Abstract
Mycobacterium tuberculosis (Mtb) PPE36, a cell-wall-associated protein, is highly specific and conserved for the Mtb complex group. Although PPE36 has been proven essential for iron utilization, little is known about it in regulating host immune responses. Here we exhibited that PPE36 was preferentially enriched in Mtb virulent strains and could efficiently inhibit host inflammatory responses and increase bacterial loads in infected macrophages and mice. In exploring the underlying mechanisms, we found that PPE36 could robustly inhibit the activation of inflammatory NF-κB and MAPK (Erk, p38, and Jnk) pathways by promoting E3 ligase Smurf1-mediated ubiquitination and proteasomal degradation of MyD88 protein. Our research revealed a previously unknown function of PPE36 on modulating host immune responses and provided some clues to the development of novel tuberculosis treatment strategies based on immune regulation.
Highlights
Tuberculosis is a global health emergency with about 10 million new TB cases and 1.2 million deaths in 2019 [1]
We found that PPE36 could promote the ubiquitination and degradation of the host MyD88 protein by facilitating the interaction of MyD88 with the E3 ligase Smurf1 and suppress the subsequent NF-kB as well as MAPK (Erk, p38, and Jnk) pathways, which led to the dampened host inflammatory responses and increased bacterial loads in macrophages
It was found that PPE36 was much more enriched in the virulent H37Rv strain than the attenuated Bacillus Calmette-Guérin (BCG) strain, and it was further significantly increased in almost 20 clinical isolates (Figure 1A), indicating that similar to other PPE family members [26], PPE36 is preferentially expressed in the virulent mycobacteria
Summary
Tuberculosis is a global health emergency with about 10 million new TB cases and 1.2 million deaths in 2019 [1]. Inoculation of the only widely used tuberculosis vaccine Bacillus Calmette-Guérin (BCG) could not be effective for all populations; the global burden of tuberculosis remains substantial. Host macrophages are the initial and primary targets of Mtb infection. In there, they reside and persist by a variety of immune evasion strategies, including hiding from pattern recognition receptor (PRR) recognition [2], preventing T cell responses by downregulating major histocompatibility complex (MHC) molecules [3], and evading macrophage killing systems [3]. The genomic plasticity of Mtb might be partially responsible for the antigenic variations of diverse strains and the variable protective efficacy of diverse BCG strains [4]
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