Involvement of Stat1 in the Phagocytosis ofM. avium

Abstract

<jats:p><jats:italic>Mycobacterium avium</jats:italic>is an intracellular pathogen preferentially infecting human macrophages where they activate the JAK/STAT1 pathway. This activation enhances the survival of infected cells, but, at the same time, makes macrophages optimal targets for drugs development against p-tyr<jats:sub>701</jats:sub>stat1. In this study, we demonstrate that the fast and transient activity of the JAK/STAT1 pathway occurs immediately after macrophages internalization of heat-killed<jats:italic>M. avium</jats:italic>or inert particles. Furthermore, we show that a persistent Stat1 pathway activation occurs only when an intracellular<jats:italic>M. avium</jats:italic>infection is established in macrophages. These results strongly indicate different mechanisms of p-tyr<jats:sub>701</jats:sub>Stat1 activation. In particular, here we report findings aiming at explaining the short-time enhancement of p-tyr<jats:sub>701</jats:sub>Stat1 and shows its predominant relationship with Fc<jats:italic>γ</jats:italic>Rs engagement during the internalization process. Furthermore, we demonstrate that opsonized live<jats:italic>M. avium</jats:italic>is phagocytosed by macrophages involving membrane receptors not related with JAK/STAT1 signalling pathway. On the contrary, heat-inactivated bacilli or latex particles seem to be internalized only after involvement of Fc<jats:italic>γ</jats:italic>Rs and subsequent Stat1 phosphorylation.</jats:p>

Selective inhibition of IFNG-induced autophagy byMir155- andMir31-responsive WNT5A and SHH signaling

“…Supporting our observation, previous reports suggest that Mycobacteria and its cell wall components, like TDM, downregulate IFNG-mediated responses by inhibiting STAT phosphorylation including p-STAT1. [52][53][54] Of note, individuals with STAT1 deficiency or defects in IFN-JAK-STAT pathway exhibit increased susceptibility to mycobacterial infections. 55,56 Impaired activation of STAT1 or reduced STAT1 phosphorylation in patients with active tuberculosis further underscores our data.…”

Mycobacterium leprae-induced Insulin-like Growth Factor I attenuates antimicrobial mechanisms, promoting bacterial survival in macrophages

“…The capacity of mycobacteria to induce NO production in murine macrophages through a JAK/STAT-dependent signaling pathway has been previously described 24 25 . However, unlike BCG and MS, known to activate the NF-κB transcriptional factor 22 26 , ML has been shown to be both a weaker stimulator and even an inhibitor of NF-κB activation 22 27 28 .…”

Modulation of Stat-1 in Human Macrophages Infected with Different Species of Intracellular Pathogenic Bacteria

“…Various findings suggest that Stat proteins play an important role in bacterial infections [ 5 , 32 ]. In a previous work, we reported that live M. avium infection in macrophages kept the Jak/Stat-1 pathway active for a considerable period (more than 7 days), subsequent to the establishment of an intracellular infection and bacteria replication in the phagosome [ 7 ]. We believe that certain membrane receptors such as FcRs correlated with the Jak/Stat-1 signaling pathway activation and may be able to mediate bacilli phagocytosis or particle internalization in macrophages after opsonization.…”

“…In a subsequent study [ 7 ] we showed that internalization of heat-killed M. avium or inert particles induced a fast and transient activity of the Jak/Stat-1 pathway when internalized by Fc γ receptor engagement, probably as a preventive defense mechanism. However, a persistent Stat-1 pathway activation occurs only when an intracellular M. avium infection is established in macrophages.…”