CD11b+, Ly6G+ Cells Produce Type I Interferon and Exhibit Tissue Protective Properties Following Peripheral Virus Infection

Abstract

The goal of the innate immune system is containment of a pathogen at the site of infection prior to the initiation of an effective adaptive immune response. However, effector mechanisms must be kept in check to combat the pathogen while simultaneously limiting undesirable destruction of tissue resulting from these actions. Here we demonstrate that innate immune effector cells contain a peripheral poxvirus infection, preventing systemic spread of the virus. These innate immune effector cells are comprised primarily of CD11b+Ly6C+Ly6G- monocytes that accumulate initially at the site of infection, and are then supplemented and eventually replaced by CD11b+Ly6C+Ly6G+ cells. The phenotype of the CD11b+Ly6C+Ly6G+ cells resembles neutrophils, but the infiltration of neutrophils typically occurs prior to, rather than following, accumulation of monocytes. Indeed, it appears that the CD11b+Ly6C+Ly6G+ cells that infiltrated the site of VACV infection in the ear are phenotypically distinct from the classical description of both neutrophils and monocyte/macrophages. We found that CD11b+Ly6C+Ly6G+ cells produce Type I interferons and large quantities of reactive oxygen species. We also observed that depletion of Ly6G+ cells results in a dramatic increase in tissue damage at the site of infection. Tissue damage is also increased in the absence of reactive oxygen species, although reactive oxygen species are typically thought to be damaging to tissue rather than protective. These data indicate the existence of a specialized population of CD11b+Ly6C+Ly6G+ cells that infiltrates a site of virus infection late and protects the infected tissue from immune-mediated damage via production of reactive oxygen species. Regulation of the action of this population of cells may provide an intervention to prevent innate immune-mediated tissue destruction.

MyD88-Dependent Immunity to a Natural Model of Vaccinia Virus Infection Does Not Involve Toll-Like Receptor 2

“…Indeed, MyD88 deficiency did not allow systemic spread of the virus following i.d. infection, indicating that the recruitment and activation of the mononuclear phagocytes that we have previously shown to restrict VACV spread from the skin (38) are MyD88 independent. The identity of the innate sensor that recruits and activates these cells remains unknown.…”

“…Viral replication decreases past day 5 of infection and is no longer detectable once the lesion is resolved by loss of necrotic tissue (22). Tissue damage develops more aggressively in many immunodeficient mouse strains (38)(39)(40), but in TLR2…”

“…VACV normally remains restricted to the ear pinnae following i.d. infection, but components of the immune system are required to prevent systemic spread (38), and these components may be distinct from those that control virus replication locally. Therefore, we also looked for evidence that TLR2 restricted the spread of virus from the ear pinnae both by quantification of virus titers in the primary site of replication following systemic infection, the ovaries, and by evaluation of morbidity following VACV infection.…”

Deletion of the K1L Gene Results in a Vaccinia Virus That Is Less Pathogenic Due to Muted Innate Immune Responses, yet Still Elicits Protective Immunity

“…I.d. infection of ears causes inflammation (41)(42)(43)(44). Thus, we were curious if edema, a classical sign of inflammation, was accelerated or delayed during vΔK1L infection.…”

“…Thus, we were curious if edema, a classical sign of inflammation, was accelerated or delayed during vΔK1L infection. Commonly, histopathology is used to examine tissue damage; this method is semiquantitative (41)(42)(43)(44). In contrast, ultrasound imaging successfully quantified inflammation for processes like fatty liver disease (45).…”