A recent publication on Nature co-authored by scientists from the Ifakara Health Institute, Swiss TPH and the University of Basel underscores the need to prioritize research efforts aimed at addressing genetic differences found in tuberculosis (TB) bacteria strains. 

This approach, emphasizes the scientists, is important for the development of improved vaccines capable of combating the various TB strains effectively.

Understanding immune cell response to TB bacteria 
The study also provides insights into how immune cells (macrophages) from TB patients respond when exposed to different strains of the Mycobacterium tuberculosis complex (MTBC), the bacteria responsible for tuberculosis in humans and animals. 

This complex includes the bacterium Mycobacterium tuberculosis, which is the primary cause of TB in humans. Other members of the MTBC include Mycobacterium bovis, Mycobacterium africanum, Mycobacterium microti, and Mycobacterium canettii. These bacteria share similar genetic characteristics and cause similar diseases, though there can be some differences in their epidemiology and pathogenicity.

Learn more about MTBC here.
Learn more about TB here.

MTBC is primarily spread through the inhalation of infectious respiratory droplets. It consists of nine human-adapted lineages that vary by geographical region. 

“The global spread of the different MTBC lineages to different human populations has been linked to waves of migration, trade and conquest. Yet, some MTBC lineages have remained restricted to a specific geographical region while others have spread around the globe,” noted the scientists.
 
Evaluating genetics’ influence on MTBC
In this study, the scientists sought to investigate whether genetic differences influence the bacteria's ability to infect human cells or predispose individuals to local bacterial strains or if people are more disposed to local strains of the bacteria.

“The global distribution of MTBC lineages indeed varies, with some being globally distributed, sometimes referred to as generalists, while others exhibit geographical restriction, referred to as specialists,” wrote the scientists.

“In this study, we aimed to assess if bacterial genetics governs MTBC pathogenesis or if local co-adaptation translates into differential susceptibility of human macrophages to infection by different MTBC genotypes.”

Hundreds of TB patients recruited in the study 
The study involved immune cells from 633 adult active TB patients recruited between June 2018 and September 2020 at Temeke District Hospital in Dar es Salaam, Tanzania. The patients’ cells were then exposed to both the same MTBC strains that originally infected the patients and different strains from other lineages. 

Different behaviors of TB strains
The findings revealed that different TB strains behaved uniquely inside immune cells. For example, the study found that strains from lineage 1 (L1) showed a significantly lower bacterial burden inside the cells compared to L2, L3 and L4 strains, while (L2) strains showed a higher growth rate within the cells compared to others. Strains from lineage 4 (L4) caused the infected cells to release higher levels of immune signals, indicating a stronger immune response.

Implications on TB control, research efforts
Discussing the findings, the researchers noted, “While our results revealed no measurable effect of local adaptation, they further highlight the strong impact of MTBC phylogenetic diversity on the variable outcome of the host–pathogen interaction in human tuberculosis.”

Furthermore, they concluded by emphasizing the implications of studying MTBC bacteria and its interaction with human hosts, stating, “In conclusion, local adaptation of MTBC strains to their human host population has been proposed to be at the basis of the MTBC phylogeography. However, at the level of the host macrophage at least, our results do not support this notion.”

“Nevertheless,” they added, “our study highlights the relevance of MTBC phylogenetic diversity on TB pathogenesis, with important implications for vaccine development.”

The study underscores the significant impact of genetic differences among MTBC strains on the infection process. Its findings are crucial as they help in understanding the complexity of TB infections and the role of bacterial genetics in disease severity. Such insights could pave the way for more targeted treatments and interventions, ultimately improving TB control and patient outcomes.

Ifakara scientists lead the study
Hellen Hiza of the Ifakara Health Institute led the study with contributions from colleagues, including Michaela Zwyer, Ainhoa Arbués, Sonia Borrell, Amanda Ross, Daniela Brites, Klaus Reither, Sébastien Gagneux, and Damien Portevin from the Swiss Tropical and Public Health Institute (Swiss TPH).

Additional contributors include Jerry Hella and Mohamed Sasamalo from Ifakara Health Institute and Zhi Ming Xu and Jacques Fellay from the Swiss Federal Institute of Technology Lausanne.

Read the publication here.