Poster Presentation The Australasian Society for Immunology 2017 Annual Scientific Meeting

Parsing the roles of innate and adaptive immune compartments in the lethal, type I IFN-driven, immunopathological disease in LCMV-infected STAT1 KO mice (#268)

So Ri Jung 1 2 3 4 , Thomas M. Ashhurst 1 3 4 5 6 , Phillip K. West 1 2 3 , Barney Viengkhou 1 2 3 4 , Darren A. Cox 1 , Markus J. Hofer 1 2 3 4 , Nicholas J.C. King 1 3 4 5 6 , Iain L. Campbell 1 3 4
  1. The Charles Perkins Centre, The University of Sydney, Sydney, Australia
  2. Biochemistry, Cell and Molecular Biology Cluster, School of Life and Environmental Sciences, The University of Sydney, Sydney, Australia
  3. The Bosch Institute, The University of Sydney, Sydney, Australia
  4. The Marie Bashir Institute for Emerging Infectious Disease (MBI), The University of Sydney, Sydney, Australia
  5. Viral Immunopathology Laboratory, Discipline of Pathology, School of Medical Sciences, Sydney Medical School, The University of Sydney, Sydney, Australia
  6. Sydney Cytometry Facility, The University of Sydney and Centenary Institute, Sydney, Australia

Following systemic infection with lymphocytic choriomeningitis virus (LCMV), STAT1 KO mice develop a lethal, type I IFN (IFN-I)-dependent disease that is prevented by the depletion of CD4+ cells. Here, we investigated the differing roles of the innate and adaptive immune compartments in this disease. When WT, STAT1 KO, RAG1 KO and STAT1/RAG1 DKO mice were infected with LCMV, WT and RAG1 KO mice showed no signs of disease. In contrast, STAT1 KO and STAT1/RAG1 DKO mice experienced a similar, rapid weight loss in the early stage of the disease. However, on days 7-8 postinfection, STAT1 KO but not STAT1/RAG1 DKO mice succumbed to the infection, despite the mice showing a similar degree of uncontrolled replication and spread of the virus in key organs. We found that innate immune-mediated, rapid weight loss in STAT1 KO and STAT1/RAG1 DKO mice was associated with an early, systemic elevation of various cytokines and chemokines including IFN-I and -II, IL-5, IL-6, and CCL2. During the later stage of the disease, however, while STAT1 KO mice had sustained levels of IFN-γ, IL-5 and CCL2, and elevated levels of CCL1 and CCL22, STAT1/RAG1 DKO mice had a reduction of cytokines and chemokines to basal levels except for IL-5. Furthermore, flow cytometric analysis of liver and spleen leukocytes revealed that STAT1/RAG1 DKO mice have a preferential recruitment and expansion of monocytes and macrophages whereas STAT1 KO mice have granulocyte-skewed recruitment during infection. We conclude that: 1) innate immune-mediated production of cytokines including IFN-I and -II during the early stage of the disease is strongly associated with the rapid weight loss of LCMV-infected STAT1 KO and STAT1/RAG1 DKO mice, 2) adaptive immune-mediated production of cytokines and chemokines and the recruitment of granulocytes in the late stage of the disease is associated with the lethality in the STAT1 KO mice.