Monday, March 2, 2020

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)


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.


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.

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

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.

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

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.

Dethlefsen, L., M. McFall-Ngai, and D. Relman. (2007). An ecological and evolutionary perspective on human-microbe mutualism and disease. Nature 449: 811-818.

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.  

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.

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.

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.  

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.

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  


Sean said...

Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2 (4 Mar 2020)

"Although ACE2 is hijacked by some coronaviruses, its primary physiological role is in the maturation of angiotensin, a peptide hormone that controls vasoconstriction and blood pressure. ACE2 is a type I membrane protein expressed in lungs, heart, kidneys and intestine (15–17). Decreased expression of ACE2 is associated with cardiovascular diseases"

Sean said...

Age adjusted Coronary Artery Disease per 100,000 Low rate of heart disease despite high rates of smoking and hypertension among Chinese. A paradox no more.

Anonymous said...

Peter, have you written anything about Mongolian spots?