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This study is a preprint and has not yet been peer-reviewed, a fact highlighted in a notice placed above the online paper: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 A reminder: these are preliminary reports that have not been peer-reviewed.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