T Cells Are Not Required for Pathogenesis in the Syrian Hamster Model of Hantavirus Pulmonary Syndrome

Abstract

Andes virus (ANDV) is associated with a lethal vascular leak syndrome in humans termed hantavirus pulmonary syndrome (HPS). In hamsters, ANDV causes a respiratory distress syndrome closely resembling human HPS. The mechanism for the massive vascular leakage associated with HPS is poorly understood; however, T cell immunopathology has been implicated on the basis of circumstantial and corollary evidence. Here, we show that following ANDV challenge, hamster T cell activation corresponds with the onset of disease. However, treatment with cyclophosphamide or specific T cell depletion does not impact the course of disease or alter the number of surviving animals, despite significant reductions in T cell number. These data demonstrate, for the first time, that T cells are not required for hantavirus pathogenesis in the hamster model of human HPS. Depletion of T cells from Syrian hamsters did not significantly influence early events in disease progression. Moreover, these data argue for a mechanism of hantavirus-induced vascular permeability that does not involve T cell immunopathology.

Andes Virus Infection of Lymphatic Endothelial Cells Causes Giant Cell and Enhanced Permeability Responses That Are Rapamycin and Vascular Endothelial Growth Factor C Sensitive

“…Immune responses have been suggested to be involved in HPS pathogenesis (45), while the VEGF-directed hyperpermeability of hantavirus-infected human endothelial cells (29,34,35,74) suggests roles for hypoxia-derived VEGF (12,23,57,64) as a mechanism of pulmonary edema in HPS patients. A recent report demonstrates that depletion of T cells in ANDV-infected Syrian hamsters has no effect on the onset, symptoms, or severity of lethal pulmonary edema, suggesting that T cell responses may not be determinants of pathogenesis (37). However, another report on ANDV-infected Syrian hamsters suggests that the low level activation of several proinflammatory genes and Th1/Th2 responses in the lungs may contribute to pathogenesis (70).…”

“…Andes virus (ANDV) causes HPS, resulting in acute pulmonary edema and respiratory insufficiency (12,14,18,22,36,47,53,59,62,86). The means by which hantaviruses cause vascular leakage and edema are likely to be multifactorial in nature, and mechanisms by which hantaviruses alter fluid barrier properties of the vasculature are still being discovered (28,29,34,35,37,45,63,70,74). Tissue and organ edema are prominent findings in hantavirus patients, and blood vessel ECs (BECs) form a primary fluid barrier that normally restricts fluid egress into tissues and permits blood and fluid recirculation (1,19,80).…”

Syngeneic Syrian hamster tumors feature tumor-infiltrating lymphocytes allowing adoptive cell therapy enhanced by oncolytic adenovirus in a replication permissive setting

“…Single-cell suspensions of excised tumors (Day 0) or TIL cultures (Days 5 and 10) were stained with the following crossreactive antibodies: anti-rat CD8b PE (clone 341, eBioscience) 48 and anti-mouse CD4 APC (clone GK1.5, eBioscience) 48 for 30 min, fixed in 4% paraformaldehyde, and analyzed with BD Accuri C6 (BD Biosciences) collecting at least 50,000 events per sample. HapT1 cells were incubated with FITC-conjugated anti-mouse/rat MHC Class II antibody (I-Ek; clone 14-4-4 S, eBioscience) 49 for 1 h and fixed in 4% paraformaldehyde for 5 min, and analyzed on BD Accuri C6.…”

Hypoxia Induces Permeability and Giant Cell Responses of Andes Virus-Infected Pulmonary Endothelial Cells by Activating the mTOR-S6K Signaling Pathway

“…HPS is characterized by thrombocytopenia, hypoxia, and acute pulmonary edema that leads to respiratory insufficiency and an associated 35 to 40% mortality rate (1,2,5,(10)(11)(12)(13). ANDV is unique in both its ability to spread from person to person and cause a lethal HPS-like disease in Syrian hamsters that closely mimics human disease in rapid onset, hypoxia, and acute pulmonary edema (9,(14)(15)(16)(17).…”