Cytokine patterns in a comparative model of arenavirus haemorrhagic fever in guinea pigs

Abstract

Arenaviruses such as Lassa virus cause a spectrum of disease in humans ranging from mild febrile illness to lethal haemorrhagic fever. The contributions of innate immunity to protection or pathogenicity are unknown. We compared patterns of expression of cytokines of innate immunity in mild versus severe arenavirus disease using an established guinea pig model based on the macrophage-tropic arenavirus Pichinde virus (PICV). Cytokine transcripts were measured by using real-time RT-PCR in target organs and blood during mild infection (caused by PICV, P2 variant) and lethal haemorrhagic fever (caused by PICV, P18 variant). In the initial peritoneal target cells, virulent P18 infection was associated with significantly increased gamma interferon (IFN-γ) and monocyte chemoattractant protein-1 (MCP-1, CCL2) mRNA levels relative to P2 infection. Peritoneal cells from P18-infected animals had decreased tumour necrosis factor alpha (TNF-α), interleukin (IL)-8 (CXCL-8) and IL-12p40 transcripts relative to mock-infected animals. Late in infection, P18-infected peripheral blood leukocytes (PBL) had decreased TNF-α, IFN-γ, and regulated upon activation, normal T cell expressed and secreted (RANTES, CCL-5) cytokine transcripts relative to P2-infected PBL. We conclude that, in severe arenavirus disease, patterns of cytokine expression in the initially infected cells favour recruitment of additional target monocytes, while inhibiting some of their pro-inflammatory responses. Suppression rather than overexpression of pro-inflammatory cytokines accompanied the terminal shock in this model of arenavirus haemorrhagic fever.

Characterization of virulence-associated determinants in the envelope glycoprotein of Pichinde virus

“…We use a safe small animal model, in which two PICV strains derived from low (P2) and high (P18) passages in guinea pigs can respectively cause avirulent and virulent infections with opposing outcomes in the animals, to characterize the virulence-associated determinants in arenavirus genome. Compared to the variable mortality rates of outbred guinea pigs infected with virulent PICV in previous studies (Jahrling et al, 1981; Scott and Aronson, 2008), we have observed more consistent high mortality rate and hemorrhagic fever symptoms in our infected animals (Figs 3–5), which is likely due to different experimental settings between our study and others. Knowledge of virulence mechanisms learned from the PICV-guinea pig model can be extrapolated to other pathogenic arenaviruses in humans.…”

Effective Oral Favipiravir (T-705) Therapy Initiated after the Onset of Clinical Disease in a Model of Arenavirus Hemorrhagic Fever

“…Because of the reported variability in lethality caused by PICV infection of outbred guinea pigs [32], [36], [37], [38], [39], we sought to establish a uniformly lethal model that would facilitate the evaluation of favipiravir. We prepared a virus stock from a single passage of the p18 guinea pig-adapted strain in Hartley guinea pigs.…”

“…PICV infection in guinea pigs has proven to be useful for the study of acute arenaviral disease [37], [38], [39], [44] and for preclinical efficacy evaluations [48], [49], as the virus can be handled safely in BSL-2 containment. There have been mixed reports on the lethality of guinea pig-adapted PICV in the readily available Hartley outbred guinea pig strain [32], [36], [37], [38], [39]. In addition to other factors, the variation in the stringency of the criteria used to define the terminal endpoints likely contributed to the reported variability.…”

Genomic Profiling of Host Responses to Lassa Virus: Therapeutic Potential from Primate to Man

“…The clinical data match results with observations in primary human cells in vitro . In animal models of fatal LF [56,122,150,167] it also seems that higher levels of IL-8 are protective against LF in vivo . While cell culture studies [46] show that replication of LASV in monocyte-derived MPs or DCs is associated with suppressing innate immune responses, in vivo studies with patients or experimental animals show that cytokines such as IP-10 and IL-8 (possibly coming from uninfected bystander cells) can recruit immune cells and increase survival.…”