Moreover, passively transferred IgA mAbs targeted against the major membrane protein α-crystallin reduced bacterial loads and pathologic changes in intranasally and intratracheally infected mice, whereas mAbs against a secreted protein did not 71, 72. These findings underline the necessity of surface location and accessibility

of Ab epitopes to finally confer protective effects. The mechanism by which Abs confer protection in infections with Mycobacterium spp. is still not fully understood. The long-term duration (up to several months) of some of the above experiments suggests that mAbs confer AP24534 nmr protection and prolonged survival by enhancing cellular immune responses. At least in one study, involvement of FcRs was excluded, as LAM-specific purified F(ab′) fragments also enhanced host survival upon M. tuberculosis infection in mice 70; however, in vitro experiments with M. bovis bacillus Calmette-Guérin (BCG) indicated a much more direct effect as these bacteria were targeted to lysosomes within minutes upon FcR stimulation of the host cell, suggesting a similar FcR signaling-dependent lysosomal targeting mechanism as is seen for Legionella65. Despite a lack of detailed mechanistic insight, promising vaccines using recombinant bacteria expressing M. tuberculosis protein Ags are being designed to enhance M. tuberculosis-specific humoral immunity 73, 74. An FcR-dependent mechanism is likely to be involved

in Ab-mediated protection against the intracellular parasite Toxoplasma gondii. Toxoplasma does not enter the host cell through phagocytosis but uses an active mechanism that is dependent on actin-mediated movement AZD5363 solubility dmso of the parasite into the cell forming a modified phagocytic vacuole in which the parasite resides and replicates 75. By mechanisms that are not completely understood to date, this vacuole does not fuse with lysosomes, and therefore acidification of the replicative niche is prevented 76. In contrast to live

Toxoplasma, dead or specific Ab-coated parasites are primarily located in lysosomes and this rerouting has been shown to be dependent on FcRs 76, 77. Once Toxoplasma is located in the lysosomal compartment, Terminal deoxynucleotidyl transferase macrophages are able to kill the parasites and replication can no longer take place 78. As studies using μMT mice showed that Abs also play a crucial role in mediating resistance to Toxoplasma in vivo, it is likely that, as in Legionella infection, Abs are able to activate macrophages via FcRs and convert them to a state where they are no longer permissive for parasite replication 79. Salmonella actively induce their uptake into host cells by using a type III secretion system (T3SS)-1 to inject effector proteins into the cytoplasm. These effectors induce reorganization of the host cell’s actin cytoskeleton, leading to the formation of phagosomes allowing Salmonella to invade phagocytic as well as nonphagocytic cells.