We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Natural killer cells expanded in vivo or ex vivo with IL-15 overcomes the inherent susceptibility of CAST mice to lethal infection with orthopoxviruses.
- Authors
Earl, Patricia L.; Americo, Jeffrey L.; Moss, Bernard
- Abstract
The wild-derived inbred CAST/EiJ mouse, one of eight founder strains in the Collaborative Cross panel, is an exceptional model for studying monkeypox virus (MPXV), an emerging human pathogen, and other orthopoxviruses including vaccinia virus (VACV). Previous studies suggested that the extreme susceptibility of the CAST mouse to orthopoxviruses is due to an insufficient innate immune response. Here, we focused on the low number of natural killer (NK) cells in the naïve CAST mouse as a contributing factor to this condition. Administration of IL-15 to CAST mice transiently increased NK and CD8+ T cells that could express IFN-γ, indicating that the progenitor cells were capable of responding to cytokines. However, the number of NK cells rapidly declined indicating a defect in their homeostasis. Furthermore, IL-15-treated mice were protected from an otherwise lethal challenge with VACV or MPXV. IL-15 decreased virus spread and delayed death even when CD4+/CD8+ T cells were depleted with antibody, supporting an early protective role of the expanded NK cells. Purified splenic NK cells from CAST mice proliferated in vitro in response to IL-15 and could be activated with IL-12/IL-18 to secrete interferon-γ. Passive transfer of non-activated or activated CAST NK cells reduced VACV spread but only the latter completely prevented death at the virus dose used. Moreover, antibodies to interferon-γ abrogated the protection by activated NK cells. Thus, the inherent susceptibility of CAST mice to orthopoxviruses can be explained by a low level of NK cells and this vulnerability can be overcome either by expanding their NK cells in vivo with IL-15 or by passive transfer of purified NK cells that were expanded and activated in vitro. Author summary: With the eradication of smallpox, monkeypox virus (MPXV) remains the only poxvirus causing significant mortality in humans. Although endemic in parts of Africa, human infections have occurred in the United States, the United Kingdom and Israel due to travelers or imported animals. Contrary to its name, MPXV primarily infects rodents and secondarily infects humans and other primates. The wild-derived CAST mouse is an excellent small animal model for studying the pathogenicity of MPXV and related orthopoxviruses including vaccinia virus (VACV) and for evaluating therapeutics. We previously found that the susceptibility of CAST mice is correlated with low numbers of natural killer (NK) cells and a delayed interferon-γ response. Here we showed that in vivo administration of the cytokine IL-15 transiently raised NK cell numbers and protected CAST mice from systemic infections with VACV and MPXV. CAST mouse NK cells that were purified and expanded in vitro with IL-15 also provided protection, further demonstrating the important role of NK cells. The rapid decline in NK cell numbers following cessation of IL-15 administration or NK cell transfer suggests that a low level of NK cell homeostasis contributes to the susceptibility of CAST mice to virus infection.
- Subjects
ISRAEL; VACCINIA; NATURAL numbers; PROGENITOR cells; VIRUS diseases; HEMAGGLUTININ; MICE; KILLER cells
- Publication
PLoS Pathogens, 2020, Vol 16, Issue 4, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1008505