Ostertagia ostertagi mediates early host immune responses via macrophage and Toll like receptor pathways

Authors: BAKSHI, MARIAM - Non ARS Employee; Hebert, Deborah - Van Hook; GULBRONSON, CONNOR - Non ARS Employee; Bauchan, Gary; Tuo, Wenbin; Zarlenga, Dante

Submitted to: Infection and Immunity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/7/2021
Publication Date: 3/8/2021
Citation: Bakshi, M., Hebert, D.A., Gulbronson, C., Bauchan, G.R., Tuo, W., Zarlenga, D.S. 2021. Ostertagia ostertagi mediates early host immune responses via macrophage and Toll like receptor pathways. Infection and Immunity. 1-42. https://doi.org/10.1128/IAI.00017-21.
DOI: https://doi.org/10.1128/IAI.00017-21

Interpretive Summary: Ostertagia ostertagi is gastro-intestinal (GI) parasite of cattle that causes marked reductions in feed intake, weight gain, milk production, and reproduction. With the emergence of drug resistance, alternative control strategies such as vaccination remain viable. However, to date, there is no vaccine against any cattle parasitic nematode because we lack understanding of the host’s early immune responses to parasite infections. Inflammation is the host’s first line of defense against infection. Our study focused on the mechanisms by which O. ostertagi exploits and controls early inflammatory responses to successfully parasitize the host using parasite excretory and secretory products to mimic an infection on cultured cells. We discovered that during an infection, O. ostertagi escapes the host’s early defenses by altering the host’s profile of both pro- and anti-inflammatory molecules that it produces during an infection. In this way, the parasite elicits conflicting responses at different stages of development to confuse the host’s immune system to self-regulate and thereby promote infection. This information will help identify parasite antigens capable of eliciting protective responses rather than those antigens it uses to counter these responses. This study will 1) benefit the research efforts of agricultural and animal health scientists in academia and industry to advance new discoveries and technologies in vaccine development; 2) help the livestock industry to enhance product development, pasture management and parasite control with the means currently available; and 3) benefit consumers by helping to develop products which are sustainable and environmentally safe.

Technical Abstract: Ostertagia ostertagi is an abomasal parasite that imposes significant economic impact on the US cattle industry. Host responses to infection have been documented; however, early immune responses are poorly understood. To this end, we examined Toll like receptors (TLRs) in peripheral blood mononuclear cells (PBMC), and macrophage (MF) mediated responses induced by excretory secretory products (ESP) of fourth stage larvae (L4) and adult worms (Ad). Results showed that O. ostertagi infection induced expression of TLR4 and TLR10 mRNA in PBMC consistent with systemic activation of the innate immune system. The lowest concentration of O. ostertagi ESP from L4 (OoESP-L4), suppressed CD40 and increased CD80 expression on cultured bovine MF. This response was not observed with ESP from adult worms (OoESP-Ad). Pro-inflammatory (TNF-a, IL-1, and IL-6) and anti-inflammatory (IL-10 and TGF-ß) cytokines were elevated in the presence of OoESP-L4 or OoESP-Ad, though expression levels of IL-1, IL-6 and IL-10 were more pronounced in the presence of OoESP-Ad than OoESP-L4. Morphologically, OoESP-L4 treated MF showed no structural changes compared to OoESP-Ad treated MF, indicating differences in activity. When MF were treated in combination with TLR ligands and OoESP-Ad, TNF-a and IL-10 were significantly induced compared to treatment with OoESP-Ad; only the lowest concentration of OoESP-Ad and TLR2 ligand had an additive effect on TGF-ß expression. We propose that L4 and adult O. ostertagi utilize competing strategies via ESP to confuse the immune system and evade the host protective responses even after long term and repeated exposure to the parasite.