Chinese scholars have made progress in the research of the mechanism of interaction between Mycobacterium tuberculosis and host

With the support of the National Natural Science Foundation of China (grant numbers: 81825014, 31830003, 82171744, 82022041), the team of researcher Liu Cuihua from the Institute of Microbiology, Chinese Academy of Sciences has made new progress
in the study of the mechanism of interaction between Mycobacterium tuberculosis and the host 。 The findings, titled "A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking ubiquitin," was published online in the journal
Science on October 14, 2022 。 Links to papers: _istranslated="1">.

Tuberculosis (TB) is a major chronic infectious disease
caused by infection with Mycobacterium tuberculosis (Mtb).
According to the World Health Organization, there were nearly 9.
9 million new TB patients worldwide in 2020 and about 1.
51 million deaths
due to Mtb infection.
Inflammasome, a polyprotein complex found in mammalian immune cells in recent years, can rapidly assemble and cleave the downstream key effector gasdermin D (GSDMD) and inflammatory cytokine precursors when stimulated by activation signals, which in turn mediates the release of mature inflammatory cytokines, and eventually leads to pyroptosis
.
Studies have suggested that the inflammasome-cell pyrococcosis pathway plays an important role
in host resistance to infection with pathogens such as Mtb.
However, whether and how these pathogens can escape this immune mechanism is unclear
.
Therefore, further identification and eluciation of the key effector proteins of pathogens such as Mtb in regulating the host inflammasome-cell pyrotic pathway are expected to provide new drug targets and intervention strategies
for infectious diseases such as TB.

By constructing a recombinant system of AIM2 and NLRP3 inflammasomes in HEK293T cells, the research team comprehensively screened the eukaryotic-like secreted proteins encoded by Mtb, identified the protein phosphatase PtpB secreted by Mtb as a potential inhibitory molecule of the host inflammasome-cell pyrotic pathway, and found that PtpB can be localized to the host cell plasma membrane during Mtb infection, and binds to and is activated by the host ubiquitin through the eukaryotic ubiquitin binding module (UIM-like).
Dephosphorylation of phosphatidinositol-4-monophosphate (PI4P) and phosphatidinositol-(4,5)-bisphosphate (PI(4,5)P₂) on the plasma membrane of host cells inhibit the N-terminal effector domain (GSDMD-N) of GSDMD on the plasma membrane, prevent the release of cytokines IL-1β and IL-18, and ultimately inhibit cell pyrosis
。 In vivo animal experiments have also confirmed that disrupting the lipphosphatase activity or ubiquitin-binding region of PtpB can significantly enhance the host's protective immune response and clearance of Mtb in the early stages of infection, and reduce the host's pathological immune damage in the late stages of infection (Fig.
).

This study revealed the pathogenic immune escape mechanism of Mtb using lipphosphatase PtpB to hijack host ubiquitin and antagonize GSDMD-mediated cell pyrosis, which provides new ideas and potential targets based on pathogen-host interaction interface for the treatment of TB
.