The Human-Tuberculosis Arms Race

by Sanjana Kulkarni
figures by Corena Loeb

The bacteria Mycobacterium tuberculosis (TB) has been infecting humans for thousands of years. Today, TB, which is thought to have originated in Africa and evolved alongside human hosts, is found across the globe and causes 1-2 million deaths annually, making it the second leading infectious disease killer after COVID-19. As new COVID-19 variants keep emerging, we can observe the evolution of the virus in response to vaccines and human immune systems. Along the same lines, because TB has been infecting humans for millennia, we can observe coevolutionary relationships between TB and humans.

Host-Pathogen Coevolution

Coevolution is when two organisms evolve alongside each other by imposing selection pressures on one another. Selection pressures are external agents in the environment that drive natural selection, making some traits (i.e. body size, intelligence, ability to use different food sources) beneficial and others harmful, allowing certain individuals to survive and reproduce. Over time, this ultimately changes the genetic makeup of the entire population, as the organisms that are better suited to their environment survive and reproduce more than others. Coevolution typically occurs between pairs of organisms that live very close together and are often dependent on each other for survival.

Pathogens are disease-causing parasites that take advantage of a host organism’s resources, linking the two together in a coevolutionary relationship. Hosts with better survival traits can resist the pathogen, but pathogens can quickly evolve novel strategies to overcome the host. TB and humans are locked in this type of evolutionary arms race. In recent years, the field of paleomicrobiology has made many discoveries about the complex relationship between TB and humans over time.

Adaptation of TB to Different Human Populations

Many pathogens, like COVID-19, infect people in different places to a similar degree. As new variants evolve, the most effective ones quickly spread across the entire world and don’t remain confined to their place of origin. In contrast, TB exhibits local adaptation, in which TB lineages are best adapted to infect and transmit between humans who live in the same geographic area. There are seven primary lineages of TB: three are distributed across most of the world, while the other four are more geographically restricted (Figure 3).

In large cities where people and bacteria from different parts of the world mix, a person is more likely to be infected with a TB lineage from the country of their ethnic origin than any other lineage. Some of this could be due to people preferentially interacting within their ethnic groups, but after accounting for such patterns, differences in severity between TB lineages, and underlying conditions in humans that affect their lung function, TB transmission and disease severity are higher when the lineage and human ethnicity match.

The likely reason for this observation is found in the evolution of the human immune system. TB infects immune cells called macrophages, which engulf (eat) pathogens and help activate other immune cells to attack the invaders (Figure 1). Different lineages of TB probably adapted to genetically-encoded features of our immune systems, which are passed from parents to children like all genes are, allowing different people to be preferentially infected with different TB lineages.

**Figure 1:** The bacteria that cause TB are rod-shaped, and spread via droplets expelled by people when they cough. TB gets into the lungs and infects macrophages, causing symptoms like coughing, chest pain, fever, and fatigue. TB can’t survive for long outside of humans, and no other animals can harbor TB in the wild (though there are related bacterial species in animals).

TB Selective Pressures on Human Immune Systems

Because of our long history with TB, natural selection has favored humans who are better able to survive this often deadly disease. Along these lines, scientists have discovered genetic variants that have been suppressed in humans because they make people more susceptible to severe TB. One well-studied variant, called P1104A, hampers the ability of a protein called TYK2 to cause inflammation and signal immune cells to mature, thus preventing it from helping to fight off TB infections.

Because of the interesting role of P1104A in TB, scientists investigated its evolutionary history in ancient European human genomes, finding that its frequency fluctuated for a few thousand years before it began to increase 5,000 years ago. After reaching a maximum prevalence of 10% in the European genome 3,000 years ago, the frequency of P1104A consistently decreased to 3% in Europeans today. Using simulations of human migration, natural selection, and other factors, scientists concluded that the drop was likely explained by negative selection, in which a genetic variant that is harmful to a species’ survival becomes rarer because individuals with it are more likely to die. The scientists found that negative selection of P1104A probably started around 2,000 years ago, which roughly coincides with the appearance of the most common lineage of TB today.

**Figure 2: The arms race between our immune systems and infections.** Our immune systems rely largely on antibodies to find and destroy infections such as COVID-19 and TB. Antibodies help clear these infections, but some viruses and bacteria are naturally better at evading the immune system and are able to survive. These then get selected for and make many copies of themselves. The immune system then needs to make new antibodies to go after the viruses or bacteria that escaped in the first round. This arms race is a general principle that applies to many host–pathogen relationships.

Human Selective Pressures on TB Latency

One of the hallmarks of TB is its ability to cause a latent infection. After infecting a person, if TB is not cleared or treated with antibiotics, it can reach a stalemate with the immune response, in which the bacteria stays in the body and replicates at very low levels without causing symptoms. If the immune system is later weakened, TB reactivates and causes severe lung disease. During latency, TB cannot spread between hosts because it does not cause respiratory symptoms and is thus unable to spread via cough droplets.

Some scientists have hypothesized that latency evolved in TB because, before humans took up farming and established permanent settlements, they lived in small nomadic groups, and a rapidly spreading pathogen would not have been very successful because there were not many people to spread to. Latency allowed TB to remain in a human and then reactivate later, hopefully when more humans were around to spread to. As human populations grew, the selection pressures changed. Latency was an effective strategy when humans lived in small groups, but bacteria that can spread quickly have an advantage in large, dense groups of hosts. Compared to the ancient (older) lineages, the modern (younger) lineages of TB cause more severe disease, have shorter latency periods, and are not detected as well by macrophages. Scientists think that the growth of human populations selected for TB strains that could better evade our immune system and cause more severe disease, allowing them to spread faster.

**Figure 3: Map of the seven major lineages of TB and their global distributions.**
Lineages two, three, and four are the modern and most widespread lineages. Lineages one, five, and six are considered the ancient lineages, while lineage seven is intermediate between the two groups. Africa is currently the only continent where all seven lineages (and two more recently discovered lineages) are found, and many bacteria related to TB that infect animals are also found here. Adapted from Figure 1 in this paper.

Summary

Infectious diseases are the strongest selective pressures on humans. Expanded access to whole-genome sequencing and more computational power is allowing us to learn much more about how infectious diseases have shaped humans. The antibiotics that we use against TB and other bacteria are some of the strongest selective pressures on pathogens today. Because these drugs are so potent, bacteria with genes conveying drug resistance have a very large survival advantage over bacteria that do not have them. TB has not evolved at the same rate throughout its history, and it is possible that antibiotic use will accelerate its evolution. With modern sequencing and analysis tools, global TB surveillance is improving, potentially allowing people to observe TB evolution in real time.

Sanjana Kulkarni is a first-year Ph.D. student in Virology at Harvard Medical School.

Corena Loeb is a first-year Ph.D. student in the Harvard-MIT program in Speech, Hearing, Bioscience and Technology

For More Information:

To learn how P1104A frequency declined in Europe, check out the paper here. A good summary of this paper can be found here.
To read more about coevolution relationships and what is known as the Red Queen hypothesis, check out this blog post or the very comprehensive Wikipedia article.
To find out how malaria has influenced human evolution through selection for the sickle cell trait and other blood cell-related disorders, check out these two articles.
HIV infection and immunosuppression can alter local adaptation in TB. See this article to find out more.
Check out this review article about how TB evolved from an environmental bacterium to one that depends on humans for survival and transmission.