According to a new study, for certain types of tuberculosis (TB), the risk of infection for an exposed individual can depend on whether they come from the same geographical area as the bacteria, specifically in cosmopolitan cities where diverse populations coexist.
Conducted by scientists from Harvard Medical School and published on August 1 in Nature Microbiology, this research provides the first robust evidence for the long-suspected relationship among pathogen traits, geographic locations, and human hosts, highlighting how these factors interact and influence the likelihood of infection.
The study bolsters a well-established theory suggesting that specific bacterial strains and their human hosts may have coevolved over many years, according to the researchers.
These findings could lead to improved methods for TB prevention and treatment, targeting the intricacies of this cunning pathogen, which sickens over 10 million people and results in more than a million deaths annually worldwide, as per data from the World Health Organization.
This analysis appears to be the first systematic comparison of the infectivity of TB strains among people of varied geographical backgrounds. The research team created a study group by merging patient case files from New York City, Amsterdam, and Hamburg, resulting in a substantial dataset for their models.
The results indicated that individuals living with someone who had a geographically specific strain of TB had a 14% lower risk of becoming infected and a 45% lower likelihood of progressing to active TB compared to those exposed to more widespread strains.
Additionally, strains limited to specific regions were found to be significantly more likely to infect individuals with ancestral ties to that area, as opposed to those from other locations.
The research highlighted that the risk of infection decreased by 38% when someone was exposed to a localized pathogen from an unfamiliar area, in contrast to exposure from their home region. This pattern held true for individuals who either lived in or had ancestral connections to the area.
This connection between pathogens and hosts indicates a shared evolutionary history, where certain biological traits make the two more compatible, thereby increasing infection risk, according to the researchers.
“The magnitude of this effect is quite striking,” noted Maha Farhat, the Gilbert S. Omenn, MD ’65, PhD Associate Professor of Biomedical Informatics at HMS. “This suggests that the implications for public health are significant.”
Why Variations Matter
As genetic sequencing becomes more prevalent, researchers have discovered that not all circulating TB strains are identical. While some lineages are widespread globally, others are confined to specific regions. Due to the complexities of TB transmission in high-incidence areas, where individuals often encounter various strains, it has been challenging to analyze these strains under consistent conditions, leaving researchers to speculate about the reasons for their differences.
Multiple factors can raise the likelihood of getting tuberculosis from close contacts. One of the strongest indicators is the bacterial load, which is assessed through sputum smear microscopy, determining the quantity of bacteria present in the individual’s respiratory system.
Yet, this new study revealed that for geographically confined strains, having ancestral ties to the region where the strain is common is an even stronger predictor of infection risk than bacterial load. In the cases examined, this common ancestry risk surpassed the risks associated with diabetes and other chronic illnesses previously linked to greater susceptibility to infection.
These revelations contribute to a growing understanding of the significance of focusing on the marked variations between different TB lineages and how they interact with various host populations.
Prior studies have established that certain genetic groups of TB are more likely to develop drug resistance, while vaccines can show varying effectiveness depending on the location. Additionally, there’s evidence that specific treatment regimens may be better suited for certain strains.
“These results underscore the necessity of understanding what differentiates various TB strains and why some are closely associated with specific human populations,” remarked Matthias Groeschel, a research fellow in biomedical informatics at HMS and the study’s lead author.
The research team also examined how distinct TB strains infect human macrophages, a type of immune cell the bacteria exploit to cause disease. They cultivated cells from donors with different backgrounds, and once more, cells from individuals with ancestry linked to the geographical origin of a particular strain were more susceptible to infection compared to those without such ties, echoing the epidemiological findings.
Until now, most investigations into how human immune cells interact with TB haven’t compared responses across diverse populations. The researchers emphasized the need for further basic research to unravel the genomic and structural discrepancies governing the interactions between bacteria and host cells.
“Recognizing the vast diversity within human and TB genetics can significantly influence how both respond to treatments and vaccines,” Farhat noted. “This understanding must inform our approach to the disease.”
“We are only beginning to grasp the significance of this diversity,” Groeschel added. “Much more remains to be discovered about its potential effects on drug and vaccine efficacy and the disease’s progression across various strains.”
Advances in Gene Sequencing Present a New Challenge
The distinct genetic groups of TB were initially identified using traditional genotyping methods. However, the global expansion of whole genome sequencing by public health agencies has allowed healthcare professionals to better characterize TB bacteria and monitor outbreaks and drug resistance.
The recognition that highly localized strains spread poorly to other regions led researchers to propose that these constrained strains might be less infectious than their widespread counterparts. This has prompted speculations that localized bacterial populations may have coevolved with their human hosts, rendering certain groups more vulnerable to specific TB types. Moreover, this could imply varying susceptibility to different treatments and vaccines based on strain-specific characteristics.
Previously, testing these hypotheses was nearly impossible due to the variable cultural and environmental factors influencing infection rates across different communities. The rarity with which constrained strains migrated also made data collection impractical for evaluating strain differences.
Collaborative Science Unveils Answers
To tackle these challenges, the research team partnered with public health authorities and research groups in the U.S., Netherlands, and Germany to compile a comprehensive database of TB case reports, pathogen genetic data, and public health records regarding infection rates among close contacts. The analysis also included demographic details about the social networks of infected individuals to examine how various TB genetic lineages propagate among different populations, resulting in a total of 5,256 TB cases and 28,889 close contacts analyzed.
“This study exemplifies the value of fostering collaborations across diverse research fields,” Groeschel remarked. “By merging public health data from three major cities and employing advanced computational biology tools, we addressed a complex question with significant implications for public health, evolutionary biology, vaccine development, and drug research.”
