Tuberculosis (TB) is a chronic infectious disease caused by M. tuberculosis (Mtb) and remains one of the leading causes of death. According to report from the World Health Organization (WHO), about 10.4 million people were estimated to have fallen ill with TB and 1.8 million people died from TB in 2015 (WHO, 2016). Mtb can secrete a variety of effector proteins into host cells during infection, thus interfering with multiple signaling pathways and cellular functions, and ultimately promoting the intracellular survival of the pathogen and causing host pathology.

Dr. LIU Cuihua’s group has been investigating the molecular mechanisms underlying Mtb-host interactions. Previous studies from her group revealed that Mtb effector proteins (such as PtpA and Mce3E) modulate host innate immunity to promote the intracellular survival of mycobacteria. They also discovered that Mtb PtpA interacts with the host ubiquitin ligase TRIM27 and antagonizes TRIM27-promoted JNK and p38 MAPK pathways activation and cell apoptosis.

Those studies revealed the mutual antagonism between Mtb and host innate immune defense, and provided potential targets for the development of anti-TB treatments based on pathogen-host interacting interfaces (Nature Immunology, 2015; The Journal of Immunology, 2015; Scientific Reports, 2016).

Increasing studies have demonstrated that pathogens (include many viruses and bacteria)-induced chronic inflammation could promote tumorigenesis and development. However, there is conflicting evidence concerning a possible association between pulmonary TB and subsequent risk of lung cancer, and causal links between Mtb-induced chronic infection and lung cancer have not been demonstrated.

In their efforts to elucidate the roles of Mtb effector protein PtpA in innate immune regulation, they noticed that PtpA could not only regulate innate immune signaling pathways in the host cytoplasm, but also enter into the host nucleus (Fig. 1).

Data from ChIP-seq analysis indicated that PtpA could potentially regulate the transcription of a variety of protein-coding genes, which are known to be involved in host innate immune signaling (such as TNFRSF8), cell proliferation and migration (such as GADD45A).

Further investigation revealed that PtpA can directly bind to the promoter region of GADD45A and inhibit its transcription. Infection with PtpA-expressing BCG can promote proliferation and migration of human lung adenocarcinoma epithelial (A549) cells, partially through targeting GADD45A.

Furthermore, several potential PtpA-targeted ncRNA genes (such as miR-488, CASC2, and miR-622) are involved in tumor progression through regulating cell apoptosis, proliferation and migration (Fig. 2).

Thus, they speculated that nuclear PtpA might potentially contribute to lung cancer development during chronic Mtb infection through regulating the transcription of certain checkpoint protein-coding genes (such as GADD45A) and ncRNAs. Their study provides mechanistic evidence supporting a causal link between Mtb-associated chronic infection and lung cancer development.

The paper entitled “The Mycobacterial phosphatase PtpA regulates the expression of host genes and promotes cell proliferation” has been published online in Nature Communications (http://www.nature.com/articles/s41467-017-00279-z.pdf ) with Dr. WANG Jing and Ge Pupu as joint first authors and Dr. LIU Cuihua as corresponding author.

This work was supported by grants from National Basic Research Programs of China, the National Natural Science Foundation of China, the Beijing Natural Science Foundation and the Youth Innovation Promotion Association from Chinese Academy of Sciences. 

　　Figure 1. PtpA is present both in the cytoplasm and nucleus of host cells (Image by Prof. LIU’s group)

　　

　　

　　Figure 2. Proposed model depicting the roles PtpA plays in the nucleus of host cells during mycobacterial infection

(Image by Prof. LIU’s group)

　　

　　

　　 　　

　　

Contact:

Dr. Cui Hua Liu

E-mail: liucuihua@im.ac.cn

CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute Of Microbiology, Chinese Academy of Sciences, 100101, Beijing, China