An Mtb-Human Protein-Protein Interaction Map Reveals that Bacterial LpqN Antagonizes CBL, a Host Ubiquitin Ligase that Regulates the Balance Between Anti-Viral and Anti-Bacterial Responses

Abstract

Although macrophages are armed with potent anti-bacterial functions, Mycobacterium tuberculosis (Mtb) replicates inside these innate immune cells. Determinants of macrophageintrinsic bacterial control, and the Mtb strategies to overcome them are poorly understood. To further study these processes, we used a systematic affinity tag purification mass spectrometry (AP-MS) approach to identify 187 Mtb-human protein-protein interactions (PPIs) involving 34 secreted Mtb proteins. This interaction map revealed two new factors involved in Mtb pathogenesis -the secreted Mtb protein, LpqN, and its binding partner, the human ubiquitin ligase CBL. We discovered that an lpqN Mtb mutant is attenuated in macrophages, but growth is restored when CBL is removed. Conversely, Cbl -/macrophages are resistant to viral infection, indicating that CBL regulates cell-intrinsic polarization between anti-bacterial and anti-viral immunity. Collectively, these findings illustrate the utility of this Mtb-human PPI map as a resource for developing a deeper understanding of the intricate interactions between Mtb and its host.

A Trifector of New Insights into Ovine Footrot for Infection Drivers, Immune Response and Host Pathogen Interactions

“…In the case of infections, some species of bacteria have been implicated in hijacking the host splicing machinery and altering the splicing pattern leading to the perturbation of the host response (22,23). Despite the lack of knowledge around the mechanism, there is evidence that certain Listeria, Salmonella and Mycobacterium species have the ability to produce factors that have a direct or indirect impact on the regulation of alternative splicing (23)(24)(25). Alternative splicing from the U6 spliceosomal RNA can interfere with the normal activation of T cell and B lymphocytes and the regulation of the signalling in several TLR's (TLR2, TLR3 and TLR4) (26), which could tie in with certain pathways (monovalent inorganic cation homeostasis, defence response to bacteria, skin development, neutrophil chemotaxis, leukocyte migration, defence response, immune system processes, immune response) which were identified as being downregulated in these data.…”