TitleThe systemic immune state of super-shedder mice is characterized by a unique neutrophil-dependent blunting of TH1 responses.
Publication TypeJournal Article
Year of Publication2013
AuthorsGopinath, S, Hotson, A, Johns, JL, Nolan, G, Monack, D
JournalPLoS Pathog
Date Published2013
KeywordsAnimals, Cell Proliferation, Female, Granulocyte Colony-Stimulating Factor, Interleukin-2, Mice, Neutrophils, Salmonella Infections, Salmonella typhimurium, Spleen, T-Lymphocytes, Regulatory, Th1 Cells

Host-to-host transmission of a pathogen ensures its successful propagation and maintenance within a host population. A striking feature of disease transmission is the heterogeneity in host infectiousness. It has been proposed that within a host population, 20% of the infected hosts, termed super-shedders, are responsible for 80% of disease transmission. However, very little is known about the immune state of these super-shedders. In this study, we used the model organism Salmonella enterica serovar Typhimurium, an important cause of disease in humans and animal hosts, to study the immune state of super-shedders. Compared to moderate shedders, super-shedder mice had an active inflammatory response in both the gastrointestinal tract and the spleen but a dampened T(H)1 response specific to the secondary lymphoid organs. Spleens from super-shedder mice had higher numbers of neutrophils, and a dampened T cell response, characterized by higher levels of regulatory T cells (T(regs)), fewer T-bet(+) (T(H)1) T cells as well as blunted cytokine responsiveness. Administration of the cytokine granulocyte colony stimulating factor (G-CSF) and subsequent neutrophilia was sufficient to induce the super-shedder immune phenotype in moderate-shedder mice. Similar to super-shedders, these G-CSF-treated moderate-shedders had a dampened T(H)1 response with fewer T-bet(+) T cells and a loss of cytokine responsiveness. Additionally, G-CSF treatment inhibited IL-2-mediated TH1 expansion. Finally, depletion of neutrophils led to an increase in the number of T-bet(+) T(H)1 cells and restored their ability to respond to IL-2. Taken together, we demonstrate a novel role for neutrophils in blunting IL-2-mediated proliferation of the TH1 immune response in the spleens of mice that are colonized by high levels of S. Typhimurium in the gastrointestinal tract.

Alternate JournalPLoS Pathog
PubMed ID23754944
PubMed Central IDPMC3675027
Grant ListHHSN272200700038C / AI / NIAID NIH HHS / United States
T32 AI007328 / AI / NIAID NIH HHS / United States
R01 A1095396 / / PHS HHS / United States
HHSN272200700038C / / PHS HHS / United States