Does Mycobacterium tuberculosis use cellular modiFICations to survive in human macrophages (ASUF 30006685)

Does Mycobacterium tuberculosis use cellular modiFICations to survive in human macrophages (ASUF 30006685) Does Mycobacterium tuberculosis use cellular modiFICations to survive in human macrophages? Importance M. tuberculosis (Mtb) and its emerging treatment challenges. The WHO estimates that one third of the worlds population is infected with Mtb, 8.7 million people developed newly-diagnosed active TB disease (13% co-infected with HIV) in 2011, and 1.4 million people died from TB in 2011 (2) (3). There were ~500,000 new MDR-TB cases in 2011, representing 3.7% of new TB patients (3). Since treatment options for XDR-TB are limited and the TB drug pipeline is insufficient to address global treatment needs (4), new therapeutic intervention strategies are needed. Our efforts could help identify a novel area for Mtb intervention. Complexity of TB pathogenesis. After respiratory spread, Mtb invades macrophages and subverts cellular signaling pathways within the phagosome. By blocking phagolysosome fusion, via modulation of normal cellular processes, Mtb evades bactericidal responses and grows in this otherwise destructive environment. Elicitation of an intense immune response ensures a persistent Mtb infection, which can remain quiescent in the human host for decades. Reactivation of latent TB can occur during immune senescence, immunosuppressive therapy, or under conditions that allow the organism to escape immunological control. FIC proteins AMP up bacterial virulence. Bacterial-mediated posttranslational modification (PTM) of host proteins is an important biochemical arms race in which pathogenic bacteria subvert cellular signaling pathways for replication and survival. AMPylation, the PTM of target proteins with adenosine monophosphate (AMP), has recently been discovered as a novel virulence mechanism by bacterial FIC (filamentation induced by cAMP) proteins. Bacterial FIC domain-containing proteins transfer AMP from ATP to threonine and tyrosine residues and function as virulence factors in Vibrio, Legionella, and Histophilus infections to disrupt host cell processes (5-7). Since intracellular bacteria secrete proteins into the phagosome, bacterial enzymes can directly alter host proteins leading to functional disruption of normal phagocytic pathways. Bacterial FIC proteins AMPylate and inhibit Rho GTPases, including Rho, Rac, and Cdc42, which are among the same AMPylation targets of the human HYPE FIC protein (8). Disruption of these targeted host GTPases, or other as yet to be identified key protein targets, results in defective cytoskeletal rearrangement leading to impairment of phagocytosis, phagosome trafficking, and phagosome maturation. The cumulative result is microbial alteration of host signaling pathways allowing the organism to survive within the macrophage and prolong infection. Human HYPE FIC is one of the interacting protein partners of Huntingtin (htt), the large protein that is abnormally elongated in the neurodegenerative disorder, Huntingtons disease (9, 10). Additionally, Drosphila flies lacking fic are viable and fertile, but blind, revealing a critical role of Fic in visual neurotransmission {Rahman, 2012 #39}.