Biology subjects

Steyn, A.

Publications and source records attributed to Steyn, A..

2 recordsLinked to original sources

bioRxiv2025

Targeting ALOX5/LTA4H driven granuloma caseation as a host-directed strategy for control of TB associated lung damage

Tuberculosis remains one of the major global health challenges with those previously exposed presenting persisting pulmonary dysfunction. Therefore, improved control measures are still required to prevent or reduce the TB-induced immunopathology in affected individuals. Host directed therapies that target host factors, have been suggested to improve on current treatments against TB. We previously reported a potential role for proteins which metabolize the arachidonic acids during TB immunopathogenesis. The study, therefore, sought to demonstrate the potential role of these proteins in TB-induced immunopathology. Using immune-histopathological assays, the association of macrophage driven ALOX5 signaling with severe pulmonary immunopathology during TB was demonstrated. Furthermore, using both in vitro and in vivo assays, the data demonstrated the contribution of ALOX5 signaling to TB-induced granulomatous inflammation. Interception of the signaling pathway through clinically approved pharmaceutical inhibitors, resulted in reduced lung damage during the disease. The resolution of TB-induced lung pathology further contributed to increased bactericidal activity. Taken together, our data strongly suggest a role for macrophage driven inflammation via ALOX5 signaling which can be targeted for the development of therapeutic treatment to prevent exacerbated TB-induced pulmonary immunopathology.

immunology↗

bioRxiv2021

Aggregated Mycobacterium tuberculosis enhances the inflammatory response

Mycobacterium tuberculosis (Mtb) readily aggregates in culture and Mtb aggregates in the lung were observed in experimental Mtb infection. However, the physiological consequences of Mtb aggregation are incompletely understood. Here we examined the human macrophage transcriptional response to aggregated Mtb relative to infection with non-aggregated single or multiple bacilli per host cell. Infection with aggregated Mtb led to an early upregulation of pro-inflammatory associated genes and enhanced TNF signaling via the NF{kappa}B pathway. Both these pathways were significantly upregulated relative to infection with single bacilli, and TNF signaling was also significantly elevated relative to infection with multiple non-aggregated Mtb. Secretion of TNF and downstream cytokines were also enhanced. On a longer timescale, aggregate infection led to overall increased acidification per macrophage and a high proportion of death in these cells after aggregate phagocytosis. Host cell death did not occur when Mtb aggregates were heat killed despite such clumps being readily picked up. To validate that Mtb aggregates do occur in the human lung, we document Mtb aggregates surrounding a cavity in a human TB lesion. Aggregates may therefore be present in some lesions and elicit a stronger inflammatory response resulting in recruitment of additional phagocytes and their subsequent death, potentially leading to necrosis and transmission.

microbiology↗