Perpetual expression of PAMPs necessary for optimal immune control and clearance of a persistent pathogen

Abstract

Pathogen-associated molecular patterns (PAMPs) are known to be fundamental in instigating immune responses but their role in influencing these responses beyond their initiation is less well understood. Here, using the protozoan parasite Trypanosoma cruzi, which is deficient in strong PAMPs, we demonstrate a requirement for the continuous expression of PAMPs for optimal anti-pathogen immunity. Although co-inoculating with, temporarily anchoring of and transgenic expression of exogenous PAMPs all result in enhanced early adaptive immune responses, only the continuous expression of bacterial PAMPs on transgenic T. cruzi sustains these responses, resulting in enhanced pathogen clearance. These findings demonstrate that PAMPs function to potentiate adaptive immune responses well beyond their initiation and may determine the efficiency of control of pathogens capable of long-term persistence.

Congenital Chagas disease as an ecological model of interactions between Trypanosoma cruzi parasites, pregnant women, placenta and fetuses

“…Whether IFN-␥ produced by NK and T cells is sufficient, or if other IFN-␥-independent mechanisms are needed to control T. cruzi acute infection in mammal hosts in general, and in congenital infection in particular, remains an open question. Indeed, T. cruzi seems a particularly stealth pathogen, since, roughly, it hardly triggers innate sensors (Kurup and Tarleton, 2013), induces a delayed CD8T cell response due to a late presentation of the highly variable immunodominant epitopes of its trans-sialidase proteins, and escapes to such response by quickly invading host cells, particularly in congenital infection in which infecting parasites are initially covered by antibodies (see above) .…”

“…; as in M+B− infants), and antibodies (present in both infant groups; see Section 7.1). Neither the infection of DCs, nor the participation of TLRs are required (see Section 6.3; Kurup and Tarleton, 2013). The expression of FcR on DC and monocyte membrane can explain the role of antibodies in such activation.…”

“…(ii) In the presence of moderate parasite amounts in the intervillous space, the placental innate defenses are only slightly activated. Indeed, T. cruzi, being partially deficient in strong PAMPs (Kurup and Tarleton, 2013), can hardly stimulate the TLRs expressed on the trophoblast (Koga et al, 2014). This does not induce the rupture of the trophoblastic barrier and transmission occurs by a new alternative route deprived of trophoblast, i.e.…”

CD8+ T cells in Trypanosoma cruzi infection

“…However these previously studied T. cruzi PAMPs are not known to be exposed on intact parasites either during or after cell invasion and thus would not be capable of interacting with host PRR. Further, we recently demonstrated that immune detection and activation of CD8 + T cell responses can be both accelerated and enhanced by the transgenic expression in T. cruzi of the well-characterized bacterial PAMPs Salmonella typhimurium flagellin and Neisseria meningitidis porin (19). Constitutive expression of these exogenous PAMPs by T. cruzi also allowed for the generation of a persistently potent adaptive immune response that extends for the full length of the infection and is associated with improved pathogen clearance and complete parasitological cure in some cases (19).…”

Strategy for the Development of Vaccines Against Chagas Disease

“…Th1 lymphocytes also stimulate the appropriate production of antibodies by B cells and the activation of cytotoxic CD8 + T cells. However, the development of adaptive immunity to T. cruzi infection is relatively slow with delayed development of T. cruzi-specific CD8 + T effector cells [21] which may be explained by diverse factors, including the postulated poor PAMP activity of T. cruzi [22]. T. cruzi is able to suppress the immune system through the release of several molecules and can promote IL-10 production by dendritic cells favoring its persistence [23].…”