Resistance to lethal ectromelia virus infection requires Type I interferon receptor in natural killer cells and monocytes but not in adaptive immune or parenchymal cells

Abstract

Type I interferons (IFN-I) are antiviral cytokines that signal through the ubiquitous IFN-I receptor (IFNAR). Following footpad infection with ectromelia virus (ECTV), a mouse-specific pathogen, C57BL/6 (B6) mice survive without disease, while B6 mice broadly deficient in IFNAR succumb rapidly. We now show that for survival to ECTV, only hematopoietic cells require IFNAR expression. Survival to ECTV specifically requires IFNAR in both natural killer (NK) cells and monocytes. However, intrinsic IFNAR signaling is not essential for adaptive immune cell responses or to directly protect non-hematopoietic cells such as hepatocytes, which are principal ECTV targets. Mechanistically, IFNAR-deficient NK cells have reduced cytolytic function, while lack of IFNAR in monocytes dampens IFN-I production and hastens virus dissemination. Thus, during a pathogenic viral infection, IFN-I coordinates innate immunity by stimulating monocytes in a positive feedback loop and by inducing NK cell cytolytic function.

The ectromelia virus virulence factor C15 facilitates early viral spread by inhibiting NK cell contact

“…C15 had no impact on the transcription of NK cell-activating cytokines IL-15 and IL-18 ( Figures 3 G and 3H), the NK cell effector molecule TNFα ( Figure 3 I) or the type I-IFNs ( Figures 3 J–3L) which are also important NK cell activators. 18 Overall, there were no instances in which transcripts increased in ΔC15 versus WT infection. Therefore, we conclude that C15 does not directly target the transcription of factors in the LN involved in NK cell recruitment or activation.…”

The ectromelia virus virulence factor C15 facilitates early viral spread by inhibiting NK cell-infected cell contacts

“…3 I) or the type I-IFNs (Figs. 3, J-L) which are also important NK cell activators (Melo-Silva et al, 2021). Overall, there were no instances in which transcripts increased in ΔC15 vs. WT infection.…”

“…Work by others indicated that C15 may impact viral spread in the draining lymph node as early as 4 days post infection (dpi) of susceptible BALB/c mice (Reynolds et al, 2017), suggesting antagonism of the innate immune response that contributes to virulence. Natural ECTV infection of mice is modeled by footpad injection, and the first stages of the host response in the draining popliteal lymph node (LN) have been well characterized in C57BL/6 (B6) mice, which are resistant to lethal ECTV infection (Fang et al, 2008;Xu et al, 2015;Wong et al, 2018Wong et al, , 2019Ferez et al, 2021;Melo-Silva et al, 2021). Natural killer (NK) cells are critical mediators of early protection and are necessary for resistance to ECTV infection in the first 4 dpi (Fang et al, 2008).…”

Imaging viral infection in vivo to gain unique perspectives on cellular antiviral immunity*

“…To further aid in VACV clearance in the skin, inflammatory monocytes produce the chemokines CXCL9 and CXCL10, which facilitate CXCR3 + effector CD8 + T cell‐mediated killing of VACV‐infected cells 35 . IFN‐I signaling in monocytes also supports the clearance of ectromelia virus (ECTV) 46 …”

“…35 IFN-I signaling in monocytes also supports the clearance of ectromelia virus (ECTV). 46 There is also a dark side to inflammatory monocytes during viral infection as monocytes recruited to virus-infected LNs can actively suppress virus-specific B cell responses. Iannacone's group demonstrated that inflammatory monocytes recruited to LCMV-infected LNs interacted with virus-specific B cells, confining B cell motility and decreasing B cell survival.…”