Regulated upon Activation Normal T-Cell Expressed and Secreted (RANTES) Contributes to Abortion Caused by Brucella abortus Infection in Pregnant Mice

Abstract

ABSTRACT. Brucella abortus (B. abortus) is a facultative intracellular pathogen that can survive inside macrophages and trophoblast giant cells, and the causative agent of brucellosis. In the present study, we found that production of regulated upon activation normal T-cell expressed and secreted (RANTES) due to B. abortus infection contributes to abortion in pregnant mice. B. abortus infected pregnant interferon-γ (IFN-γ) knockout mice died within 15 days of infection, but non-pregnant IFN-γ knockout mice were still alive. With infection by wild type B. abortus, a large amount of RANTES production was observed in pregnant IFN-γ knockout mice, and induction of RANTES was also observed in normal pregnant mice infected with the wild type, but not in those infected with the intracellular replication-defective mutant. Production of RANTES and IFN-γ were inhibited in mice inoculated with the respective RANTES or IFN-γ antibody. Neutralization of RANTES, induced by B. abortus infection, served to prevent abortion. These results indicate that the production and function of RANTES are correlated with IFN-γ in pregnant mice infected with B. abortus.

Comparative analysis of the early transcriptome of Brucella abortus – Infected monocyte-derived macrophages from cattle naturally resistant or susceptible to brucellosis

“…In parallel, abortion is the main clinical symptom of brucellosis in cattle, but little is known about the molecular mechanism. In a recent publication, it was demonstrated that the increased expression of RANTES contributes to abortion in B. abortus -infected pregnant mice (Watanabe et al, 2008). This finding enables speculation that the increase rate of abortion induced in S cows after challenging with B. abortus (Harmon et al, 1985) could be in part due to the increased expression of RANTES gene.…”

What have we learned from brucellosis in the mouse model?

“…routes barely induce physiopathological symptoms at early stages of infection. The absence of obvious clinical signs correlates with: i) normal blood cell and platelet counts; ii) the lack of a recruitment of proinflammatory cells at the site of infection; iii) the presence of minimal levels of serum IL-1β, TNF-α, IL-10 and IL-6; iv) very low amounts of MCP-1 and RANTES chemokines [48,137]; and, v) the absence of synthesis and degradation of fibrinogen and coagulopathies [48]. IL-10 is not detected in serum and its corresponding transcript only appears after 3 days of infection [126].…”

“…This suggests that the regulatory role of IL-10 is minor or irrelevant at early times of Brucella infection. At these early times, INF-γ and IL-12, are barely detected in serum or cell extracts and these cytokines become evident only during the next infection phase [63,135,137,138,141]. However, the low levels of INF-γ and IL-12 are not unique to early Brucella infections, since they are also observed at the onset of murine salmonellosis [142].…”

“…After the 1 st week of the acute phase, significant amounts of INF-γ, IL-12, IL-6 and RANTES are present in sera of susceptible mice (Figure 5) [114,135,137,141,148,149]. After the 2 nd week, these cytokines steadily decrease approaching basal levels by the 6 th week, already in the next infection phase (Figure 5A).…”

Congenital toxoplasmosis: candidate host immune genes relevant for vertical transmission and pathogenesis

“…[65][66][67] Similarly, CCL5 (RANTES) production in response to Brucella abortus correlated with IFN-g induction and contributed to abortion in mice. 68 Two polymorphisms of CCL5 in either the mother or the product would have opposite effects on congenital toxoplasmosis occurrence or pathology: the À28 C/G or G/G would be protective against infection, but without proper control it could relate to sterile abortion. 69 On the contrary, carriers of the À403A allele would have low CCL5 levels and thus people with this allele would have higher risk of vertical transmission.…”