Brain tissue-resident immune memory cells are required for long-term protection against CNS infection with rabies virus

Immune memory cells residing in previously infected, nonlymphoid tissues play a role in immune surveillance. In the event that circulating antibodies fail to prevent virus spread to the tissues in a secondary infection, these memory cells provide an essential defense against tissue reinfection. CNS tissues are isolated from circulating immune cells and antibodies by the blood-brain barrier, making the presence of tissue-resident immune memory cells particularly needed to combat recurrent infection by neurotropic viruses. Wild-type and laboratory-engineered rabies viruses are neurotropic, differ in pathogenicity, and have varying effects on BBB functions. These viruses have proven invaluable tools in demonstrating the importance of tissue-resident immune memory cells in the reinfection of CNS tissues. Only Type 1 immune memory is effective at therapeutically clearing a secondary infection with wild-type rabies viruses from the CNS and does so despite the maintenance of blood-brain barrier integrity. Lay abstract The immune system is a complex network of cells and organs that help the body fight infection caused by the invasion of germs, such as bacteria and viruses. When battling such an attack, our immune system learns how to recognize the invader's specific characteristics by generating immune memory cells. These cells can deal with the infectious agent more rapidly and effectively when it is reencountered. Immune memory cells have various properties depending on their localization in the body. Specialized immune memory cells that remain in organs, rather than traveling back into the bloodstream, are called tissue-resident memory cells and are the key responders to reinfection of the tissue where they reside. Here, we review the role of brain tissue-resident immune memory cells in fighting the deadly rabies virus.