The Virulence-Transmission Trade-Off: Exploring the Biological Determinants and Epidemiological Consequences of Subclinical Tuberculosis
Human tuberculosis (TB) remains a global health emergency, causing 10 million new cases and 1.5 million deaths every year. TB manifests as a spectrum, ranging from self-cured or asymptomatic infection to active pulmonary and extra-pulmonary disease. Until recently, the common view was that only symptomatic patients with active pulmonary TB can spread the disease. Thus, global TB control has been focusing on active TB in the hope of reducing transmission. However, recent findings indicate that 50% of individuals excreting live TB bacilli report no symptoms; a phenomenon referred to as subclinical TB. Ecological theory predicts an optimal degree of intermediate virulence (defined as the reduction of host fitness caused by the pathogen) that maximizes the transmission of a given pathogen over time (i.e. the effective reproduction number RE). This virulence-transmission trade-off depends on disease specificities that include host and pathogen characteristics, the mechanisms of pathogenesis, and the mode of transmission. Here, we propose that subclinical TB is a reflection of such a virulence-transmission trade-off that varies as a function of the infecting bacterial strain.
TB in humans is caused by nine phylogenetic lineages (L1-L9) of the Mycobacterium tuberculosis Complex (MTBC). L1, L5 and L6 (also known as “ancient”) have repeatedly been associated with lower virulence in model systems compared to the “modern” lineages L2, L3 and L4. Some studies have shown that “ancient” lineages also have a lower transmission rate per unit of time. However, the proportion of these “ancient” lineages has remained constant over the years. So what are the factors maintaining the “ancient” lineages in the face of the more virulent ”modern” lineages? In the context of a virulence-transmission trade-off, we postulate that the “ancient” MTBC lineages pursue a different life-history strategy compared to the “modern” lineages by causing subclinical TB, thereby extending the period during which patients remain infectious, which in turn maximizes RE. We further postulate that these lineage-specific strategies reflect differently in the host-pathogen interaction and host immune responses to infection in subclinical versus active TB.
The goal of this project is to study subclinical TB in the light of a virulence-transmission trade-off and by focusing on both the bacterial and human host determinants. We will address the following Hypotheses: i) subclinical TB is an evolutionary strategy characteristic of the “ancient” MTBC lineages when compared to the more virulent “modern” lineages, ii) the contrasting evolutionary strategies of “ancient” versus “modern” MTBC lineages reflect in molecular and phenotypic differences during the host-pathogen interaction, and iii) subclinical TB can transmit and give rise to secondary cases of active or subclinical TB.
We will test these hypotheses by pursuing the following four Specific Objectives:
- Compare the clinical, epidemiological and bacteriological characteristics of subclinical and active TB;
- Define the genomic and phenotypic characteristics of “ancient” versus “modern” MTBC lineages;
- Determine the infectiousness of subclinical TB compared to active TB and their cellular host responses to infection by “ancient” versus “modern” MTBC lineages in a defined human population from Tanzania;
- Quantify the transmission rate, period of patient infectiousness, effective reproduction number and directionality of transmission in “ancient” versus “modern” MTBC lineages in cases of subclinical TB compared to active TB.
This project builds on our past work on the host-pathogen genetic interactions in TB, during which we have gained a detailed understanding of the genomic diversity of the human host and MTBC populations in Dar es Salaam, Tanzania. Many host and bacterial specimens as well as genomic information have already been collected from active TB patients. We have also developed a customized human SNP array, which will allow controlling for human genomic diversity during phenotypic profiling in this new project. We will use these existing resources as a starting point to pursue our new research questions. Specifically, this project addresses evolutionary questions related to the virulence-transmission trade-off hypothesis by focusing on one of the most important infectious diseases. Moreover, it will generate new insights into the human host- and pathogen biology as well as epidemiology of subclinical and active TB, and at the same time, investigate an urgent but understudied public health problem.