Prophylaxis with cationic liposome–DNA complexes protects hamsters from phleboviral disease: Importance of liposomal delivery and CpG motifs

Abstract

Cationic lipid DNA complexes (CLDC) are cationic/neutral lipid carriers complexed with plasmid DNA that when administered systemically results in a robust T H 1 cytokine response. CLDC have been shown to be effective in prophylaxis and therapeutic treatment of animal models of viral disease. To determine the contribution of liposomal delivery and CpG content of the plasmid DNA to the efficacy of CLDC; plasmid, CpG-free plasmid DNA, or CpG-containing oligodeoxynucleotides (ODN) with and without liposomes, as well as poly (I:C 12 U), were evaluated for their ability to elicit protection against lethal Punta Toro virus (PTV, Bunyaviridae, phlebovirus) challenge in hamsters. CLDC containing plasmid significantly improved survival, decreased systemic and liver viral loads, and reduced liver damage due to progression of viral infection. Mouse-reactive ODNs complexed with liposomes failed to protect hamsters, whereas ODNs known to cross-react with human and mouse (CpG 2006) or non-liposomal poly (I:C 12 U) showed survival benefit but did not limit liver injury. Liposomes complexed with a non-CpG motif-containing plasmid reduced liver viral load and tissue damage, but did not protect hamsters from death. To evaluate the mechanisms of the enhanced activity of CLDC, microarray experiments examined differences in the gene expression profile. The results suggest a broad T H 1 response elicited by liposomal delivery of a diverse sequence containing CpG and non-CpG elements may be a more effective antiviral treatment than other nucleic acid based immunotherapeutics.

Efficacy of favipiravir (T-705) and T-1106 pyrazine derivatives in phlebovirus disease models

“…PTV infection in humans is generally asymptomatic or limited to a mild febrile illness (Peters and LeDuc, 1984). Small animal and cell culture model systems based on infection with the less biohazardous PTV and RVFV vaccine strain, MP-12, respectively, are often employed to evaluate experimental therapies early in the preclinical development process (Gowen et al, 2009; Gowen et al, 2006a; Gowen et al, 2006b; Gowen et al, 2008b; Gowen et al, 2007a; Gowen et al, 2007b; Sidwell et al, 1988; Smee et al, 1991). Ultimately, advanced studies employing authentic RVFV strains in rodent or nonhuman primate models are required for continued preclinical development (Gowen and Holbrook, 2008; Peters et al, 1986).…”

Punta Toro virus (Bunyaviridae, Phlebovirus) infection in mice: Strain differences in pathogenesis and host interferon response

“…The eastern Panamanian Adames strain of PTV (PTV-A) causes disease in hamsters and mice similar to that seen in natural RVFV infections, and therefore serves as a safer and more cost effective alternative to study disease pathogenesis (Anderson et al, 1990; Fisher et al, 2003; Gowen et al, 2006a; Perrone et al, 2007; Pifat and Smith, 1987) and pre-clinical antiviral drug development (Gowen et al, 2006b, 2007a, 2007b; 2009; Sidwell et al, 1988b). Though previous studies indicated PTV-A was only able to induce disease in weanling age mice (Pifat and Smith, 1987), recent work in our lab has established PTV-A’s ability to produce lethal disease in 7–8-week-old mice (Gowen et al, 2006a); however, the disease histopathology has not been examined in these older mice.…”

The Stimulated Innate Resistance Event in Bordetella pertussis Infection Is Dependent on Reactive Oxygen Species Production

“…Basic knowledge, such as the mechanism by which bacterial clearance may be achieved in the host, is expected to contribute to the development of new strategies to improve the control of this disease. Recently, a number of studies have described the development of novel antimicrobial strategies that target the host immune response rather than the pathogen (12)(13)(14). These immunotherapeutics target host pathways that either directly activate effector cells or relieve pathogen-induced suppression of host killing mechanisms, resulting in the control and elimination of a wide variety of microorganisms (14).…”