Trichinella spiralis Calreticulin Binds Human Complement C1q As an Immune Evasion Strategy

Abstract

As a multicellular parasitic nematode, Trichinella spiralis regulates host immune responses by producing a variety of immunomodulatory molecules to escape from host immune attack, but the mechanisms underlying the immune evasion are not well understood. Here, we identified that T. spiralis calreticulin (Ts-CRT), a Ca2+-binding protein, facilitated T. spiralis immune evasion by interacting with the first component of human classical complement pathway, C1q. In the present study, Ts-CRT was found to be expressed on the surface of different developmental stages of T. spiralis as well as in the secreted products of adult and muscle larval worms. Functional analysis identified that Ts-CRT was able to bind to human C1q, resulting in the inhibition of C1q-initiated complement classical activation pathway reflected by reduced C4/C3 generation and C1q-dependent lysis of antibody-sensitized sheep erythrocytes. Moreover, recombinant Ts-CRT (rTs-CRT) binding to C1q suppressed C1q-induced THP-1-derived macrophages chemotaxis and reduced monocyte–macrophages release of reactive oxygen intermediates (ROIs). Blocking Ts-CRT on the surface of newborn larvae (NBL) of T. spiralis with anti-Ts-CRT antibody increased the C1q-mediated adherence of monocyte–macrophages to larvae and impaired larval infectivity. All of these results suggest that T. spiralis-expressed Ts-CRT plays crucial roles in T. spiralis immune evasion and survival in host mostly by directly binding to host complement C1q, which not only reduces C1q-mediated activation of classical complement pathway but also inhibits the C1q-induced non-complement activation of macrophages.

Molecular basis of differential parasitism between non-encapsulated and encapsulatedTrichinellarevealed by a high-quality genome assembly

“…19). Of note, 6 genes showed species-specific divergence in at least two stages of T. pseudospiralis (Supplementary Table 12), which were mostly reported as being involved in parasitism, as evident by enhanced parasite invasion and motility (Kostianovsky et al 2007; Hashimoto et al 2010; Helwig et al 2013; Rausch and Hastings 2015; Zhao et al 2017). The sequences of these genes were then further curated by Sanger sequencing, considering their potential significance in Trichinella parasitism (Supplementary Fig.…”

Comparative Proteomic Analysis of Serum from Pigs Experimentally Infected with Trichinella spiralis, Trichinella britovi, and Trichinella pseudospiralis

“…In other comprehensive studies, Näreaho et al [129] observed a strong C3 binding to the stichocytes of T. spiralis and T. nativa muscle larvae as well as the muscular part of the adult stage, but not to the newborn. Recently, Zhao et al [130] have shown that calreticulin, a Ca 2+ -binding protein that has been identified on the surface and in secretory products of various T. spiralis stages, can bind C1q and, as a consequence, reduce C3 generation. Interestingly, in the present study, no changes in the complement expression level were found in the serum of pigs experimentally infected with T. spiralis and T. britovi compared to the control group, which may indicate a different inflammatory myopathy pattern between T. pseudospiralis and encapsulated species of Trichinella triggering the infection.…”

A Multiple Antigen Peptide Vaccine Containing CD4+ T Cell Epitopes Enhances Humoral Immunity against Trichinella spiralis Infection in Mice

“…The vaccine candidates include excretory-secretory (ES) antigens [7], recombinant proteins [8,9], and DNA vaccines [10], inducing different levels of partial protective immunity in animal models. However, as a tissue-dwelling helminth, it is difficult to develop an effective vaccine which induces sterile immunity because T. spiralis has a complex life cycle, diverse stagespecific antigens, and immune-evasion strategies [11,12]. Subunit peptide vaccine based on multiple protective epitopes may overcome these problems and thus provides a novel approach to develop vaccines against infectious diseases such as trichinellosis [13].…”