Localized complement activation in the development of protective immunity against Ostertagia ostertagi infections in...

The abomasal nematode Ostertagia ostertagi is a major causal agent contributing to production inefficiencies in the cattle industry in temperate regions of the world. Protective immunity to infections develops very slowly and resistance to reinfection manifests only after prolonged exposure. Mechanisms underlying the development of protective immunity remain largely unexplored. Immune animals, which have significantly reduced worm burdens, were developed after multiple drug-attenuated experimental infections and were compared to a primary infected group and their respective uninfected controls. In this study, transcriptomic analysis identified three signaling pathways significantly impacted during both primary and repeat infections, the complement system, leukocyte extravasation and acute phase responses. Increased mRNA levels of complement components C3, factor B (CFB) and factor I (CFI) in the abomasal mucosa of the infected cattle were confirmed using quantitative PCR while Western blot analysis established the presence of elevated levels of activated C3 proteins in the mucosa. One of the initiators of local complement activation could be related to secretory IgA and IgM because infections significantly up-regulated expression of J chain (IGJ), as well as polymeric Ig receptor (PIGR) and an IgM-specific receptor (FAIM3), suggesting sustained increases in both synthesis and transepithelial transport of IgA and IgM during the infection. The elevated levels of pro-inflammatory cytokines, such as IL-4 and IL-1β, during infection may be involved in gene regulation of complement components. Our results suggest enhanced tissue repair and mucin secretion in immune animals may also contribute to protective immunity. These results are the first evidence that local complement activation may be involved in the development of long-term protective immunity and provide a novel mechanistic insight into resistance against O. ostertagi in cattle.