Ancestral East Asians and adaptation to coronaviruses

 

Early farming village in China (Wikicommons – Xinyang City Museum, Gary Todd)

 

Respiratory viruses began to propagate more easily when hunting and gathering gave way to farming and as settlements grew larger. Humans may have then evolved to use coronaviruses as a natural vaccine against deadlier respiratory diseases, like tuberculosis and pneumonia.

 

 

A new genomic study has found that East Asians had to adapt to epidemics of coronaviruses some 25,000 years ago. The authors looked at gene variants for proteins that interact with coronaviruses in five East Asian populations: Han Chinese (Beijing); Han Chinese (South China); Dai (Yunnan, China); Japanese; and Vietnamese. There were three main findings:

 

·         Ancestral East Asians had to adapt to coronavirus epidemics around 25,000 years ago

·         They adapted by acquiring mutations that are close to genes that regulate the development of lung tissue and other tissues affected by COVID-19

·         Those mutations either promote or block infection by coronaviruses (Souilmi et al. 2021, p. 3505).

 

The last finding is puzzling. Did those ancestral East Asians become more vulnerable or less vulnerable to coronaviruses? The authors simply say that half of those mutations from 25,000 years ago have “anti- or proviral effects” versus 29% of all proteins that interact with coronaviruses (Souilmi et al. 2021, p. 3509). Fine. But how many of those mutations were antiviral and how many proviral?

 

It might seem strange that natural selection would actually make people more susceptible to coronavirus infections. Yet such susceptibility could be beneficial. A viral infection can boost immunity to other pathogens, including deadly ones that cause tuberculosis, pneumonia, or pneumonic plague. Until recently, coronaviruses were typically mild in their effects, producing what we call the “common cold.” They may thus act as a natural vaccine against deadlier respiratory diseases (Frost 2020).

 

Respiratory diseases are believed to have become serious for humans when hunting and gathering gave way to farming. People became sedentary and their settlements grew larger with time, thus providing respiratory viruses with better conditions for propagation (Comas et al. 2013). This theoretical model is in conflict, however, with the above finding that ancestral East Asians began adapting to coronaviruses some 25,000 years ago, long before they adopted farming and became sedentary. We’re thus left with the unlikely conclusion that coronavirus epidemics began among scattered bands of hunter-gatherers.

 

The estimate of 25,000 years ago is probably wrong. The authors arrived at that figure by calculating the latest date when the ancestors of the four East Asian groups were still a single population. But East Asians are not descended from a single population. Their origins are best described by the "Two-Layer" (TL) hypothesis:

 

·         Modern humans spread into East Asia through a northern route and a southern route.

·         The southerners were then replaced to varying degrees by northerners who spread out of northeast Asia and successively occupied northern China, southern China, and Southeast Asia (Oxenham and Buckley 2016; Xu et al. 2006).

·         Thus, as you go farther south in East Asia, the population has a greater admixture from the earlier southern “layer”—from hunter-gatherers who closely resemble the relic groups that still exist in parts of Southeast Asia, i.e., the Andaman Islanders, the Aeta of the Philippines and the Maniq and Semang of the Malayan Peninsula.

 

Admixture from that older southern substrate pushes back in time the latest common ancestors, who never existed. Adaptation to coronaviruses therefore happened at a later date, probably when the “northerners” pushed into what is now northern China and adopted farming. They then grew in population, pushed farther south, and intermixed with the hunter-gatherers who lived there. 

 

 

References

 

Comas, I., M. Coscolla, T. Luo, et al. (2013). Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nature Genetics 45: 1176–1182. https://doi.org/10.1038/ng.2744

 

Frost, P. (2020). Does a commensal relationship exist between coronaviruses and some human populations? Journal of Molecular Genetics 3(2): 1-2. https://researchopenworld.com/does-a-commensal-relationship-exist-between-coronaviruses-and-some-human-populations/

 

Frost, P. (2022). A natural vaccine. Evo and Proud, February 21 http://evoandproud.blogspot.com/2022/02/a-natural-vaccine.html

 

Oxenham, M., and H.R. Buckley. (2016). The population history of mainland and island Southeast Asia, in M. Oxenham and H.R. Buckley (eds) The Routledge Handbook of Bioarchaeology in Southeast Asia and the Pacific Islands. Routledge.

 

Souilmi, Y., M.E. Lauterbur, R. Tobler, C.D. Huber, A.S. Johar, S.V. Moradi, W.A. Johnston, N.J. Krogan, K. Alexandrov, and D. Enard. (2021). An ancient viral epidemic involving host coronavirus interacting genes more than 20,000 years ago in East Asia. Current Biology 31(16), 3504–3514.e9. https://doi.org/10.1016/j.cub.2021.05.067

 

Xue, Y., T. Zerjal, W. Bao, S. Zhu, Q. Shu, J. Xu, R. Du, S. Fu., P. Li, M.E. Hurles, H. Yang, C. Tyler-Smith. (2006). Male demography in East Asia: A north-south contrast in human population expansion times. Genetics 172: 2431-2439, https://doi.org/10.1534/genetics.105.054270

A natural vaccine?

 

Geographic distribution of the G allele (TIMPRSS2), which is associated with a higher death rate from COVID-19. It’s most frequent on the Indo-Gangetic Plain, which has the longest continuous history of urban settlement in South Asia. Did that environment select for susceptibility to coronaviruses as a way to boost resistance to deadlier respiratory viruses?

 

 

The common cold is caused by over 200 strains of rhinoviruses, coronaviruses, adenoviruses, and enteroviruses. Coronaviruses differ from other respiratory viruses in one key respect: they can enter lung tissue via the ACE2 receptor. So if that receptor is altered to allow easier entry, the host would become more susceptible to the common cold but not to other respiratory diseases, including much deadlier ones that cause tuberculosis, pneumonia, or pneumonic plague.

 

The last point is important because there is evidence that a viral infection can protect against subsequent infection by respiratory viruses. When mice are infected with γherpesvirus 68, which is similar to Epstein-Barr virus, there is production of large quantities of IFN-γ and activation of macrophages that protect against Listeria monocytogenes (which causes listeriosis), Mycobacterium tuberculosis (which causes tuberculosis), and Yersinia pestis (which causes bubonic and pneumonic plague) (Barton et al., 2007; Miller et al., 2019). A cytomegalovirus infection likewise protects against Listeria monocytogenes and Yersinia pestis (Barton et al., 2007).

 

Coevolution between coronaviruses and early urban settlement

 

Beginning some 10,000 years ago, hunting and gathering gave way to farming, and nomadism to sedentism. People began to live in progressively larger settlements along the Nile in Egypt, the Tigris and the Euphrates in Mesopotamia, the Indus and the Ganges in northern India, and the Yellow and the Yangtze in China. That is where large numbers of humans first lived in close proximity to each other, and they were particularly vulnerable to the spread of respiratory diseases from one person to another. There may thus have been selection among them for increased susceptibility to coronaviruses, which are normally mild in their effects, as a means to increase resistance to deadlier respiratory viruses.

 

A recent Indian study by Pandey et al. (2022) suggests that coronavirus susceptibility may have coevolved with risk of infection by life-threatening respiratory viruses like tuberculosis, pneumonia, and pneumonic plague, at least in South Asia. People are more susceptible to infection by coronaviruses if they have the G allele of the TMPRSS2 gene. The research team found that the G allele is significantly associated with a higher fatality rate for COVID-19, apparently because it helps coronaviruses enter lung tissue via the ACE2 receptor.

 

Pandey et al. (2022) also charted the geographic distribution of the G allele in South Asia. This allele is most frequent among inhabitants of the Indo-Gangetic Plain, i.e., the fertile lowlands that border the Indus and Ganges rivers of northern India and Pakistan. This is also where urbanization has existed for the longest continuous time in South Asia, specifically since the early first millennium BCE. The Indo-Gangetic Plain has had "an uninterrupted sequence of economic development, state formation, and cultural expansion affecting the entire subcontinent as well as Central, East and Southeast Asia" (Heitzman 2008, pp. 12-13).

 

These findings are roughly consistent with an earlier finding by the same research team. Srivastava et al. (2020) found that an ACE2 allele, at rs2258666, has a negative relationship with the fatality rate for COVID-19. It is also most frequent in the northeast of India, which until recent times was sparsely populated, and whose inhabitants lived in dispersed rural settlements.

 

References

 

Barton, E.S., D.W. White, J.S. Cathelyn, K.A. Brett-McClellan, M. Engle, et al. (2007). Herpesvirus latency confers symbiotic protection from bacterial infection. Nature

447: 326-329.

https://doi.org/10.1038/nature05762

 

Frost, P. (2020). Does a commensal relationship exist between coronaviruses and some human populations? Journal of Molecular Genetics 3(2): 1-2.

https://researchopenworld.com/does-a-commensal-relationship-exist-between-coronaviruses-and-some-human-populations/

 

Heitzman, J. (2008). The City in South Asia. London: Routledge

 

Miller, H.E., K.E. Johnson, V.L. Tarakanova, and R.T. Robinson. (2019). γ-herpesvirus latency attenuates Mycobacterium tuberculosis infection in mice. Tuberculosis 116: 56-60.

https://doi.org/10.1016/j.tube.2019.04.022

 

Pandey, R.K., A. Srivastava, P.P. Singh, and G. Chaubey. (2022). Genetic association of TMPRSS2 rs2070788 polymorphism with COVID-19 case fatality rate among Indian populations. Infection, Genetics and Evolution 98 https://doi.org/10.1016/j.meegid.2022.105206

 

Shirato, K., M. Kawase, and S. Matsuyama. (2018). Wild-type human coronaviruses prefer cell-surface TMPRSS2 to endosomal cathepsins for cell entry. Virology 517: 9-15.

https://doi.org/10.1016/j.virol.2017.11.012

 

Srivastava, A., A. Bandopadhyay, D. Das, R.K. Pandey, V. Singh, N. Khanam, N. Srivastava, P.P. Singh, P.K. Dubey, A. Pathak, P. Gupta, N. Rai, G.N.N. Sultana, and G. Chaubey. (2020). Genetic Association of ACE2 rs2285666 Polymorphism with COVID-19 Spatial Distribution in India. Frontiers in Genetics. September 25

https://doi.org/10.3389/fgene.2020.564741

 

The genetics of susceptibility to COVID-19

Left: Frequency of an rs2258666 allele in Indian populations (TT-plus strand or AA-minus strand). Right: COVID-19 case-fatality rate (August 2020).

 

 

ACE2 is a cell receptor that mediates the infection of lung tissue by coronaviruses, either the one that causes COVID-19 or others that cause the common cold. The ACE2 gene has 1,700 alleles, some of which are associated with increased susceptibility to coronavirus infection (Frost 2020).

 

This difference in susceptibility has been shown in a recent Indian study (Srivastava et al. 2020). COVID-19 is most fatal in the western states of Gujarat, Maharashtra, Madhya Pradesh, and Punjab. Conversely, it is least fatal in the northeast states of Assam, Arunachal Pradesh, and Nagaland. This pattern closely correlates with genetic variation at the rs2285666 locus of ACE2. The presence or absence of a single allele explains 35% of the variation in the COVID-19 case-fatality rate.

 

The authors conclude that some kind of selection has been acting on rs2285666. If we look at the map, susceptibility to COVID-19 seems to be strongest in those regions with the longest history of sedentary living and large urban centers. Conversely, it seems to be weakest in the Northeast, which is home to people who, until recent times, belonged to small communities that routinely moved from one cultivable area to another.

 

These findings are consistent with the hypothesis that the ACE2 receptor has coevolved with human environments. Because respiratory viruses boost the immune response of lung tissue and thereby prevent more serious pulmonary diseases (e.g., tuberculosis, pneumonia, pneumonic plague), some human populations may have gained protection from severe respiratory infections by becoming more susceptible to mild respiratory infections, such as those normally caused by coronaviruses. This commensal relationship would have been especially adaptive where respiratory pathogens could easily propagate, that is, in crowded environments where many people live in proximity not only to each other but also to livestock. In regions that have long had crowded environments, natural selection may have favored susceptibility to infection by coronaviruses, which are normally mild in their effects, as a means to maintain a strong immune response to deadly pulmonary diseases (Frost 2020).

 

 

****************************************************

 

I'm sorry for the break in my posting. When the pandemic first struck, I expected to have a lot of time on my hands, so I began a series of writing projects: four articles and a manuscript for a book. Unfortunately, my free time dried up over the summer, and my workload became overwhelming. I hope I've now found the right balance between my writing projects and my regular work.

 

References

 

Frost, P. (2020). Does a commensal relationship exist between coronaviruses and some human populations? Journal of Molecular Genetics 3(2): 1-2.

https://researchopenworld.com/does-a-commensal-relationship-exist-between-coronaviruses-and-some-human-populations/

 

Srivastava, A., A. Bandopadhyay, D. Das, R.K. Pandey, V. Singh, N. Khanam, N. Srivastava, P.P. Singh, P.K. Dubey, A. Pathak, P. Gupta, N. Rai, G.N.N. Sultana, and G. Chaubey. (2020). Genetic Association of ACE2 rs2285666 Polymorphism with COVID-19 Spatial Distribution in India. Frontiers in Genetics. September 25

https://doi.org/10.3389/fgene.2020.564741

This is where the virus is least deadly

Patterson Town Hall, (Wikicommons - Anthony22). Putnam County NY has the lowest IFR for COVID-19 in the United States.



SARS-CoV-2 is more virulent in southern Europe than in northern Europe. The reason, I’ve argued, is that the Mediterranean Basin is one of several regions where humans have coevolved for a longer time with crowded social environments. By "crowded" I mean not only proximity to other people but also proximity to domesticated animals. In such environments, which are prone to deadly pulmonary diseases like tuberculosis and pneumonia, natural selection may have favored susceptibility to infection by coronaviruses, which are normally mild in their effects, as a means to maintain a strong immune response to respiratory infections (Frost 2020). 

If we look at case fatality rates, Italy and Spain have been hit much worse than Germany, Switzerland, Austria, and Iceland. The United Kingdom falls between the two extremes, although a confounding factor is its large population of non-native origin (Singh 2020).

This pattern also shows up in a meta-study of infection fatality rates. Meyerowitz-Katz and Merone (2020) examined thirteen estimates of IFR from a wide range of countries. They came to two main conclusions:

- Mean IFR is 0.75% but varies considerably between countries;

- IFR has increased over time, being lower in February and March than in April and May.

Earlier estimates were based on the assumption that the average time lag between infection and death is two weeks on average. Actually, it's probably longer, perhaps a month. Later deaths may have thus been missed by estimates made in February and March.

If we look only at IFRs from April and May, the meta-study shows a north-south cline in the virulence of SARS-CoV-2:

Germany - 0.36%
France - 0.70%, 0.80%
Italy - 0.95%, 1.29%, 1.60%

For the same time period, the meta-study also presented three estimates from the United States:

New York City - 0.93%
California - 0.20%
United States - 1.30%

The last study provides estimates ranging from a low of 0.5% in Putnam County NY to a high of 3.6% in King County WA (Basu 2020). These numbers are so high because IFR is calculated only in relation to symptomatic cases. In my opinion, this study is not comparable to the others and should not have been included in the metastudy. It is nonetheless useful for charting the virulence of SARS-CoV-2 within the United States.

So why would the virus be less virulent in Putnam County NY than in King County WA? Let's consider the demographics in each case. The first county is 80% non-Hispanic White, 14% Hispanic, 3% Black, and 2% Asian. The second county is 65% non-Hispanic White, 15% Asian, 9% Hispanic, and 6% Black. Putnam County is whiter and probably less cosmopolitan than King County, which encompasses the Seattle area. This impression is strengthened by the voting pattern in Putnam County, which trends much more Republican than Democrat (Wikipedia 2020). The virus thus seems to be least virulent among "old stock" Euro Americans. I would also predict low virulence in Amerindian communities.

Virulence may also differ between west coast Hispanics and east coast Hispanics, as suggested by the difference between California and New York City. East Coast Hispanics are less often Mexican and more often Puerto Rican. They may thus be more vulnerable because they are more Mediterranean and less Amerindian by ancestry.


References

Basu, A. (2020). Estimating The Infection Fatality Rate Among Symptomatic COVID-19 Cases In The United States. Health affairs (Project Hope). 2020:101377hlthaff202000455.
https://www.healthaffairs.org/doi/full/10.1377/hlthaff.2020.00455

Frost, P. (2020). Does a commensal relationship exist between coronaviruses and some human populations? Journal of Molecular Genetics 3(2): 1-2.
https://researchopenworld.com/does-a-commensal-relationship-exist-between-coronaviruses-and-some-human-populations/

Meyerowitz-Katz, G. and L. Merone. (2020).  A systematic review and meta-analysis of published research data on COVID-19 infection-fatality rates.  medRxiv, May 18, 2020
https://www.medrxiv.org/content/10.1101/2020.05.03.20089854v2 

Singh, S. (2020). BCG vaccines may not reduce COVID-19 mortality rates. medRxiv April 11, 2020 
https://www.medrxiv.org/content/10.1101/2020.04.11.20062232v1

Wikipedia (2020). Putnam County, New York.
https://en.wikipedia.org/wiki/Putnam_County,_New_York 

Does a commensal relationship exist between coronaviruses and some human populations?

Nanjing Road, Shanghai (Wikicommons - Stephen Codrington). Populations with a long history of social crowding may have become more susceptible to coronavirus infection.


I've published a paper on coevolution between coronaviruses and "crowded" social environments. Comments are welcome. Here is the abstract:


Coronaviruses enter lung tissue via the ACE2 receptor, which varies structurally among human populations. In particular, the Chinese population has fewer variants that bind weakly to the coronavirus S-protein. This global variation suggests that the ACE2 receptor has coevolved with different environments, some of which have favored susceptibility to infection of lung tissue by coronaviruses. 

It has been argued that respiratory viruses boost the immune response of lung tissue and thereby prevent more serious pulmonary diseases, like tuberculosis, pneumonia, and pneumonic plague. This preventive effect has been shown with other viral pathogens, notably γherpesvirus 68 and cytomegalovirus. Some human populations may have therefore gained protection from severe respiratory infections by becoming more susceptible to mild respiratory infections, such as those normally caused by coronaviruses. 

This commensal virus-host relationship would have been especially adaptive wherever respiratory pathogens could easily propagate, i.e., in crowded environments, where many people live in proximity not only to each other but also to animal sources of infection. In regions that have long had crowded environments, natural selection may have favored susceptibility to infection by coronaviruses, which are normally mild in their effects, as a means to maintain a strong immune response to deadly pulmonary diseases.


Reference

Frost, P. (2020c). Does a commensal relationship exist between coronaviruses and some human populations? Journal of Molecular Genetics 3(2): 1-2.
https://researchopenworld.com/does-a-commensal-relationship-exist-between-coronaviruses-and-some-human-populations/   

COVID-19 update

A dying man, stoned on suspicion of spreading the plague - Felix Jenewein, 1899 (Wikicommons)



SARS-CoV-2, though novel, belongs to a long-existing group of respiratory pathogens: coronaviruses. Until the first appearance of SARS in 2002, these pathogens did little harm to their hosts, usually causing nothing worse than a common cold. So they may have coevolved with us. Furthermore, this coevolution may have taken different forms in different human populations and different cultural environments.

Coronaviruses infect lung tissue via a receptor, ACE2, that varies structurally not only between Asians and other human groups but also between different Asian groups. In particular, the Chinese population has fewer alleles that code for weak binding to the coronavirus S-protein (Cao et al. 2020). Different ACE2 alleles are also associated with differences in susceptibility to diabetic retinopathy, an eye disease with a distinct global pattern of prevalence: 22% in Italy, 23% in China, 30% in the United Kingdom, and 40% in the United States (Adams 2020).

This geographic pattern doesn’t exist because some populations have become more resistant to coronaviruses. Instead, the reverse seems to have happened: some populations have become more susceptible to coronavirus infection, perhaps as a means to prevent more serious pulmonary infections, like tuberculosis and pneumonic plague (Shekhar et al. 2017). Such an effect has been shown with γherpesvirus 68 and cytomegalovirus (Barton et al. 2007; Miller et al. 2019). This crude vaccination boosts the immune response through increased production of IFN-γ and increased activation of macrophages.

Historically, tuberculosis was especially common in crowded environments, where people lived in proximity not only to each other but also to domesticated animals (Comas et al. 2013). Such environments have existed continuously for the longest time in China, as well as in areas like the Indo-Gangetic Plain, the Fertile Crescent, and the Mediterranean Basin. Those areas are where people should be most susceptible to coronavirus infection.

This may explain why COVID-19 has been more severe in southern Europe than in northern Europe. It is surprising that infection tends to become less severe with latitude when one would expect the opposite: respiratory viruses spread more effectively under conditions of lower temperature, lower humidity, and lower solar UV.


Ongoing research?

These geographic differences have caught the interest of a molecular epidemiologist at the University of Hawai'i, Maarit Tiirikainen:

"There have been major differences in the rates of SARS-CoV-2 infection and the severe disease between the different geographic regions since the beginning of the COVID-19 pandemic, even among young individuals," Dr. Tiirikainen said. "Epidemiological studies-so-called Genome Wide Association Studies (GWAS)-indicate that populations carry different variants of the ACE2 gene. This variation in the gene coding for the ACE2 receptor may have an effect on the number of ACE2 receptors on the lung cells, as well as on how effectively the virus binds to the receptor. There may also be genetic differences in immune and other important genes explaining why some people get more sick than others."

She is collaborating with a genomics company, LifeDNA, in a study that will initially focus on Hawai'i's multiethnic inhabitants, specifically their diversity of ACE2 alleles in relation to the latest coronavirus (LifeDNA 2020 – h/t to Steve Sailer).


Parting thoughts

All humans can get infected by coronaviruses, but the infection tends to vary in severity from one population to another. This variance may reflect differences in genetic adaptation in different cultural environments.

Of course, adaptation may also be cultural. Because natural selection acts on the end result, and not on the means to that end, the means may be a purely learned algorithm, like adding spices to food or avoiding physical contact with strangers. One might not have understood why or how such practices worked, but they did work and would be passed on to subsequent generations, thus becoming the traditional way of doing things. Today, we’re likely to reject such practices as outmoded superstitions.

So be modern. Hug a stranger.


References

Adams N. (2020). Cracking the code to the 2019 novel coronavirus (COVID-19): Lessons from the eye. Eye Reports 6(1). 
https://eyereports.org/index.php/eyereports/article/view/97

Barton E.S., White D.W., Cathelyn J.S., Brett-McClellan K.A., Engle M., Diamond M.S., et al. (2007). Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447: 326-329. 
https://www.nature.com/articles/nature05762

Cao Y., Li L., Feng Z., Wan S., Huang P., Sun X., et al. (2020). Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discovery 6(11). 
https://www.nature.com/articles/s41421-020-0147-1%3C/blockquote%3E 

Comas I., Coscolla M., Luo T., Borrell S., Holt K.E., Kato-Maeda M., et al. (2013). Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nature Genetics 45(10): 1176-1182.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800747/

LifeDNA (2020). COVID-19: LifeDNA and University of Hawai’i Collaborate on Studying Why Certain Populations Are Hit Harder. Research focuses on ACE2 receptor, probing the role of genetics in both susceptibility to infection and severity of response April 2, University of Hawai'i Cancer Center 
https://www.uhcancercenter.org/about-us/newsroom/600-covid-19-lifedna-and-university-of-hawai-i-collaborate-on-studying-why-certain-populations-are-hit-harder

Miller H.E., Johnson K.E., Tarakanova V.L., Robinson R.T. (2019). γ-herpesvirus latency attenuates Mycobacterium tuberculosis infection in mice. Tuberculosis 116: 56-60. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876742/

Shekhar S., Schenck K., Petersen F.C. (2017). Exploring host-commensal interactions in the respiratory tract. Frontiers in Immunology 8: 1971. 
https://www.frontiersin.org/articles/10.3389/fimmu.2017.01971/full

Coevolution with the plague

Houses being burned during an outbreak of pneumonic plague in China (Wikicommons). In China, large urban populations coevolved with deadly pulmonary infections, like tuberculosis, pneumonia, and pneumonic plague. Because resistance was boosted by regular exposure to normally mild infections by coronaviruses, there was natural selection for more susceptibility to them.



Two posts ago I argued that coronaviruses have coevolved with the Chinese population, to the point of developing a commensal relationship. A few points:

-  Such viruses include the common cold and are normally mild in their effects.

- Repeated coronaviral infections of lung tissue may actually help increase resistance to more serious pulmonary infections, like tuberculosis, pneumonia, and the Spanish flu of 1918—which curiously spared China. 

- Chinese lung tissue would thus facilitate coronaviral infections as a sort of routine vaccination. 

- If this is true, modern medicine has inadvertently made the Chinese population particularly vulnerable to deadly diseases like the Wuhan coronavirus by reducing the prevalence of milder pulmonary infections.


The examples of herpesvirus and cytomegalovirus

This cross-immunity is seen with other viruses. In mice, gammaherpesvirus 68 (similar to Epstein-Barr virus) provides immunity against much deadlier bacterial pathogens: Listeria monocytogenes; Yersinia pestis, which has caused plagues like the Black Death; and Mycobacterium tuberculosis, i.e. tuberculosis (Barton et al. 2007; Miller et al. 2019). Infection with cytomegalovirus likewise immunizes against Listeria monocytogenes and Yersinia pestis (Barton et al. 2007).

Quite a few writers have argued that many common pathogens are actually allies that help us fight more serious diseases: 

The microbial communities of humans are characteristic and complex mixtures of microorganisms that have co-evolved with their human hosts. The species that make up these communities vary between hosts as a result of restricted migration of microorganisms between hosts and strong ecological interactions within hosts, as well as host variability in terms of diet, genotype and colonization history. The shared evolutionary fate of humans and their symbiotic bacteria has selected for mutualistic interactions that are essential for human health, and ecological or genetic changes that uncouple this shared fate can result in disease. (Dethlefsen et al. 2007)

So it’s possible that humans have coevolved with mildly acting viruses as a means to ward off pathogens that cause more serious pulmonary infections, such as pneumonic plague and tuberculosis. Moreover, this coevolution may have taken different forms in different human populations, a possibility raised by Miller et al. (2019): "our results suggest human γHV-infection may be an important but unrecognized factor which modifies TB outcome, particularly in high TB burden countries where most children acquire EBV [Epstein-Barr virus] by 3 years of age."

Comas et al. (2013) describe the evolution of tuberculosis in our species and how it became more common in certain human environments, particularly "crowded" ones:

Crowd diseases are generally highly virulent and depend on high host population densities to maximize pathogen transmission and reduce the risk of pathogen extinction through exhaustion of susceptible hosts. Many crowd diseases emerged during the Neolithic Demographic Transition (NDT) starting around ten thousand years ago (kya), as the development of animal domestication increased the likelihood of zoonotic transfer of novel pathogens to humans, and agricultural innovations supported increased population densities that helped sustain the infectious cycle. The marked expansion of MTBC [Mycobacterium tuberculosis complex] during the NTD, but not during earlier human expansion events, suggests that the success of this pathogen was primarily driven by increases in human host density, which is typical of crowd diseases.

Perry et al. (2010) have shown that Helicobacter pylori, a bacterium that lives in the stomach lining, greatly reduces the risk of tuberculosis infection. Again, less serious infections help ward off much more serious ones, like tuberculosis:

Why only 10% of infected individuals succumb to tuberculosis remains one of the most vexing public health questions—one which the one-pathogen-one-disease paradigm is ill-equipped to answer. While preliminary, our work suggests that one factor contributing to the clinical outcome of TB infection may be a concurrent chronic infection. The hypothesis that the human microbiome has evolved to provide context-specific competitive risk advantages to the host also raises the intriguing possibility that our microbiota can be manipulated to modulate disease risk from M. tuberculosis, as well as other common human pathogens. (Perry et al. 2010)

Have the Chinese coevolved with coronaviruses?

Common viral infections may have a similar protective effect. If we go back to the Barton et al. study, we find that it was criticized by Yager et al. (2009) on the grounds that the cross-immunity seems to last only five months after acute infection. To benefit from this cross-immunity, lung tissue should therefore be regularly infected with a virus whose adverse effects are both mild and temporary, like most coronaviruses.

Are the Chinese innately more susceptible to coronaviruses? Attention has focused on a study by Zhao et al. (2020), who, using lung tissue from several donors, studied a receptor, ACE2, that acts as the point of entry for some coronaviruses, including the one responsible for the outbreak in Wuhan. They found that the receptor was concentrated in certain cells and that the number of such cells in lung tissue was five times greater in the Asian donor. Yes, there was only one Chinese donor, but the chances are very low that the same normal distribution would produce such an extreme outlier.

This finding is also consistent with those of previous studies. Cheng et al. (2007) looked at other receptors for viral infections and found differences between Chinese and other human populations. In the specific case of pulmonary diseases, Seitz et al. (2012) studied the prevalence of bronchiectasis in the United States and found a prevalence 2.5 to 3.9 times higher among Asian Americans than among Euro Americans or African Americans. Kwak et al. (2010) likewise found a high prevalence of bronchiectasis in Korean adults.

Since my last post on the subject, two more studies have come out.


The Cai study

Cai (2020) failed to find significant differences in ACE2 receptor gene expression between Asian and Caucasian lung tissue but did find an interaction between smoking history and ethnicity: "we found ACE2 is most actively expressed in AT2-reformed cells in former Asian smokers but not in Caucasian current smokers and African American non-smokers." However, this difference wasn’t significant. 

This study has an adequate sample size (n=345) but uses a questionable classification by ethnicity. The lung tissue samples were from a U.S. company, Gene Expression Omnibus, which classifies its samples as "Caucasian," "African American," or "Asian." Although most Asian Americans are of East Asian descent, many have roots in Southeast Asia or South Asia. As we will see, there are probably significant differences in the ACE2 receptor even between Asian groups.


The Cao et al. study 

Cao et al. (2020) looked at the different alleles for the ACE2 receptor gene in two databases: the China Metabolic Analytics Project and the 1000 Genomes Project. They found large differences in allele frequencies among human populations, not only between Asians and other human groups but also between different Asian groups. "These data suggested that there was a lack of natural resistant mutations for coronavirus S-protein binding in [some] populations."

Their conclusion more or less sums up current knowledge:

Recent reports of the ACE2 expression analysis in lung tissues from Asian and Caucasian populations are still controversial. The single-cell RNA-seq analysis reported that the Asian donor had much higher ACE2 expression cell ratio than white and African-American donors. In contrast, the ACE2 expression analysis using the RNA-seq and microarray datasets from control lung tissues indicated there were no significant differences between Asian and Caucasian, or male and female. The ACE2-expressing cells are a very small part of cells in lung tissues. The sample size and the purity of ACE2-positive cells in the selected samples would influence the conclusions. Our analysis showed the differences in distribution and AFs [allele frequencies] of eQTLs for ACE2 in different populations, indicating the diversity of ACE2 expression pattern in populations. […] In addition, our data showed the moderate difference in AFs of eQTLs between South Asian and EAS [East Asians], which suggests the potential difference of ACE2 expression in different populations and ethnics in Asia. (Cao et al. 2020)

Conclusion

Without knowing what these alleles actually do, we can only say that the ACE2 receptor has coevolved differently with different human populations and, presumably, different natural and social environments. In particular, crowded environments, with high rates of life-threatening pulmonary infections, notably tuberculosis, pneumonia, and pneumonic plague, should have favored individuals who are more susceptible to infection by coronaviruses. 

Historically, such environments would encompass not only China but also other areas that have long had large urban populations and a correspondingly long coevolution with pulmonary infections. These areas would notably include the Indo-Gangetic Plain in India and the Fertile Crescent of the Middle East.


References

Barton, E.S., D.W. White, J.S. Cathelyn, K.A. Brett-McClellan, M. Engle, M.S. Diamond, V.L. Miller. H.W. Virgin IV. (2007). Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447:326-9.
https://www.nature.com/articles/nature05762

Cai, G. (2020).  Bulk and single-cell transcriptomics identify tobacco-use disparity in lung gene expression of ACE2, the receptor of 2019-nCov. medRxiv February 17
https://www.medrxiv.org/content/10.1101/2020.02.05.20020107v2

Cao, Y., L. Li, Z. Feng, et al. (2020). Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discovery 6: 11.
https://www.nature.com/articles/s41421-020-0147-1

Cheng, P-L, H-L. Eng, M-H. Chou, H-L. You, T-M. Lin, (2007). Genetic polymorphisms of viral infection-associated Toll-like receptors in Chinese population. Translational Research 150(5): 311-318
https://www.sciencedirect.com/science/article/pii/S1931524407000953

Comas, I., M. Coscolla, T. Luo, S. Borrell, K.E. Holt, M. Kato-Maeda, et al. (2013). Out-of-Africa migration and Neolithic coexpansion of Mycobacterium tuberculosis with modern humans. Nature genetics 45(10): 1176-1182.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800747/

Dethlefsen, L., M. McFall-Ngai, and D. Relman. (2007). An ecological and evolutionary perspective on human-microbe mutualism and disease. Nature 449: 811-818.
https://www.researchgate.net/profile/David_Relman/publication/5902740_Dethlefsen_L_McFall-Ngai_M_Relman_DA_An_ecological_and_evolutionary_perspective_on_human-microbe_mutualism_and_disease_Nature_449_811-818/links/0deec5278790b8a5be000000.pdf

Kwak, H.J., J.Y. Moon, Y.W. Choi, T.H. Kim, J.W. Sohn, H.J. Yoon, D.H. Shin, S.S. Park, and S.H. Kim. (2010). High prevalence of bronchiectasis in adults: analysis of CT findings in a health screening program. Tohoku Journal of Experimental Medicine 222: 237-242.
https://pdfs.semanticscholar.org/dd5d/c5d64f82c84277b74024af0671c8ec070fa6.pdf  

Miller, H. E., K.E. Johnson, V.L. Tarakanova, and R.T. Robinson. (2019). γ-herpesvirus latency attenuates Mycobacterium tuberculosis infection in mice. Tuberculosis (Edinburgh, Scotland) 116: 56-60.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876742/

Perry, S., B.C. de Jong, J.V. Solnick, M. de la Luz Sanchez, S. Yang, P.L. Lin, et al. (2010). Infection with Helicobacter pylori is associated with protection against tuberculosis. PloS one 5(1), e8804.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2808360/

Seitz, A.E., K.N. Olivier, J. Adjemian, S.M. Holland, and D.R. Prevots. (2012). Trends in bronchiectasis among medicare beneficiaries in the United States, 2000 to 2007. Chest 142(2): 432-439.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3425339/  

Yager, E.J., F.M. Szaba, L.W. Kummer, K.G. Lanzer, C.E. Burkum, S.T. Smiley, and M.A. Blackman. (2009). γ-Herpesvirus-induced protection against bacterial infection is transient. Viral immunology 22(1): 67-72.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952138/

Zhao, Y., Z. Zhao, Y. Wang, Y. Zhou, Y. Ma, and W. Zuo. (2020). Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov. bioRxiv January 26
https://www.biorxiv.org/content/10.1101/2020.01.26.919985v1.full  

A Pandora's box?

Chinese lung tissue seems to be receptive to coronaviruses, perhaps because frequent mild infections stimulate the immune system to protect against more serious pulmonary infections, like pneumonia and tuberculosis. This may be why China escaped the ravages of the Spanish flu in 1918. Have modern measures for public health opened a Pandora's box in China? (Wikipedia – CDC)



Are Chinese people more vulnerable than others to the Wuhan coronavirus? The question is raised by Zhao et al. (2020), who examined lung tissues from several donors and studied a receptor that acts as the point of entry for some coronaviruses, including the ones responsible for the SARS outbreak of 2002-2003 and the ongoing outbreak in Wuhan, China. They found that the receptor was concentrated in cells that promote viral reproduction and transmission. They also found that the number of these cells in lung tissue varied with ethnic origin:

A comparison between eight individual samples demonstrated that the Asian male one has an extremely large number of ACE2-expressing cells in the lung. We also noticed that the only Asian donor (male) has a much higher ACE2-expressing cell ratio than white and African American donors (2.50% vs. 0.47% of all cells). This might explain the observation that the new Coronavirus pandemic and previous SARS-Cov pandemic are concentrated in the Asian area.

This study is a preprint and has not yet been peer-reviewed, a fact highlighted in a notice placed above the online paper:

bioRxiv is receiving many new papers on coronavirus 2019-nCoV. A reminder: these are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information.

I often consult bioRxiv, and this is the first time I've seen such a notice. It's not as if this study has been widely publicized in the mainstream media.

A peer reviewer would make the same criticism that the authors themselves make: the sample size is small. In fact, there was only one Asian in the entire sample. Nevertheless, sampling error cannot easily explain the five-fold difference between the Asian donor and the non-Asian ones. Moreover, this finding is consistent with those of previous studies. Cheng et al. (2007) looked at other receptors for viral infections and found differences between Chinese and other human populations. In the specific case of pulmonary diseases, Seitz et al. (2012) studied the prevalence of bronchiectasis in the United States and found that Asian Americans had a prevalence 2.5 to 3.9 times higher than those of Euro Americans and African Americans. Kwak et al. (2010) similarly found a high prevalence of bronchiectasis in Korean adults.

These ethnic differences should be no surprise. Many pathogens can infect some populations more easily than others. This was shown by a study of the TLR2 polymorphism, which influences resistance to such infections as leprosy, tuberculosis, staphylococcal infections, and sepsis:

Interestingly, recent data have pointed out that TLR2 polymorphisms are associated with disseminated tuberculosis or exert specific effects on susceptibility to certain mycobacterial strains, such as the Beijing strains of Mycobacterium tuberculosis. The Beijing strains have a clear geographical distribution, raising the possibility that human TLR2 has coevolved in various populations depending on the type of infectious pressure in a particular region, similarly to what has been reported for polymorphisms in other innate immune genes such as TLR4 or Mal/TIRAP. (Iona et al. 2012)

The argument here is that an infectious disease will favor the survival and reproduction of those people who are more resistant to it. So, over succeeding generations, the average person will become naturally more resistant. The degree of resistance will vary from one population to another because the incidence of infectious pathogens typically varies from one population to another.

In this case, the average Chinese person seems to be naturally less resistant to coronaviruses. That is a bit surprising. The Chinese have cohabited with various forms of livestock for a long time, longer than most humans, and should have become more resistant to viral infections that jump the species barrier, like the current coronavirus in Wuhan. Yet, here, the reverse is true.

Perhaps we're looking at this coevolution the wrong way. Perhaps coronaviruses usually do more good than harm. Perhaps, over time, there has been selection to make the average Chinese person less resistant to them. This possibility has been explored in a recent paper by Shekhar et al. (2017). Certain viral infections of the respiratory tract seem to help their hosts by boosting resistance to bacterial infections:

Little is known about the interaction of the host with commensal viruses and fungi that inhabit the respiratory system. Latent infection with herpesviruses can lead to opportunistic infections in immunocompromised individuals. Recent findings, however, highlight a new role for these viruses in increasing host resistance to bacterial infections. Infection with herpesviruses in mice results in chronic production of large quantities of IFN-γ and activation of macrophages that confer protection from subsequent infection with Listeria monocytogenes and Yersinia pestis. (Shekhar et al. 2017)

So you periodically come down with a mild flu, and you can better resist more serious pulmonary infections, like pneumonia and tuberculosis. Of course, now and again, the flu might be deadly, like the one in 1918. Interestingly, China was largely unaffected by the Spanish flu pandemic: "in 1918, China was spared from the worst ravages of the pandemic, due to the apparent greater resistance to the virus among the Chinese population compared to other regions of the world" (Wikipedia 2020).

Since then, public hygiene measures have steadily reduced chronic exposure to mild pulmonary infections in the Chinese population. If the Spanish flu struck China today, would the Chinese people be just as unaffected? Is this why the Wuhan outbreak has been so severe?


Conclusion

The Chinese population has developed a commensal relationship with coronaviruses, which are usually mild and seem to prepare the immune system for serious pulmonary infections. Through a process of coevolution, the Chinese have become five times more susceptible to coronaviruses than other human populations. 

Far from being an enemy, these viruses may actually be a friend that plays a valuable immunological role. By creating a cleaner social environment, the Chinese authorities may have unwittingly opened a Pandora's box. 

As for non-Chinese people, it doesn't follow that they will be immune to the new coronavirus, only that they will be less vulnerable.

On a final note, the economic disruption due to the Wuhan outbreak will lead to a contraction in Chinese production, and this contraction will exacerbate the ongoing problem of China's shrinking workforce. There are going to be fewer and more expensive consumer goods on the global market. Ironically, all of this is happening as we enter the 2020s—a decade already predicted to be a time of crisis. 


References

Cheng, P-L, H-L. Eng, M-H. Chou, H-L. You, T-M. Lin, (2007). Genetic polymorphisms of viral infection-associated Toll-like receptors in Chinese population. Translational Research 150(5): 311-318
https://www.sciencedirect.com/science/article/pii/S1931524407000953 

Ioana, M., B. Ferwerda, T. S. Plantinga, M. Stappers, M. Oosting, M. McCall, A. Cimpoeru, F. Burada, N. Panduru, R. Sauerwein, O. Doumbo, J. W. M. van der Meer, R. van Crevel, L. A. B. Joosten, and M. G. Netea. (2012). Different Patterns of Toll-Like Receptor 2 Polymorphisms in Populations of Various Ethnic and Geographic Origins. Infection and Immunity 80(5): 1917-1922
https://iai.asm.org/content/80/5/1917 

Kwak, H.J., J.Y. Moon, Y.W. Choi, T.H. Kim, J.W. Sohn, H.J. Yoon, D.H. Shin, S.S. Park, and S.H. Kim. (2010). High prevalence of bronchiectasis in adults: analysis of CT findings in a health screening program. Tohoku Journal of Experimental Medicine 222: 237-242.
https://pdfs.semanticscholar.org/dd5d/c5d64f82c84277b74024af0671c8ec070fa6.pdf

Seitz, A.E., K.N. Olivier, J. Adjemian, S.M. Holland, and D.R. Prevots. (2012). Trends in bronchiectasis among medicare beneficiaries in the United States, 2000 to 2007. Chest 142(2):432-439.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3425339/

Shekhar, S., K. Schenck, and F. C. Petersen (2017). Exploring Host-Commensal Interactions in the Respiratory Tract. Frontiers in Immunology 8: 1971
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776090/  

Wikipedia. (2020). Spanish flu
https://en.wikipedia.org/wiki/Spanish_flu 

Zhao, Y., Z. Zhao, Y. Wang, Y. Zhou, Y. Ma, and W. Zuo. (2020). Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov. bioRxiv January 26
https://www.biorxiv.org/content/10.1101/2020.01.26.919985v1.full