Publications by Year: 2025

UNLABELLED: We previously reported that live, but not dead, virulent Mycobacterium tuberculosis (Mtb) H37Rv bacilli induce cell death in human lung fibroblast cell lines, MRC-5, MRC-9, and TIG-1. Here, using two distinct Mtb strains from two different lineages (HN878 lineage 2 and H37Rv lineage 4), we confirmed cell death at day 2 after infection with a device that measures cell growth/cytotoxicity in real time (Maestro-Z [AXION]). Mtb bacilli uptake by the fibroblast was confirmed with a transmission electron microscope on day 2. Expressions of inflammatory cytokines and interleukin (IL)-1β, IL-6, and IL-8 were observed when exposed to live, but not dead bacteria. The cell death of fibroblasts induced by both Mtb strains tested was prevented by caspase-1/4 and NLRP3 inflammasome inhibitors, but not by caspase-3 and caspase-9 inhibitors. Therefore, we classified the fibroblast cell death by Mtb infection as pyroptosis. To investigate the biological and pathological relevance of fibroblast cell death by Mtb infection, we performed dual RNA-Seq analysis on Mtb within fibroblasts and Mtb-infected fibroblasts at day 2. In Mtb bacilli tcrR, secE2, ahpD, and mazF8 genes were highly induced during infection. These genes play roles in survival in a hypoxic environment, production of a calcium-binding protein-inducing cytokine, and regulation of transcription in a toxin-antitoxin system. The gene expressions of IL-1β, IL-6, and IL-8, caspase-4, and NLRP3, but not of caspase-3 and caspase-9, were augmented in Mtb bacilli-infected fibroblasts. Taken together, our study suggests that Mtb bacilli attempt to survive in lung fibroblasts and that pyroptosis of the host fibroblasts activates the immune system against the infection.

IMPORTANCE: The role of "non-classical immune cells," that is, fibroblasts, epithelial cells, adipocytes, etc., except for the "classical immune cells," that is, macrophages and lymphoid cells, is not well known in the infection of Mtb bacilli. We have previously found that live, but not dead, Mtb bacilli induce cell death in human lung fibroblasts, except in human macrophages and monocytes. The present study reveals that fibroblasts ingest Mtb bacilli the same as macrophages and that in vivo Mtb bacilli within fibroblasts attempt to survive in the host cells, and pyroptosis, including the production of inflammatory cytokines, is induced in the Mtb-infected fibroblasts. Our results suggest that pyroptosis of the host fibroblasts activates the immune system against the infection.

BACKGROUND: Nigeria bears a high burden of infectious diseases, with the second-highest human immunodeficiency virus (HIV) prevalence globally and the largest tuberculosis (TB) burden in Africa. The country faces significant challenges from armed conflicts, insurgency, kidnapping and banditry, which severely strain its healthcare system, particularly for people living with HIV (PLHIV). This study hypothesizes that PLHIV in conflict-affected regions of Nigeria experience a higher burden of TB than those in non-conflict areas.

METHODS: This cross-sectional household survey utilised a two-stage cluster sampling design to examine HIV/TB co-infection and associated behaviours in Nigeria, based on data from the 2018 Nigeria HIV/ acquired immune deficiency syndrome (AIDS) Indicator and Impact Survey. The sample included adults aged 15 to 64 in the selected households. We mapped the distribution of HIV/TB co-infection across the country and calculated its prevalence, stratified by conflict and non-conflict zones. Adjusted odds ratios (AOR) and 95% confidence intervals (CIs) from survey-weighted logistic regression models were used to assess the likelihood of being diagnosed with TB disease among PLHIV.

RESULTS: We analysed weighted data from 1,319,719 PLHIV across Nigeria, with 200,201(15.2%) residing in conflict zones and 1,119,518 (84.8%) in non-conflict zones. Overall, the prevalence of HIV/TB co-infection was 40.4% (52,118), with PLHIV residents of conflict zones exhibiting a significantly higher prevalence (59%, 14,976) compared to those from non-conflict zones (36%, 37,413). After adjusting for confounders, PLHIV in conflict zones were more than four times more likely to acquire TB than those from non-conflict zones (AOR: 4.21, 95% CI: 1.72-10.5, p = 0.002).

CONCLUSIONS: Conflicts amplify the risk of TB among PLHIV in Nigeria, highlighting an urgent need for targeted interventions to strengthen healthcare access in these regions. The efforts are essential in achieving the goals of reducing TB prevalence by 50% and TB mortality by 75% by 2025, as well as meeting the 95-95-95 targets to control HIV by 2030.

The Coronavirus Immunotherapeutic Consortium (CoVIC) conducted side-by-side comparisons of over 400 anti-SARS-CoV-2 spike therapeutic antibody candidates contributed by large and small companies as well as academic groups on multiple continents. Nine reference labs analyzed antibody features, including in vivo protection in a mouse model of infection, spike protein affinity, high-resolution epitope binning, ACE-2 binding blockage, structures, and neutralization of pseudovirus and authentic virus infection, to build a publicly accessible dataset in the database CoVIC-DB. High-throughput, high-resolution binning of CoVIC antibodies defines a broad and predictive landscape of antibody epitopes on the SARS-CoV-2 spike protein and identifies features associated with durable potency against multiple SARS-CoV-2 variants of concern and high in vivo efficacy. Results of the CoVIC studies provide a guide for selecting effective and durable antibody therapeutics and for immunogen design as well as providing a framework for rapid response to future viral disease outbreaks.