Ruger has some nice small frame pistols and revolvers that might interest you. Springfield, Glock, Kahr and S&W also offer compact and subcompact semis in calibers from .380 through .45ACP. If possible go to a range and rent a few models so that your wife can get a feel for the different models. What's important is that she settle on a gun that is not only comfortable to shoot but also one that she is confident using.
A .22lr caliber is not really suitable for SD purposes, in my opinion. They are cheap and fun plinkers, and yes a .22lr can be lethal, but you don't want to stake your life on one.
Some of my favs...Springfield XDm 3.8" subcompact: 9mm, .40S&W, 45ACP
Ruger LCR .357 magnum, .38 spc
"The whole of the Bill (of Rights) is a declaration of the right of the people at large or considered as individuals.... It establishes some rights of the individual as unalienable and which consequently, no majority has a right to deprive them of." (Albert Gallatin of the New York Historical Society, October 7, 1789)
"A free people ought not only to be armed and disciplined, but they should have sufficient arms and ammunition to maintain a status of independence from any who might attempt to abuse them, which would include their own government." - George Washington
Sounds like you want a full-framed style of gun, just scaled back a bit in size...rather than a stripped down micro or subcompact. So a medium frame with a not so fat grip, but also a barrel with decent length.
Do a little research on these guns:
Kahr CW9 (medium/compact single stack 9mm)
Sig P230 (medium sized 380)
Sig P239 (single stack 9mm)
Bersa Thunder (medium sized 380/9mm)
The safest bet when it comes to a quality 22lr is a Ruger or Browning. But a Walther P22 would be pretty "Mosquito-esque", and probably less finicky than the Sigs I've seen. As to the above list, there'll be no telling until she actually holds the gun. And then bear in mind that if she happens to be recoil sensitive, she'll have more success (and enjoyment) shooting something with at least a little bit of weight.
As mentioned above, find a range that rents or friends who own, and let her try.
There are a number of great suggestions above. I would second the P22, since you mentioned a .22 in your OP. Then if she wants a defensive pistol, she can move up to the P380 without having to learn new controls or adjust to another "feel." Plus, she can get in cheap practice with her .22.
And if you like Walther, you might also look at the PPS.
"An armed society is a polite society." Robert A. Heinlein
"After a shooting spree, they always want to take the guns away from the people who didn't do it. I sure as hell wouldn't want to live in a society where the only people allowed guns are the police and the military."
William S. Burroughs
Thanks for the suggestions, I'll have to take her to a few lgs and check for those models. I think the m&p is to big for her hands if I remember correctly.
She may have to get a snub nose like the one in the first reply. She had a hard time racking the slide on my gun.
I figured she would have to go try and shoot a few but was looking to get a few model suggestions to look out for.
Appreciate the help