HIV infection disrupts the sympatric host-pathogen relationship in human tuberculosis

Abstract

The phylogeographic population structure of Mycobacterium tuberculosis suggests local adaptation to sympatric human populations. We hypothesized that HIV infection, which induces immunodeficiency, will alter the sympatric relationship between M. tuberculosis and its human host. To test this hypothesis, we performed a nine-year nation-wide molecular-epidemiological study of HIV-infected and HIV-negative patients with tuberculosis (TB) between 2000 and 2008 in Switzerland. We analyzed 518 TB patients of whom 112 (21.6%) were HIV-infected and 233 (45.0%) were born in Europe. We found that among European-born TB patients, recent transmission was more likely to occur in sympatric compared to allopatric host-pathogen combinations (adjusted odds ratio [OR] 7.5, 95% confidence interval [95% CI] 1.21-infinity, p = 0.03). HIV infection was significantly associated with TB caused by an allopatric (as opposed to sympatric) M. tuberculosis lineage (OR 7.0, 95% CI 2.5-19.1, p<0.0001). This association remained when adjusting for frequent travelling, contact with foreigners, age, sex, and country of birth (adjusted OR 5.6, 95% CI 1.5-20.8, p = 0.01). Moreover, it became stronger with greater immunosuppression as defined by CD4 T-cell depletion and was not the result of increased social mixing in HIV-infected patients. Our observation was replicated in a second independent panel of 440 M. tuberculosis strains collected during a population-based study in the Canton of Bern between 1991 and 2011. In summary, these findings support a model for TB in which the stable relationship between the human host and its locally adapted M. tuberculosis is disrupted by HIV infection.

Figure 1. Phylogeography of the six main Mycobacterium tuberculosis lineages.

A: Phylogenetic tree of the main M. tuberculosis lineages described in our study based on the neighbor-joining phylogeny across 23 M. tuberculosis complex whole-genome sequences (from Ref. [72]). Numbers on branches refer to the corresponding number of single nucleotide polymorphisms inferred. B: Distribution of the main phylogenetic M. tuberculosis lineages among Swiss tuberculosis cases included in the study (n = 518), by geographic origin of the patients. In (A) Mycobacterium canettii was used as the outgroup. SNPs, single nucleotide polymorphisms. In (B) the sizes of the pie charts correspond to the number of patients included in the study: European region (233 patients), Middle-East/North Africa (27), Indian subcontinent (36), Western Pacific (19), Central/South America (24), South-East Asia (48), and Eastern (55), Western (46) and Southern region (30) of sub-Saharan Africa. Lineage 1: Indo-Oceanic lineage; Lineage 2: East-Asian lineage (includes Beijing strains); Lineage 3: Delhi/CAS; Lineage 4: Euro-American lineage; Lineages 5 and 6: West African lineages.

Figure 2. Graphical model showing direct and indirect potential effects of HIV infection on tuberculosis (TB) caused by an allopatric Mycobacterium tuberculosis strain, in the context of other potential factors influencing this association.