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17-11-2011 | Immunology | Article

Protein phosphatase key to Mycobacterium tuberculosis immune evasion


Free abstract

MedWire News: Canadian researchers have discovered that protein tyrosine phosphatase A (PtpA) plays a key role in Mycobacterium tuberculosis (Mtb) survival within host macrophages.

"The etiological agent of tuberculosis (TB), Mtb, is one of the most devastating infectious agents in the world. One third of the world's population is exposed to Mtb, which causes nearly 3 million deaths annually, and is expected to cause an estimated 1 billion new infections by 2020," note Yossef Av-Gay and colleagues from the University of British Columbia in Vancouver.

They explain that Mtb primarily infects alveolar macrophages, which provide the first line of defense against microbial invasion.

Normally, infection of macrophages would result in the formation of a phagosome, which then fuses with the endosomal network and becomes profoundly acidic.

The researchers say that the acidification process occurs though recruitment of vacuolar-H+-ATPase (V-ATPase), a multisubunit protein-pump complex that actively transports protons across membranes using energy from ATP hydrolysis.

To investigate the exact mechanism by which Mtb accomplishes this, Av-Gay and team conducted a series of cellular experiments.

They found that Mtb PtpA - a signaling protein already known to be essential for Mtb pathogenicity - binds to subunit H of macrophage V-ATPase during macrophage infection, and is essential for intracellular survival.

Further analysis revealed that the binding of PtpA to V-ATPase inhibits Mtb phagosome acidification by inhibiting V-ATPase trafficking to the mycobacterial phagosome during phagosome maturartion. This process is also dependent on the phosphatase activity of PtpA.

The researchers suggest that inhibition of phagosome acidification in the mycobacterial phagosome is a two-step process: "During Mtb infection, PtpA binding to subunit H may first disrupt initial membrane tethering and localize it to the proximity of its catalytic substrate VPS33B," they write.

Subsequent dephosphorylation of VPS33B - a key regulator of membrane fusion - by PtpA would then inactivate the entire membrane fusion machinery and its downstream effectors, preventing delivery of V-ATPase to the mycobacterial phagosome, they add.

"These findings show that inhibition of phagosome acidification in the mycobacterial phagosome is directly attributed to PtpA, a key protein needed for Mtb survival and pathogenicity within host macrophages," the researchers remark in the Proceedings of the National Academy of Sciences.

In a statement to the press, Av-Gay added that he is "delighted" with the findings. "We have been engaged in studying the interaction between the TB bacterium and the human macrophage over the past decade. Through learning about the tricks it uses, we now have new targets, so that we can develop better drugs against this devastating disease," he said.

By Laura Dean

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