Immunization with AgTRIO, a Protein in Anopheles Saliva, Contributes to Protection against Plasmodium Infection in Mice.

Plasmodium infection begins with the bite of an anopheline mosquito, when sporozoites along with saliva are injected into a vertebrate host. The role of the host responses to mosquito saliva components in malaria remains unclear. We observed that antisera against Anopheles gambiae salivary glands partially protected mice from mosquito-borne Plasmodium infection. Specifically, antibodies to A. gambiae TRIO (AgTRIO), a mosquito salivary gland antigen, contributed to the protection. Mice administered AgTRIO antiserum showed lower Plasmodium liver burden and decreased parasitemia when exposed to infected mosquitoes. Active immunization with AgTRIO was also partially protective against Plasmodium berghei infection. A combination of AgTRIO antiserum and antibodies against Plasmodium circumsporozoite protein, a vaccine candidate, further decreased P. berghei infection. In humanized mice, AgTRIO antiserum afforded some protection against mosquito-transmitted Plasmodium falciparum. AgTRIO antiserum reduced the movement of sporozoites in the murine dermis. AgTRIO may serve as an arthropod-based target against Plasmodium to combat malaria.

Mosquito saliva serine protease enhances dissemination of dengue virus into the mammalian host.

Dengue virus (DENV), a flavivirus of global importance, is transmitted to humans by mosquitoes. In this study, we developed in vitro and in vivo models of saliva-mediated enhancement of DENV infectivity. Serine protease activity in Aedes aegypti saliva augmented virus infectivity in vitro by proteolyzing extracellular matrix proteins, thereby increasing viral attachment to heparan sulfate proteoglycans and inducing cell migration. A serine protease inhibitor reduced saliva-mediated enhancement of DENV in vitro and in vivo, marked by a 100-fold reduction in DENV load in murine lymph nodes. A saliva-mediated infectivity enhancement screen of fractionated salivary gland extracts identified serine protease CLIPA3 as a putative cofactor, and short interfering RNA knockdown of CLIPA3 in mosquitoes demonstrated its role in influencing DENV infectivity. Molecules in mosquito saliva that facilitate viral infectivity in the vertebrate host provide novel targets that may aid in the prevention of disease.

Sculpting MHC class II-restricted self and non-self peptidome by the class I Ag-processing machinery and its impact on Th-cell responses.

It is generally assumed that the MHC class I antigen (Ag)-processing (CAP) machinery - which supplies peptides for presentation by class I molecules - plays no role in class II-restricted presentation of cytoplasmic Ags. In striking contrast to this assumption, we previously reported that proteasome inhibition, TAP deficiency or ERAAP deficiency led to dramatically altered T helper (Th)-cell responses to allograft (HY) and microbial (Listeria monocytogenes) Ags. Herein, we tested whether altered Ag processing and presentation, altered CD4(+) T-cell repertoire, or both underlay the above finding. We found that TAP deficiency and ERAAP deficiency dramatically altered the quality of class II-associated self peptides suggesting that the CAP machinery impacts class II-restricted Ag processing and presentation. Consistent with altered self peptidomes, the CD4(+) T-cell receptor repertoire of mice deficient in the CAP machinery substantially differed from that of WT animals resulting in altered CD4(+) T-cell Ag recognition patterns. These data suggest that TAP and ERAAP sculpt the class II-restricted peptidome, impacting the CD4(+) T-cell repertoire, and ultimately altering Th-cell responses. Together with our previous findings, these data suggest multiple CAP machinery components sequester or degrade MHC class II-restricted epitopes that would otherwise be capable of eliciting functional Th-cell responses.

Proteasomes, TAP, and endoplasmic reticulum-associated aminopeptidase associated with antigen processing control CD4+ Th cell responses by regulating indirect presentation of MHC class II-restricted cytoplasmic antigens.

Cytoplasmic Ags derived from viruses, cytosolic bacteria, tumors, and allografts are presented to T cells by MHC class I or class II molecules. In the case of class II-restricted Ags, professional APCs acquire them during uptake of dead class II-negative cells and present them via a process called indirect presentation. It is generally assumed that the cytosolic Ag-processing machinery, which supplies peptides for presentation by class I molecules, plays very little role in indirect presentation of class II-restricted cytoplasmic Ags. Remarkably, upon testing this assumption, we found that proteasomes, TAP, and endoplasmic reticulum-associated aminopeptidase associated with Ag processing, but not tapasin, partially destroyed or removed cytoplasmic class II-restricted Ags, such that their inhibition or deficiency led to dramatically increased Th cell responses to allograft (HY) and microbial (Listeria monocytogenes) Ags, both of which are indirectly presented. This effect was neither due to enhanced endoplasmic reticulum-associated degradation nor competition for Ag between class I and class II molecules. From these findings, a novel model emerged in which the cytosolic Ag-processing machinery regulates the quantity of cytoplasmic peptides available for presentation by class II molecules and, hence, modulates Th cell responses.

Minor histocompatibility antigens: presentation principles, recognition logic and the potential for a healing hand.

PURPOSE OF REVIEW: There is ample evidence indicating a pathologic role for minor histocompatibility antigens in inciting graft-versus-host disease in major histocompatibility complex (MHC)-matched bone marrow transplantation and rejection of solid organ allografts. Here we review the current knowledge of the genetic and biochemical bases for the cause of minor histoincompatibility and the structural basis for the recognition of the resulting alloantigens by the T-cell receptor. RECENT FINDINGS: Recent evidence indicates that we as independently conceived individuals are genetically unique, thus, offering a mechanism for minor histoincompatibility between MHC-identical donor-recipient pairs. Furthermore, advances in delineating the mechanisms underlying antigen cross-presentation by MHC class I molecules and a critical role for autophagy in presenting cytoplasmic antigens by MHC class II molecules have been made. These new insights coupled with the X-ray crystallographic solution of several peptide/MHC-T-cell receptor structures have revealed mechanisms of histoincompatibility. SUMMARY: On the basis of these new insights, ways to test for allograft compatibility and concoction of immunotherapies are discussed.