Dermal fibroblast cultures recapitulate differences between deermice and mice in responses to a Toll-like receptor agonist

The white-footed deermouse Peromyscus leucopus is a primary reservoir for
the agents of Lyme disease and other zoonoses in North America. These and
other species of Peromyscus are tolerant of the infection by the bacteria,
protozoa, and viruses they host. This is mainly achieved by mitigating the
damaging effects of the innate immune response. In previous studies, we
demonstrated differences between P. leucopus and either inbred or outbred
M. musculus in the degree of sickness and profiles of biomarkers after
exposure to bacterial lipopolysaccharide, a TLR4 agonist. To develop a
method for broadly assessing of innate immunity of capture-release mammals
in nature, we evaluated using bulk and single-cell RNA-seq primary dermal
fibroblast cultures of P. leucopus and M. musculus in their short-term
responses to a lipopeptide that is a TLR2 agonist. As we had observed for
experimental animals, the fibroblast cultures of the two species displayed
both similarities and differences in their responses to the agonist. The
notable differences included the greater magnitude of an anti-viral
profile of cytokines and other effectors in the deermouse fibroblasts and
the occurrence of an interleukin-11 response in the mouse cultures but not
deermouse. We also observed in both species' cultures an increased
transcription of several types of endogenous retrovirus (ERV) elements
after exposure of the cells to the agonist. The P. leucopus cells were
distinguished from M. musculus cells in the generally shorter retroviral
open reading frames among the differentially expressed sequences. This was
consistent with previous findings about ERV transcription in P. leucopus
and M. musculus and suggests a greater suppression of ERV activity in P.
leucopus. The results affirm the feasibility of this in vitro model for
both laboratory- and field-based studies without need for euthanasia, and
that inherent differences between deermice and mice in innate immune
responses can be demonstrated in primary fibroblasts as well as the
animals themselves.