US State Department spokesman John Kirby's warning that the collapse of US-Russian cooperation in Syria could lead to a rise in extremism and potential attacks against Russia drew Moscow's anger.
The Russian Foreign and Defense Ministries both cast it as US encouragement of terror attacks on Russia.
"We can't assess those statements as anything else but a call, a directive for action," Foreign Ministry spokeswoman Maria Zakharova said at a briefing.
Defense Ministry spokeswoman Maj. Gen. Igor Konashenkov said Kirby's statement amounted to "the most frank confession by the US side so far that the whole 'opposition' ostensibly fighting a 'civil war' in Syria is a US-controlled international terrorist alliance."
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The remarks by Russian officials have shown a degree of mistrust and strain between Moscow and Washington after the collapse of the US-Russia-brokered truce and the Syrian army onslaught on Aleppo backed by Russian warplanes.
The growing friction makes it increasingly unlikely that the cease-fire could be revived.
US Secretary of State John Kerry threatened yesterday to cut all cooperation with Moscow on Syria unless an onslaught on Aleppo ends.
Kirby, asked what the consequences would be for Russia if cooperation with the US in Syria collapsed, said "that extremists and extremists groups will continue to exploit the vacuums that are there ... Which will include, no question, attacks against Russian interests, perhaps even Russian cities, and Russia will continue to send troops home in body bags."