Published in PLoS Pathogens, D. Kumar explains the novelty of his team's finding


Published this month in PLoS Pathogens, D.Kumar, Cellular Immunology Group and collaborators:

Alternate splicing of transcripts shape macrophage response to Mycobacterium tuberculosis infection

From the author:

This study, in addition to providing new dimensions to the extent of manipulations that the pathogen could enforce on the host, also promises to help develop novel ways to test susceptibility to tuberculosis and identify individuals at risk of developing the disease if exposed to the bug.

Not every individual infected with Mycobacterium tuberculosis, the pathogen responsible for tuberculosis (TB) in humans, develops active disease. There are no concrete parameters yet, that can truly define how tolerance versus susceptibility to tuberculosis is manifested in the human population. 

TB continues to be a formidable challenge for global health management, with nearly a third of world population harboring the infection and about 1.5 million deaths annually attributed to this disease. It is believed that the TB bug is among the most successful pathogens of humans, aided by their ability to adapt and modify the highly hostile defense mechanism of the hosts. The adaptive ability of the bacteria and host processes altered by them upon infection has been relentlessly studied to understand the pathogenesis of TB. Better understanding of these mechanisms will prove crucial for developing next generation of anti-tuberculosis agents.

Among many host physiological processes, changes in gene expression are a fundamental means through which cells adapt to environmental cues or stimuli like infections. Altered gene expression eventually leads to synthesis of new proteins, many of which participates in mounting the effective anti-bacterial response of the cells. Notably, regulation of gene expression in higher organisms including humans is a highly complex process where several intermediate processing steps of newly synthesized RNA are required before their translation into corresponding proteins can take place.

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This study reports that RNA splicing, one of the key intermediate processing steps of transcription, is heavily modified in the immune cells infected with Mycobacterium tuberculosis. Advancements in nucleic acid sequencing technology allowed us to sequence each of the RNA transcripts present in the infected cells with a very high degree of precision, an endeavor never performed so comprehensively for Mtb-infected host macrophages. They show infection of host macrophages by Mycobacterium tuberculosis results in massive alterations in the pattern of splicing in the host.

Genes in higher organisms are coded in a discontinuous stretch, interspersed with regions, which do not eventually become part of the protein. These interspersed regions (introns) from the transcripts must be precisely removed through the process of splicing to achieve a continuous stretch of useful sequence (exons) before they are translated into a functional protein. The splicing of a transcript may not always yield the same product, due to inclusion or exclusion of certain specific exons during splicing, giving rise to the alternate spliced variants of the transcripts. 

Since alternate splicing can influence transcript stability, stability of the translated products, loss/gain of function, interacting partners and sub-cellular localization, implications on host responses to infection could be overwhelming. Targeted experiments confirmed that alternate spliced variants of host genes helped infecting Mtb strains to survive better within the macrophages. The study proposes that regulators of splicing, either from host and/or pathogen, therefore, constitute an attractive set of targets to develop novel therapeutic strategies to control tuberculosis.

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