burgdorferi in ancient remains of any date.  I discussed the initial report of these findings back in the summer of 2012. 

 

The more we learn about Ötzi’s environment and lifestyle, the less mysterious it seems. There are no signs of human habitation or land management in these high Alpine regions. Indicators of deforestation, farming, and pasture maintenance are lacking from lake sediment and pollen studies. Festi, Putzer and Oeggl (2013) found the first signs of human land management in the Ötztal Alps to began about 1000 years after Ötzi’s time. During the Copper Age, subsistence occupation of the valley floor was sufficient for the population of Ötzi’s time. They did minimal farming, and breeding of caprines (sheep, goats, and ibex). Festi, Putzer and Oeggl (2013) note that Ötzi’s mummy is the only piece of evidence for humans that high in the Otztal Alps before the Bronze Age.

Before Ötzi’s time, landscape management in the Mesolithic was to support red deer herds that were “in a state of semi-domestication by means of active hunting” (Rollo et al, 2002). (Native Americans managed deer populations in similar ways by promoting a landscape where deer thrive near their hunting grounds.) The importance of deer to Ötzi is underscored by everything about him from the red deer meat in his stomach to the roe deerskin that made up his quiver and antler in some of his tools (Rollo et al, 2012). Two different species of deer have been confirmed by genetic analysis.  Most of his clothing was made of sheep and goat skins (O’Sullivan et al, 2016).

The agent of Lyme disease, B. burgdorferi, is transmitted primarily by the tick Ixodes ricinus, common on deer, sheep, cattle, humans and dogs as adults and feed on rodents and small mammals as nymphs. Ticks often thrive at the forest edge where there are grasses for them to climb up to catch passing deer. It seems likely that they would also thrive in along upland forest edges as well. Ixodes ricinus is found throughout the Alps.  It is feasible that Lyme disease was a greater problem for humans when we relied on deer as a staple food.

Ötzi’s B. burgdorferi has yet to be confirmed by a second group. Interestingly, a recent study of B. burgdorferi’s phylogeny suggests that it originated in Europe and later spread to ‘post-Columbian’ North America (Margos et al, 2008). Although Lyme disease was only recognized in the 20th century, it is apparently an ancient disease caused by multiple Borrelia species. And Ötzi’s sequence has not been added to any phylogeny I’ve found, odd. Overlooked, or a problematic sequence?


References

Festi, D., Putzer, A., & Oeggl, K. (2013). Mid and late Holocene land-use changes in the Otztal Alps, territory of the Neolithic Iceman “Otzi”. Quaternary International, 353, 1–18. http://doi.org/10.1016/j.quaint.2013.07.052

Margos, G., Gatewood, A. G., Aanensen, D. M., Hanincová, K., Terekhova, D., Vollmer, S. A., et al. (2008). MLST of housekeeping genes captures geographic population structure and suggests a European origin of Borrelia burgdorferi. Proceedings of the National Academy of Sciences, 105(25), 8730–8735. http://doi.org/10.1073/pnas.0800323105

O’Sullivan, N. J., Teasdale, M. D., Mattiangeli, V., Maixner, F., Pinhasi, R., Bradley, D. G., & Zink, A. (2016). A whole mitochondria analysis of the Tyrolean Iceman’s leather provides insights into the animal sources of Copper Age clothing. Scientific Reports, 6, 1–9. http://doi.org/10.1038/srep31279

Rollo, F., Ubaldi, M., Ermini, L., & Marota, I. (2002). Otzi’s last meals: DNA analysis of the intestinal content of the Neolithic glacier mummy from the Alps. Proceedings of the National Academy of Sciences of the United States of America, 99(20), 12594–12599. http://doi.org/10.1073/pnas.192184599

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

War as a Driver in Tuberculosis Evolution

by Michelle Ziegler

Russia has been all over the news lately. Beyond our recent election, increased Russian activity on the world stage has public health consequences for Europe and farther afield. It has been known for a long time that post-Soviet Russia had and continues to have serious public health problems. One of their particular problems that they have shared with the world is their alarmingly high rate of antibiotic resistant tuberculosis. There is no mystery over the root cause of their antibiotic resistance woes — poor antibiotic stewardship (Garrett, 2000; Bernard et al 2013).

A study by Vegard Eldholm and colleagues that came out this fall sheds light on the origins of particularly virulent tuberculosis strains with high rates of antibiotic resistance that recently entered Europe.  A large outbreak among Afghan refugees and Norwegians in Oslo, Norway, provided a core set of 26 specimens for this study that could be compared with results generated elsewhere in Europe (Eldholm et al, 2010). The Oslo outbreak clearly fits within the Russian clade A group that is concentrated to the east of the Volga River in countries of the former Soviet Union. They name this cluster the Central Asian Clade, noting that it co-localizes with region of origin of migrants carrying the MDR strains of tuberculosis reported in Europe.

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Figure 5. Phylogeny of the Afghan Strain Family (ASF). Colored boxes represent the country of origin: Afghanistan is orange; other countries are gray. (Eldholm et al, 2016)

When the Oslo samples are added to the family tree, phylogeny, of recent tuberculosis isolates from elsewhere in Europe a distinctive pattern emerges. The branches on the family tree are short and dense, suggesting that this is recent diversity, that they calculate to have occurred within approximately the last twenty years (Eldholm et al, 2016).

The Central Asian Clade spread into Afghanistan before drug resistance began to develop, probably during the Soviet-Afghan war (1979-1989) producing the Afghan Strain Diversity clade. Slightly later, the Central Asian Clade still in the former Soviet states begins to accumulate antibiotic resistance as the public health infrastructure crumbles in the wake of the dissolution of the USSR. The invasion of Afghanistan by the US and its allies in 2002 toppled the Afghan state, crippling infrastructure and spurring refugee movements within and out of Afghanistan. The lack of modern public health standards in Afghanistan since their war with the introduction of these strains by the Soviets in the 1980s provided fertile ground for the establishment and diversity of tuberculosis in the country. Instability has been pervasive throughout the entire region sending refugees and economic migrants from both Afghanistan and the former Soviet states into Europe.

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Movements of the Central Asian Clade (CAC) since c. 1960 and the subsequent Afghan Strain Family (ASF). (Eldholm et al, 2016)

Their dating of the last common ancestor for the Central Asian Clade to c. 1961 is significantly younger than the previous dating of 4,415 years before present for the Russian clade A (CC1) of the Beijing lineage of Mycobacteria tuberculosis. They account for this difference by noting differences in their methods of assessing sequence differences and note that their method is in line with other recent evolutionary rates for other tuberculosis clades.  The diagnosis dates and length of the arms on their reconstructed phylogeny suggests that there were multiple, independent introductions of the cases from Afghanistan and the former Soviet republics. This is consistent with a repeated periods of refugee movements from central Asia into Europe.

The rapid proliferation and diversification of the Afghan Strain Family may be explained by a known syndemic between tuberculosis and war (Ostrach & Singer, 2013). Conditions of war everywhere disrupt food systems, destroy critical infrastructures such as electricity and water systems, interrupts medical supplies, and the human public health infrastructure of the country. Malnutrition and stress are known contributors to immune suppression. Many pathogens flourish simultaneously in these conditions increasing the infectious challenges the population must fend off. Diarrheal diseases are the most acute and demanding of rapid attention, allowing longer-term diseases like tuberculosis to slip through the overburdened healthcare system. Afghanistan has experienced nearly forty years of war, political instability, and repeated infrastructure destruction. Thus, they were primed for both the establishment of new tuberculosis strains during the Afghan-Soviet war in the 1980s along with the proliferation and diversification of tuberculosis during the Afghan-American war of the last sixteen years.

Established syndemics between tuberculosis and war have been made retrospectively following the Vietnam war and the Persian Gulf war of 1991 (Ostrach & Singer, 2013). In Vietnam, prolonged malnutrition caused an eruption of tuberculosis along with malaria, leprosy, typhoid, cholera, plague, and parasitic diseases.  A WHO survey in 1976 found that Vietnam had twice the incidence of tuberculosis over all of its neighboring countries (Ostrach & Singer, 2013). When the military intentionally targets water infrastructure as it did in Vietnam and Iraq, the production of civilian infectious disease is a tactic of war. In both Vietnam and post-Gulf war Iraq, more civilians died of malnutrition and infectious disease than enemy soldiers died of all causes (Ostrach & Singler, 2013).

It seems likely that this is just one of the first studies to establish a link between serious infectious disease developments and the Afghan wars. The current war zones throughout central Asia and the Middle East already have ramifications for the public health of the entire world that walls along borders will not be able to stop. Most of the cases in the Oslo outbreak were Norwegians, not Afghan immigrants. Diseases will spread beyond the migrants so country of origin screening will be of little use before long.


Reference

Eldholm, V., Pettersson, J. H. O., Brynildsrud, O. B., Kitchen, A., Rasmussen, E. M., Lillebaek, T., et al. (2016). Armed conflict and population displacement as drivers of the evolution and dispersal of Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America, 201611283–16. http://doi.org/10.1073/pnas.1611283113

Ostrach, B., & Singer, M. C. (2013). Syndemics of War: Malnutrition-Infectious Disease Interactions and the Unintended Health Consequences of Intentional War Policies. Annals of Anthropological Practice, 36(2), 257–273. http://doi.org/10.1111/napa.12003

Bernard, C., Brossier, F., Sougakoff, W., Veziris, N., Frechet-Jachym, M., Metivier, N., et al. (2013). A surge of MDR and XDR tuberculosis in France among patients born in the Former Soviet Union. Euro Surveillance: Bulletin Européen Sur Les Maladies Transmissibles = European Communicable Disease Bulletin, 18(33), 20555.