Human genetic ancestry, Mycobacterium tuberculosis diversity and tuberculosis disease severity in Dar es Salaam, Tanzania

Abstract

43 Infectious diseases have affected humanity for millennia and are among the strongest 44 selective forces. Tuberculosis (TB) is an ancient disease, caused by the human-adapted 45 members of the Mycobacterium tuberculosis complex (MTBC). The outcome of TB infection 46 and disease is highly variable, and co-evolution between human populations and their MTBC 47 strains may account for some of this variability. Particular human genetic ancestries have 48 been associated with higher susceptibility to TB, but socio-demographic aspects of the 49 disease can confound such associations. Here, we studied 1,000 TB patients from Dar es 50 Salaam, Tanzania, together with their respective MTBC isolates, by combining human and 51 bacterial genomics with clinical data. We found that the genetic background of the TB patient 52 population was strongly influenced by the Bantu migrations from West Africa, which is in 53 contrast to the corresponding MTBC genotypes that were mainly introduced from outside 54 Africa. These findings suggest a recent evolutionary history of co-existence between the 55 human and MTBC populations in Dar es Salaam. We detected no evidence of an effect of 56 human genetic ancestry, or MTBC phylogenetic diversity alone, nor their interaction, on TB 57 disease severity. Treatment-seeking, social and environmental factors are likely to be the 58 main determinants of disease severity at the point of care in this patient population. 59 3 bioRxiv preprint doi: https://doi.org/10.1101/2024.08.10.607244; this version posted August 10, 2024. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license. 60 Author Summary 61 Tuberculosis (TB) is an ancient infectious disease that continues to challenge global health 62 efforts. Here, we explored the interplay between human and bacterial genetics on TB in Dar 63 es Salaam, Tanzania. We found that neither the genetic ancestry of the patient, nor the 64 bacterial genotype alone, nor their interaction, influenced the severity of TB. Our finding 65 indicate that in this patient population, social and environmental factors may be the main 66 determinants of TB disease severity. 67 4 bioRxiv preprint doi: https://doi.org/10.1101/2024.08.10.607244; this version posted August 10, 2024. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license. 68