Inhibition of cytokine gene expression and induction of chemokine genes in non-lymphatic cells infected with SARS coronavirus - PubMed (original) (raw)

Inhibition of cytokine gene expression and induction of chemokine genes in non-lymphatic cells infected with SARS coronavirus

Martin Spiegel et al. Virol J. 2006.

Abstract

Background: SARS coronavirus (SARS-CoV) is the etiologic agent of the severe acute respiratory syndrome. SARS-CoV mainly infects tissues of non-lymphatic origin, and the cytokine profile of those cells can determine the course of disease. Here, we investigated the cytokine response of two human non-lymphatic cell lines, Caco-2 and HEK 293, which are fully permissive for SARS-CoV.

Results: A comparison with established cytokine-inducing viruses revealed that SARS-CoV only weakly triggered a cytokine response. In particular, SARS-CoV did not activate significant transcription of the interferons IFN-alpha, IFN-beta, IFN-lambda1, IFN-lambda2/3, as well as of the interferon-induced antiviral genes ISG56 and MxA, the chemokine RANTES and the interleukine IL-6. Interestingly, however, SARS-CoV strongly induced the chemokines IP-10 and IL-8 in the colon carcinoma cell line Caco-2, but not in the embryonic kidney cell line 293.

Conclusion: Our data indicate that SARS-CoV suppresses the antiviral cytokine system of non-immune cells to a large extent, thus buying time for dissemination in the host. However, synthesis of IP-10 and IL-8, which are established markers for acute-stage SARS, escapes the virus-induced silencing at least in some cell types. Therefore, the progressive infiltration of immune cells into the infected lungs observed in SARS patients could be due to the production of these chemokines by the infected tissue cells.

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Figures

Figure 1

Figure 1

Virus titers. Simian Vero cells (white bars), human Caco-2 cells (grey bars), and human low-passage HEK 293 cells (black bars) were infected at a multiplicity of infection (MOI) of 5 infectious particles per cell. Virus titers in the supernatants were determined 24 h post-infection and 48 h post-infection by plaque assays.

Figure 2

Figure 2

Interferon production by virus-infected human cells. Caco-2 cells (A) and HEK 293 cells (B) were infected with SARS-CoV or the IFN-inducing control viruses Bunyamwera delNSs (BdelNSs), Sendai virus (SeV), Newcastle disease virus (NDV), or were left uninfected (mock). At 8 h (left panels) or at 16 h (right panels) post-infection, total RNA was isolated and investigated by RT-PCR for the presence of different IFN mRNAs. The cellular γ-actin mRNA served as loading control. Note that for the reliable detection of IFN-α in Caco-2 cells (A, upper right panel) the infection time had to be extended to 24 h.

Figure 3

Figure 3

Interferon-stimulated genes. RNA samples of Caco-2 cells (A) and HEK 293 cells (B) described in Fig. 2 were investigated by RT-PCR for the presence of ISG56 and MxA mRNAs. As for IFN-α (see Fig. 2A), for detection of MxA mRNA in Caco-2 cells an extended infection period of 24 h was necessary (A, lower right panel).

Figure 4

Figure 4

Chemokine production. RNA samples of Caco-2 cells (A) and HEK 293 cells (B) described in Fig. 2 were assayed by RT-PCR for IP-10 and RANTES mRNA levels.

Figure 5

Figure 5

Interleukin production. RNA samples of Caco-2 cells (A) and HEK 293 cells (B) described in Fig. 2 were investigated by RT-PCR for the presence of IL-6 and IL-8 mRNAs.

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