The Role of IFN in Respiratory Syncytial Virus Pathogenesis

Abstract

Formalin-inactivated respiratory syncytial virus (RSV) vaccine preparations have been shown to cause enhanced disease in naive hosts following natural infection. In this study we demonstrate a similar pattern of enhanced disease severity following primary RSV infection of IFN-nonresponsive STAT1−/− mice. STAT1−/− mice showed markedly increased illness compared with wild-type BALB/c animals following RSV inoculation despite similar lung virus titers and rates of virus clearance. Histologically, STAT1−/− animals had eosinophilic and neutrophilic pulmonary infiltrates not present in wild-type or IFN-γ−/−-infected mice. In cytokine analyses of infected lung tissue, IFN-γ was induced in both STAT1−/− and wild-type mice, with preferential IL-4, IL-5, and IL-13 induction only in the STAT1−/− animals. Eotaxin was detected in the lungs of both wild-type and STAT1−/− mice following infection, with a 1.7-fold increase over wild-type in the STAT1−/− mice. Using a peptide epitope newly identified in the RSV fusion protein, we were able to demonstrate that wild-type memory CD4+ T cells stimulated by this peptide produce primarily IFN-γ, while STAT1−/−CD4+ cells produce primarily IL-13. These findings suggest that STAT1 activation by both type I (αβ) and type II (γ) IFNs plays an important role in establishing a protective, Th1 Ag-specific immune response to RSV infection.

Differential Regulation of GM1 and Asialo-GM1 Expression by T Cells and Natural Killer (NK) Cells in Respiratory Syncytial Virus Infection

“…It has been shown that RSV-infected STAT1 Ϫ/Ϫ mice have higher lung IFN-␥ levels than RSV-infected BALB/c mice at 6 d.p.i. (63). Similarly, we found that IFN-␥ levels were sixfold higher in control Ab-treated STAT1 Ϫ/Ϫ mice than control Ab-treated BALB/c mice (Fig.…”

“…Despite exhibiting profound weight loss and mortality, anti-ASGM1-Ab and control Ab-treated RSV-infected STAT1 Ϫ/Ϫ mice were able to clear infectious RSV to below plaque assay detection levels. STAT1 Ϫ/Ϫ mice exhibit Th-2-type inflammation in response to RSV infection that includes eosinophilia and neutrophilia (63). We speculate that cell types other than activated NK and T cells (e.g., neutrophils or eosinophils) may contribute to control of RSV and play a role in severe immunopathology in STAT1 Ϫ/Ϫ mice .…”

“…NK and CD8 ϩ T-cell GM1 and ASGM1 expression in RSV-infected STAT1 Ϫ/Ϫ RSV-infected STAT1 Ϫ/Ϫ mice exhibit higher viral loads, greater disease severity, and enhanced Th-2-type inflammation compared to RSV-infected wild-type BALB/c mice (21,63). STAT1 Ϫ/Ϫ mice have impaired NK and T-cell cytotoxic functions (17,18).…”

Mucosal inoculation with an attenuated mouse pneumovirus strain protects against virulent challenge in wild type and interferon-gamma receptor deficient mice

“…The role of IFNγ has also been explored in the HRSV mouse challenge model [47][48][49] and has been detected in lung tissue in response to acute infection with virulent PVM J3666 [50; Table 3]. IFNγ has also been associated with a "Th1/ Th2 imbalance" [51,52], and has been implicated in a variety of pathologic outcomes related to hRSV infection, including prolonged respiratory dysfunction [53], and the exaggerated inflammatory response to an earlier parenteral vaccine formulation [54,55]. The IFNγR−/− mice used in this study, originally developed by Huang and colleagues [56] have a phenotypically normal immune system, but when challenged, demonstrate increased susceptibility to vaccinia virus, listeria and mycobacteria species despite normal cytotoxic and T helper cell responses.…”

Contribution of cytokines to pathology and protection in virus infection

“…However, compared to the case for other severe respiratory viral infections leading to lower respiratory tract infections, IFN--γ production by peripheral blood mononuclear cells appears to be decreased in RSV disease, perhaps pointing to its role in pathogenesis [114]. STAT1 activation by both type I and type II IFNs has been shown to play an important role in establishing a protective, Th1 Ag--specific immune response to RSV infection, however, with an accompanying preferential IL--4, IL--5, and IL--13 induction [117]. Paradoxically, IL--9 depletion at the time of immunization alone alleviated disease by reducing subsequent Th2 cytokine production without a concomitant increase in IFN--γ or TNF production [119].…”