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The Anti-Inflammatory Immune Response in Early Trichinella spiralis Intestinal Infection Depends on Serine Protease Inhibitor-Mediated Alternative Activation of Macrophages.

ABSTRACT: Trichinella spiralis is recognized for its ability to regulate host immune responses via excretory/secretory (ES) products. Serine protease inhibitors (serpins) play an important role in ES product-mediated immunoregulatory effects during T. spiralis infection. In this study, the immunoregulatory properties of a serpin derived from T. spiralis (Ts-serpin) were explored in BALB/c mice. The results showed that naturally occurring Ts-serpin was detected in the stichosomes of muscle larvae and adult worms. Moreover, enhancing (by injection of a soluble-expressed recombinant Ts-serpin [rTs-serpin]) or blocking (by passive immunization with anti-rTs-serpin serum) the effects of Ts-serpin changed the levels of cytokines related to inflammation induced by T. spiralis infection in the serum, mesenteric lymph nodes, and peritoneal cavity, which then led to a change in the adult worm burden in early T. spiralis infection. Moreover, the phenotypic changes in peritoneal macrophages were found to be related to Ts-serpin-mediated immunoregulation. Furthermore, a STAT6 activation mechanism independent of IL-4R? has been found to regulate protein-mediated alternative activation of bone marrow-derived macrophages and mimic the immunoregulatory role of Ts-serpin in T. spiralis infection. Finally, the anti-inflammatory properties of rTs-serpin and bone marrow-derived macrophage alternative activation by rTs-serpin were demonstrated using a trinitrobenzene sulfonic acid-induced inflammatory bowel disease model. In summary, a protein-triggered anti-inflammatory mechanism was found to favor the survival of T. spiralis in the early stage of infection and help to elucidate the immunoregulatory effects of T. spiralis on the host immune response.

SUBMITTER: Xu N

PROVIDER: S-EPMC7887736 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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The Anti-Inflammatory Immune Response in Early Trichinella spiralis Intestinal Infection Depends on Serine Protease Inhibitor-Mediated Alternative Activation of Macrophages.

Xu Ning N Bai Xue X Liu Yan Y Yang Yaming Y Tang Bin B Shi Hai Ning HN Vallee Isabelle I Boireau Pascal P Liu Xiaolei X Liu Mingyuan M

Journal of immunology (Baltimore, Md. : 1950) 20210125 5

Trichinella spiralis is recognized for its ability to regulate host immune responses via excretory/secretory (ES) products. Serine protease inhibitors (serpins) play an important role in ES product-mediated immunoregulatory effects during T. spiralis infection. In this study, the immunoregulatory properties of a serpin derived from T. spiralis (Ts-serpin) were explored in BALB/c mice. The results showed that naturally occurring Ts-serpin was detected in the sti ...[more]

PMID: 33495238

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Project description:Trichinellosis is a serious zoonositc parasitosis worldwide. Because its clinical manifestations aren't specific, the diagnosis of trichinellosis is not easy to be made. Trichinella spiralis muscle larva (ML) excretory-secretory (ES) antigens are the most widely applied diagnostic antigens for human trichinellosis, but the major drawback of the ES antigens for assaying anti-Trichinella antibodies is the false negative in the early Trichinella infection period. The aim of this study was to characterize the T. spiralis putative serine protease (TsSP) and to investigate its potential use for diagnosis of trichinellosis.The full-length TsSP sequence was cloned and expressed, and recombinant TsSP (rTsSP) was purified by Ni-NTA-Sefinose Column. On Western blotting analysis the rTsSP was recognized by T. spiralis-infected mouse serum, and the natural TsSP was identified in T. spiralis ML crude and ES antigens by using anti-rTsSP serum. Expression of TsSP was detected at various T. spiralis developmental stages (newborn larvae, muscle larvae, intestinal infective larvae and adult worms). Immunolocalization identified the TsSP principally in cuticles and stichosomes of the nematode. The sensitivity of rTsSP-ELISA and ES-ELISA was 98.11% (52/53) and 88.68% (47/53) respectively (P > 0.05) when the sera from trichinellosis patients were examined. However, while twenty-one serum samples of trichinellosis patients' sera at 19 days post-infection (dpi) were tested, the sensitivity (95.24%) of rTsSP-ELISA was distinctly higher than 71.43% of ES-ELISA (P < 0.05). The specificity (99.53%) of rTsSP-ELISA was remarkably higher than 91.98% of ES-ELISA (P < 0.01). Only one out of 20 serum samples of cysticercosis patients cross-reacted with the rTsSP. Specific anti-Trichinella IgG in infected mice was first detected by rTsSP-ELISA as soon as 7 dpi and antibody positive rate reached 100% on 10 dpi, whereas the ES-ELISA did not permit detection of 100% of infected mice before 16 dpi.The rTsSP is a potential early diagnostic antigen for human trichinellosis.

Project description:BackgroundTrichinellosis is a serious zoonosis with a worldwide distribution. Fecund adult worms in the intestine release newborn larvae (NBL) that enter the general circulation from 4 days post infection (dpi). Alternatively activated macrophages in the peritoneal cavities and the diaphragms in Trichinella spiralis infected mice have been reported. However, a role of newborn larvae is poorly understood.MethodsThe total numbers of peritoneal macrophages in mice infected with 500 muscle-stage larvae were counted during early infection and then total RNA was extracted. Peritoneal macrophages from uninfected C57BL/6 mice were incubated with IL-4 or LPS as a control, or co-cultured with live NBL, and peritoneal macrophages were obtained from mice injected with live or frozen dead NBL into peritoneal cavity. Total RNA was extracted from these macrophages. Two types of gene expression, classical and alternative activation, were examined in the macrophages and diaphragms of the infected mice using semi-quantitative reverse transcription-PCR.ResultsThe number of peritoneal macrophages in T. spiralis infected mice increased significantly. mRNA peak expression of alternative activation markers, Ym1 and arginase-1 (Arg1), was confirmed in the peritoneal macrophages and in diaphragm of mice around 15 dpi, while mRNA expression of classical activation markers, TNFα, IP-10, and iNOS was not detected. Injection of live NBL into the peritoneal cavities induced mRNA expression of Ym1 and Arg1 in the peritoneal macrophages of mice 9 dpi. However, dead NBL did not induce such gene expression. Alternative activation was not detected in the peritoneal macrophages co-cultured with NBL in vitro.ConclusionGene expression of alternative activation makers, Ym1 and Arg1, was confirmed in the peritoneal macrophages and diaphragms of mice infected with T. spiralis. However, gene expression of classical activation markers was not detected. Live NBL induced an alternative activation of peritoneal macrophages in vivo, but not in vitro.

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The Anti-Inflammatory Immune Response in Early Trichinella spiralis Intestinal Infection Depends on Serine Protease Inhibitor-Mediated Alternative Activation of Macrophages.

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The Anti-Inflammatory Immune Response in Early <i>Trichinella spiralis</i> Intestinal Infection Depends on Serine Protease Inhibitor-Mediated Alternative Activation of Macrophages.

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