After having learned of the Assassins being present in India as well, he sent a fleet of thirteen ships to Calicut, led by Pedro Álvares Cabral. However, the Assassins destroyed the fleet and only three ships managed to return to Portugal. Manuel then sent Vasco da Gama and a fleet of 800 men to Calicut to root out the Assassins, though many of the men fell during a fierce Assassin attack, sending a clear message to Portugal and making clear they didn't accept their interference.
Manuel then ordered a lock-down in Lisbon, preventing anyone from escaping, and forced all citizens to convert to Christianity. The Assassins managed to evacuate many citizens, though they knew they could never get all of them out of the city. Realizing they had to do something, they provided the citizens with weapons, armor, and a basic combat training, giving them a chance to stand up against their king.
Later during the Seven Years' War, then-Assassin Shay Cormac was sent by Achilles Davenport to retrieve a Piece of Eden from an Isu Temple below the Carmo Convent in Lisbon, unintentionally disturbing the Temple and resulting in a devastating earthquake.