Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2016 Nov 10:7:472.
doi: 10.3389/fimmu.2016.00472. eCollection 2016.

The Ly49E Receptor Inhibits the Immune Control of Acute Trypanosoma cruzi Infection

Jessica Filtjens  1 , Nicolas Coltel  2 , Sabrina Cencig  2 , Sylvie Taveirne  1 , Els Van Ammel  1 , Aline Van Acker  1 , Tessa Kerre  1 , Patrick Matthys  3 , Tom Taghon  1 , Bart Vandekerckhove  1 , Yves Carlier  2 , Carine Truyens  2 , Georges Leclercq  1
Affiliations

The Ly49E Receptor Inhibits the Immune Control of Acute Trypanosoma cruzi Infection

Jessica Filtjens et al. Front Immunol. .

Abstract

The protozoan parasite Trypanosoma cruzi circulates in the blood upon infection and invades various cells. Parasites intensively multiply during the acute phase of infection and persist lifelong at low levels in tissues and blood during the chronic phase. Natural killer (NK) and NKT cells play an important role in the immune control of T. cruzi infection, mainly by releasing the cytokine IFN-γ that activates the microbicidal action of macrophages and other cells and shapes a protective type 1 immune response. The mechanisms by which immune cells are regulated to produce IFN-γ during T. cruzi infection are still incompletely understood. Here, we show that urokinase plasminogen activator (uPA) is induced early upon T. cruzi infection and remains elevated until day 20 post-infection. We previously demonstrated that the inhibitory receptor Ly49E, which is expressed, among others, on NK and NKT cells, is triggered by uPA. Therefore, we compared wild type (WT) to Ly49E knockout (KO) mice for their control of experimental T. cruzi infection. Our results show that young, i.e., 4- and 6-week-old, Ly49E KO mice control the infection better than WT mice, indicated by a lower parasite load and less cachexia. The beneficial effect of Ly49E depletion is more obvious in 4-week-old male than in female mice and weakens in 8-week-old mice. In young mice, the lower T. cruzi parasitemia in Ly49E KO mice is paralleled by higher IFN-γ production compared to their WT controls. Our data indicate that Ly49E receptor expression inhibits the immune control of T. cruzi infection. This is the first demonstration that the inhibitory Ly49E receptor can interfere with the immune response to a pathogen in vivo.

Keywords: IFN-γ; Ly49E receptor; Trypanosoma cruzi; immune control; natural killer cells; urokinase plasminogen activator.

PubMed Disclaimer

Figures

Figure 1
Figure 1
uPA levels are increased during the acute phase of T. cruzi infection. (A) uPA plasma levels were determined by ELISA in WT C57Bl/6 mice of the indicated age. (B) Four-week-old WT C57Bl/6 mice were inoculated s.c. with 50 trypomastigotes. uPA plasma levels were determined prior to infection (dpi 0) or at dpi 20 and 27. (C) Eight-week-old WT C57Bl/6 mice were inoculated s.c. with 100 trypomastigotes. uPA plasma levels were determined at dpi 0 or at dpi 4, 9, 18, and 25. (A–C) Statistically significant differences are indicated with *p ≤ 0.05, **p < 0.01, and ***p < 0.001 (Mann–Whitney U-test).
Figure 2
Figure 2
T. cruzi infection is better controlled in young Ly49E KO mice compared to their WT controls. Four-week-old WT and Ly49E KO male (A) and female (B) mice were inoculated s.c. with 50 trypomastigotes at day 0. Blood parasitemia levels were examined microscopically at the indicated time points, as indicated in the left panels of (A,B). The change in body weight is shown in the right panels (initial weight at the time of infection is set at 0). Results are expressed as Box and Whiskers showing the median from 4 WT and 4 KO male mice and 12 WT and 6 KO female mice. Significant differences between WT and Ly49E KO mice are indicated with *p < 0.05 (Mann–Whitney U-test).
Figure 3
Figure 3
The harmful effect of the Ly49E receptor on the course of T. cruzi infection weakens with mouse age. WT and Ly49E KO were inoculated s.c. with 100 trypomastigotes at day 0 at the age of 6 (A) or 8 weeks (B,C). Blood parasitemia levels were determined at the indicated time points (left panels). Right panels – body weight changes at the indicated days after infection, relative to the initial weight at the time of infection. Results are expressed as Box and Whiskers showing the median from 14 WT and 14 KO 6-week-old mice (A), 5 WT and 5 KO 8-week-old male mice (B) and 5 WT and 5 KO 8-week-old female mice (C). Statistically significant differences between WT and Ly49E KO mice are indicated with *p ≤ 0.05 and **p < 0.01 (Mann–Whitney U-test).
Figure 4
Figure 4
Enhanced IFN-γ production in T. cruzi-infected Ly49E KO mice compared to their WT controls. Four-week-old male WT and Ly49E KO mice were inoculated s.c. with 50 trypomastigotes at day 0. (A) Blood parasitemia levels are shown at the indicated time points (WT, n = 24; Ly49E KO, n = 24). (B) Plasma levels of the indicated cytokines were determined in non-infected mice (WT, n = 3; Ly49E KO, n = 3) and at day 20 (WT, n = 24; Ly49E KO, n = 24) and day 27 post-infection (WT, n = 21; Ly49E KO, n = 21). (C) Intracellular IFN-γ and TNF-α were determined by flow cytometry at day 27 post-infection (WT, n = 6; Ly49E KO, n = 6). The results are presented as the absolute cell number of IFN-γ- (left panels) and TNF-α-positive cells (right panels) in the indicated lymphocyte subpopulations in either spleen (upper panels) or liver (lower panels). Statistical analysis was performed using the Mann–Whitney U-test (*p < 0.05 and **p < 0.01).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Bern C. Chagas’ disease. N Engl J Med (2015) 373:1882.10.1056/NEJMc1510996 - DOI - PubMed
    1. Rassi A, Jr, Rassi A, Marin-Neto JA. Chagas disease. Lancet (2010) 375:1388–402.10.1016/S0140-6736(10)60061-X - DOI - PubMed
    1. Pinazo MJ, Posada Ede J, Izquierdo L, Tassies D, Marques AF, de Lazzari E, et al. Altered hypercoagulability factors in patients with chronic Chagas disease: potential biomarkers of therapeutic response. PLoS Negl Trop Dis (2016) 10:e0004269.10.1371/journal.pntd.0004269 - DOI - PMC - PubMed
    1. Andrade LO, Andrews NW. The Trypanosoma cruzi-host-cell interplay: location, invasion, retention. Nat Rev Microbiol (2005) 3:819–23.10.1038/nrmicro1249 - DOI - PubMed
    1. Santana JM, Grellier P, Schrevel J, Teixeira AR. A Trypanosoma cruzi-secreted 80 kDa proteinase with specificity for human collagen types I and IV. Biochem J (1997) 325(Pt 1):129–37.10.1042/bj3250129 - DOI - PMC - PubMed