Tuberculosis in migrants - screening, surveillance and ethics.

Tuberculosis (TB) is the leading infectious cause of human mortality and is responsible for nearly 2 million deaths every year. It is often regarded as a 'silent killer' because it predominantly affects the poor and marginalized, and disease outbreaks occur in 'slow motion' compared to Ebola or coronavirus 2 (COVID-19). In low incidence countries, TB is predominantly an imported disease and TB control in migrants is pivotal for countries to progress towards TB elimination in accordance with the World Health Organisations (WHO's) End TB strategy. This review provides a brief overview of the different screening approaches and surveillance processes that are in place in low TB incidence countries. It also includes a detailed discussion of the ethical issues related to TB screening of migrants in these settings and the different interests that need to be balanced. Given recognition that a holistic approach that recognizes and respects basic human rights is required to end TB, the review considers the complexities that require consideration in low-incidence countries that are aiming for TB elimination.

Post-migration follow-up programme for migrants at increased risk of developing tuberculosis: a cohort study.

Following pre-migration screening for tuberculosis (TB), migrants who are deemed to be at a high risk of developing TB must attend post-entry follow-up in Australia. We aimed to evaluate the effectiveness of post-migration TB follow-up in the state of New South Wales to diagnose TB in these high-risk migrants. In this retrospective cohort study, we assessed the risk of TB in migrants who arrived in New South Wales between 2000 and 2015 and were referred for post-migration follow-up. Clinical notes were examined for a nested cohort to determine whether TB was diagnosed via the follow-up programme or via passive case finding. Of the 32 550 migrants referred for follow-up, 428 (1.3%) developed TB. The incidence of TB was 436 per 100 000 person-years (95% CI 384-491 per 100 000 person-years) in the first 2 years after arrival and 128 per 100 000 person-years (95% CI 116-140 per 100 000 person-years) over the mean study observation period of 10.3 years. An estimated 63% of cases were diagnosed via follow-up. TB notifications occurred 0.55 years earlier since time of arrival in Australia in migrants who attended follow-up than in those who did not. Post-migration follow-up detected 63% of TB cases in high-risk migrants and potentially prevented delay of TB diagnosis.

Assessment of live candidate vaccines for paratuberculosis in animal models and macrophages.

Mycobacterium avium subsp. paratuberculosis (basonym M. paratuberculosis) is the causative agent of paratuberculosis, a chronic enteritis of ruminants. To control the considerable economic effect that paratuberculosis has on the livestock industry, a vaccine that induces protection with minimal side effects is required. We employed transposon mutagenesis and allelic exchange to develop three potential vaccine candidates, which were then tested for virulence with macrophages, mice, and goats. All three models identified the WAg906 mutant as being the most attenuated, but some differences in the levels of attenuation were evident among the models when testing the other strains. In a preliminary mouse vaccine experiment, limited protection was induced by WAg915, as evidenced by a reduced bacterial load in spleens and livers 12 weeks following intraperitoneal challenge with M. paratuberculosis K10. While we found macrophages and murine models to be rapid and cost-effective alternatives for the initial screening of M. paratuberculosis mutants for attenuation, it appears necessary to do the definitive assessment of attenuation with a ruminant model.

Gene expression in HIV-1/Mycobacterium tuberculosis co-infected macrophages is dominated by M. tuberculosis.

The resurgence of tuberculosis worldwide has closely mirrored the HIV pandemic. In regions like sub-Saharan Africa, a large proportion of individuals are co-infected with Mycobacterium tuberculosis and HIV. Macrophages are the reservoir host cells for both pathogens, however the interactions between both pathogens in co-infected cells remain poorly understood. Thus, the global gene responses of primary human macrophages following productive co-infection with highly purified HIV and M. tuberculosis were analyzed using cDNA microarrays. A broad range of genes was up-regulated in response to co-infection or M. tuberculosis infection of primary macrophages, including those encoding pro-inflammatory chemokines and cytokines, their receptors, signalling associated genes, type I IFN signalling genes and genes of the tryptophan degradation pathway. Real-time RT-PCR analysis confirmed up-regulation of a wide variety of genes including indoleamine 2,3 dioxygenase and Sp110 in M. tuberculosis and co-infected samples. Downstream analysis confirmed significant elevation of the chemokines CCL3, CCL4 and CCL8 in M. tuberculosis and co-infected culture supernatants. In contrast, the changes seen in gene expression following HIV infection alone were fewer in number and significantly less in magnitude. Thus, the effects of M. tuberculosis infection on global gene expression dominated the effects of HIV-1 in co-infected primary human macrophages.

Contribution of L-alanine dehydrogenase to in vivo persistence and protective efficacy of the BCG vaccine.

The tuberculosis (TB) vaccine strain Mycobacterium bovis BCG is unable to utilise alanine and this deficiency is thought to inhibit the growth of the vaccine in vivo and limit vaccine efficacy. In this report we demonstrate that L-alanine catabolism can be conferred on BCG by introduction of the gene encoding L-alanine dehydrogenase (Ald) of Mycobacterium tuberculosis. Restoration of Ald activity did not change the in vivo growth of BCG in macrophages or mice, and protection against aerosol M. tuberculosis infection was not altered by addition of ald to the BCG vaccine. These results demonstrate that the inability to utilise L-alanine is not a contributing factor to the attenuated phenotype of BCG and does not influence the protective efficacy of the vaccine against TB.