PE11 Protein of Mycobacterium tuberculosis is Associated with Increased Inflammation and Fibrosis in the Liver

Abstract

Tuberculosis (TB) is a communicable disease caused by Mycobacterium tuberculosis (Mtb), which mainly infects the lungs, but can also spread to other organs, including the liver. Mtb infection is known to cause inflammation and fibrosis, leading to liver cirrhosis or hepatocellular carcinoma. Hence, identification of Mtb etiological factors is essential for designing therapeutics to ameliorate TB-associated liver pathology. One of the Mtb virulent proteins, PE11, is specifically present in pathogenic mycobacteria but absent in nonpathogenic Mycobacterium smegmatis, and its expression is increased in Mtb-infected macrophages and in active TB patients. The current study aims to investigate the role of the Mtb PE11 protein in liver inflammation and pathology using mouse models and in vitro cultures. We observed that the liver tissue of mice infected with M. smegmatis expressing Mtb PE11 (Msmeg-PE11) had higher expression of pro-inflammatory markers, enhanced immune cell infiltration, and increased fibrosis markers as compared to the mice infected with M. smegmatis harboring an empty vector (Msmeg-pVV). We observed increased expression of fibrosis-associated factors such as TGF-β, α-SMA, collagen III, and TIMP1 in the liver of Msmeg-PE11-infected mice, suggesting hepatic stellate cell activation, a central event in liver fibrosis. Furthermore, the PE11-deleted Mtb strain showed reduced inflammatory and fibrosis markers in the liver of infected mice as compared to the liver of wild-type Mtb-infected mice, indicating a probable role of PE11 in liver pathology during Mtb infection. Importantly, immunization with recombinant PE11 protein protected mice against mycobacterial growth and against liver inflammation and fibrosis, suggesting Mtb PE11 as a potential vaccine candidate and therapeutic to protect the host against Mtb infection and ameliorate TB-associated liver inflammation and pathology.