Lethal Monkeypox Virus Infection of CAST/EiJ Mice Is Associated with a Deficient Gamma Interferon Response

Abstract

Monkeypox virus (MPXV) is endemic in Africa, where it causes disease in humans resembling smallpox. A recent importation of MPXV-infected animals into the United States raises the possibility of global spread. Rodents comprise the major reservoir of MPXV, and a variety of such animals, even those native to North America, are susceptible. In contrast, common inbred strains of mice, including BALB/c and C57BL/6, are greatly resistant to MPXV. However, several inbred strains of mice derived from wild mice, including CAST/EiJ, exhibit morbidity and mortality at relatively low inoculums of MPXV. Elucidating the basis for the susceptibility of CAST/EiJ mice could contribute to an understanding of MPXV pathogenicity and host defense mechanisms and enhance the value of this mouse strain as a model system for evaluation of therapeutics and vaccines. Here we compared virus dissemination and induced cytokine production in CAST/EiJ mice to those in the resistant BALB/c strain. Following intranasal infection, robust virus replication occurred in the lungs of both strains, although a relatively higher inoculum was required for BALB/c. However, while spread to other internal organs was rapid and efficient in CAST/EiJ mice, the virus was largely restricted to the lungs in BALB/c mice. Gamma interferon (IFN-γ) and CCL5 were induced in lungs of BALB/c mice concomitant with virus replication but not in CAST/EiJ mice. The importance of IFN-γ in protection against MPXV disease was demonstrated by the intranasal administration of the mouse cytokine to CAST/EiJ mice and the resulting protection against MPXV. Furthermore, C57BL/6 mice with inactivation of the IFN-γ gene or the IFN-γ receptor gene exhibited enhanced sensitivity to MPXV.

Evasion of the Innate Immune Type I Interferon System by Monkeypox Virus

“…Thus, the lack of a full-length E3 homologue may be one factor that limits the pathogenesis of MPXV in mice. Earl et al (21) showed that in MPXV-infected (intranasal route) inbred strains of mice, such as BALB/c and C57/Blk, there is a large IFN-and CCL5 response in the lungs which is absent in MPXV-infected CAST/EiJ mice, a strain susceptible to MPXV. Further, they showed that inbred strains with mutated IFN-or IFN-receptor genes displayed an intermediate phenotype in MPXV susceptibility between wildtype strains and CAST/EiJ mice, suggesting that there were additional host factors impacting pathogenesis (21).…”

“…Earl et al (21) showed that in MPXV-infected (intranasal route) inbred strains of mice, such as BALB/c and C57/Blk, there is a large IFN-and CCL5 response in the lungs which is absent in MPXV-infected CAST/EiJ mice, a strain susceptible to MPXV. Further, they showed that inbred strains with mutated IFN-or IFN-receptor genes displayed an intermediate phenotype in MPXV susceptibility between wildtype strains and CAST/EiJ mice, suggesting that there were additional host factors impacting pathogenesis (21). Since the natural host of MPXV is thought to be a rodent (22), it is possible that MPXV has evolved several mechanisms to limit pathogenesis in the native host, including by increasing sensitivity to type I IFNs through partial truncation of the MPXV E3 homologue.…”

Exposure of rhesus monkeys to cowpox virus Brighton Red by large-particle aerosol droplets results in an upper respiratory tract disease

“…NK cells increased the most for the 5Â10 5 and 5Â10 4 p.f.u. group, underscoring their importance for resolution of poxvirus-induced disease (Americo et al, 2010;Bai et al, 2005;Born et al, 2000;Earl et al, 2012;Harris et al, 1995). Predictably, T-cells and immature B-cells increased in surviving subjects independent of dose.…”

Genetic studies of the susceptibility of classical and wild-derived inbred mouse strains to monkeypox virus

“…Moreover, immunological reagents are not available for these rodents. Although the commonly used classical inbred mouse strains are relatively resistant to MPXV, a few wild-derived inbred strains are susceptible (Americo et al, 2010) and one of these, the CAST/EiJ mouse, has been further studied (Americo et al, 2014; Earl et al, 2012). The susceptibility to MPXV varied by age and route and was greater by the intraperitoneal route (LD 50 = 14 PFU) compared to the intranasal route (LD 50 = 680 PFU) for 6-week old female mice (Americo et al, 2010).…”

“…Scarification and footpad inoculation only caused local lesions. The low interferon γ response of CAST mice to infection with MPXV and the protection afforded by exogenous interferon γ may be clues to the nature of their susceptibility (Earl et al, 2012). Moreover, the sensitivity of CAST mice extends to other orthopoxviruses including vaccinia virus and cowpox virus (Americo et al, 2014).…”